adenomatous polyposis coli

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TABLE OF CONTENTS Volume 9, Number 2, Apr-Jun 2005

Previous Issue / Next Issue

Genes GATA1 (GATA binding protein 1 (globin transcription factor1)) (Xp11.23). Shai Izraeli. Atlas Genet Cytogenet Oncol Haematol 2005; 9 (2): 193-199. [Full Text] [PDF] URL : http://AtlasGeneticsOncology.org/Genes/GATA1ID40689chXp11.html LTA (Lymphotoxin-A) (6p21.3). Fei Chen. Atlas Genet Cytogenet Oncol Haematol 2005; 9 (2): 200-203. [Full Text] [PDF] URL : http://AtlasGeneticsOncology.org/Genes/LTAID41209ch6p21.html MLH1 (human mutL homolog 1) (3p21.3). Enrico Domingo, Simo Schwartz Jr. Atlas Genet Cytogenet Oncol Haematol 2005; 9 (2): 204-209. [Full Text] [PDF] URL : http://AtlasGeneticsOncology.org/Genes/MLH1ID149ch3p21.html PTPN11 (Protein tyrosine phosphatase, non-receptor type, 11) (12q24.1). Marco Tartaglia, Bruce D Gelb. Atlas Genet Cytogenet Oncol Haematol 2005; 9 (2): 210-219. [Full Text] [PDF] URL : http://AtlasGeneticsOncology.org/Genes/PTPN11ID41910ch12q24.html ACTB (Actin, beta) (7p22). Anna Dahlén, Fredrik Mertens, Nils Mandahl, Ioannis Panagopoulos. Atlas Genet Cytogenet Oncol Haematol 2005; 9 (2): 220-225. [Full Text] [PDF] URL : http://AtlasGeneticsOncology.org/Genes/ACTBID42959ch7p22.html ADD3 (adducin 3) (10q25.1-q25.2). José Luis Vizmanos. Atlas Genet Cytogenet Oncol Haematol 2005; 9 (2): 226-232. [Full Text] [PDF]

Atlas Genet Cytogenet Oncol Haematol 2005; 2

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URL : http://AtlasGeneticsOncology.org/Genes/ADD3ID520ch10q25.html APC (adenomatous polyposis coli) (5q21) - updated. Jennifer Tirnauer. Atlas Genet Cytogenet Oncol Haematol 2005; 9 (2): 233-238. [Full Text] [PDF] URL : http://AtlasGeneticsOncology.org/Genes/APC118.html GLI1 (glioma-associated oncogene homolog 1) (12q13.2-14.1). Anna Dahlén, Fredrik Mertens, Nils Mandahl, Ioannis Panagopoulos. Atlas Genet Cytogenet Oncol Haematol 2005; 9 (2): 239-245. [Full Text] [PDF] URL : http://AtlasGeneticsOncology.org/Genes/GLIID310ch12q13.html NKX2-5 (NK2 transcription factor related, locus 5 (Drosophila). (5q35.2). Roderick MacLeod, Stefan Nagel. Atlas Genet Cytogenet Oncol Haematol 2005; 9 (2): 246-254. [Full Text] [PDF] URL : http://AtlasGeneticsOncology.org/Genes/NKX25ID42958ch5q35.html SS18L1 (synovial sarcoma translocation gene on chromosome 18-like 1) (20q13.3). Clelia Tiziana Storlazzi, Fredrik Mertens, Ioannis Panagopoulos. Atlas Genet Cytogenet Oncol Haematol 2005; 9 (2): 255-259. [Full Text] [PDF] URL : http://AtlasGeneticsOncology.org/Genes/SS18L1ID474ch20q13.html WHSC1L1 (Wolf-Hirschhorn syndrome candidate 1 like gene 1) (8p11.2). Jean Loup Huret. Atlas Genet Cytogenet Oncol Haematol 2005; 9 (2): 260-264. [Full Text] [PDF] URL : http://AtlasGeneticsOncology.org/Genes/WHSC1L1NSD3ID42810ch8p11.html WISP3 (WNT-1 inducible signaling pathway protein 3) (6q22-q23). Celina G Kleer, Lei Ding. Atlas Genet Cytogenet Oncol Haematol 2005; 9 (2): 265-271. [Full Text] [PDF] URL : http://AtlasGeneticsOncology.org/Genes/WISP3ID469ch6q22.html

Leukaemias i(5)(p10) in acute myeloid leukemia. Claudia Schoch. Atlas Genet Cytogenet Oncol Haematol 2005; 9 (2): 272-274. [Full Text] [PDF] URL : http://AtlasGeneticsOncology.org/Anomalies/i5pID1376.html Splenic lymphoma with villous lymphocytes (SLVL) - updated. Xavier Troussard, Hossain Mossafa. Atlas Genet Cytogenet Oncol Haematol 2005; 9 (2): 275-278. [Full Text] [PDF] URL : http://AtlasGeneticsOncology.org/Anomalies/splenvillousID2063.html t(1;14)(q21;q32) FCGR2B/IGH. Jacques Boyer. Atlas Genet Cytogenet Oncol Haematol 2005; 9 (2): 279-280. [Full Text] [PDF]


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URL : http://AtlasGeneticsOncology.org/Anomalies/t0114q21q32ID1341.html t(1;14)(q25;q32). Jacques Boyer. Atlas Genet Cytogenet Oncol Haematol 2005; 9 (2): 281-282. [Full Text] [PDF] URL : http://AtlasGeneticsOncology.org/Anomalies/t0114q25q32LHX4ID1352.html t(8;11)(p11;p15). Jean Loup Huret. Atlas Genet Cytogenet Oncol Haematol 2005; 9 (2): 283-285. [Full Text] [PDF] URL : http://AtlasGeneticsOncology.org/Anomalies/t0811p11p15ID1200.html t(10;11)(q25;p15). José Luis Vizmanos. Atlas Genet Cytogenet Oncol Haematol 2005; 9 (2): 286-290. [Full Text] [PDF] URL : http://AtlasGeneticsOncology.org/Anomalies/t1011q25p15ID1285.html t(11;20)(p15;q11). Tetsuaki Sekikawa, Junko Horiguchi-Yamada. Atlas Genet Cytogenet Oncol Haematol 2005; 9 (2): 291-295. [Full Text] [PDF] URL : http://AtlasGeneticsOncology.org/Anomalies/t1120p15q11ID1155.html

Solid Tumours Adrenal cortical carcinoma. Constantine A Stratakis, Ludmila Matyakhina. Atlas Genet Cytogenet Oncol Haematol 2005; 9 (2): 296-301. [Full Text] [PDF] URL : http://AtlasGeneticsOncology.org/Tumors/AdrenalCorticalCarcinID5088.html Bone tumors: an overview. Yvonne M Schrage, Judith VMG Bovée.. Atlas Genet Cytogenet Oncol Haematol 2005; 9 (2): 302-314. [Full Text] [PDF] URL : http://AtlasGeneticsOncology.org/Tumors/BoneTumorID5143.html Pericytoma with t(7;12)(p22;q13). Anna Dahlén, Fredrik Mertens, Nils Mandahl, Ioannis Panagopoulos. Atlas Genet Cytogenet Oncol Haematol 2005; 9 (2): 315-319. [Full Text] [PDF] URL : http://AtlasGeneticsOncology.org/Tumors/Pericytomt0712ID5192.html

Cancer Prone Diseases Bloom syndrome - updated. Mounira Amor-Guéret. Atlas Genet Cytogenet Oncol Haematol 2005; 9 (2): 320-328. [Full Text] [PDF] URL : http://AtlasGeneticsOncology.org/Kprones/BLO10002.html Waardenburg syndrome (WS).


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Carolina Vicente-Dueñas, Camino Bermejo-Rodríguez, María Pérez-Caro, Inés GonzálezHerrero, Manuel Sánchez-Martín, Isidro Sánchez-García.. Atlas Genet Cytogenet Oncol Haematol 2005; 9 (2): 329-337. [Full Text] [PDF] URL : http://AtlasGeneticsOncology.org/Kprones/WaardenburgID10089.html Shwachman-Diamond Syndrome (SDS). Markus Schmugge, David Betts. Atlas Genet Cytogenet Oncol Haematol 2005; 9 (2): 338-341. [Full Text] [PDF] URL : http://AtlasGeneticsOncology.org/Kprones/ShwachmanID1058.html

Deep Insights Cancer cytogenetics update 2005. Felix Mitelman. Atlas Genet Cytogenet Oncol Haematol 2005; 9 (2): 342-346. [Full Text] [PDF] URL : http://AtlasGeneticsOncology.org/Deep/CancerCytogenet2005ID20050.html The nuclear pore complex becomes alive: new insights into its dynamics and involvement in different cellular processe. Joachim Köser, Bohumil Maco, Ueli Aebi, Birthe Fahrenkrog. Atlas Genet Cytogenet Oncol Haematol 2005; 9(2): 347-382. [Full Text] [PDF] URL : http://AtlasGeneticsOncology.org/Deep/NuclearPoreComplID20048.html

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Atlas of Genetics and Cytogenetics in Oncology and Haematology

GATA1 (GATA binding protein 1 (globin transcription factor1)) Identity Other names

ERYF1 GF1 NFE1

Hugo

GATA1

Location

Xp11.23

DNA/RNA Description Genomic sequence 7,757 bases, mRNA six exons (five coding) 1497bp. Plus strand

Protein

Alternative models for generation of GATA1 isoforms. The full GATA1 protein can only be translated from the full GATA1 mRNA, whereas the GATA1s protein can be translated either from the full gata-1mRNA or from the shorter splice variant in which exon 2 is skipped.

Description The full length GATA1 protein is 413 amino acids; 42.7 KDa. However two major protein isoforms are formed by alternative splicing of the mRNA and alternative translation initiation sites as shown in the figure. The shorter GATA1 protein (GATA1s) lacks the first 83 aa. ("The Nterminal activation domain AD"). GATA1s is less active in activation of megakaryocytic promoters. Both proteins contain two Zinc finger domains mediating protein interactions and DNA binding. Expression Bone-Marrow - Erythroid, Megakaryocytic, Mast and Eosonophillic precursors. Atlas Genet Cytogenet Oncol Haematol 2005; 2

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Localisation Nuclear Function

Transcription Factor, essential for eryhtroid and megakaryocytic development

Homology

A member of the family of GATA proteins.

Mutations Germinal

Implicated in germline mutations in the N- Zinc finger domain that mediates the interaction with FOG1 and/or binding to DNA, cause Xlinked Dyserythropoietic anemia with thrombocytopenia. The syndrome can be also be manifested only by X-linked macrothrombocytopenia

Somatic

see below

Implicated in Entity

Acquired somatic mutations in GATA1 occur in virtually all children with Down Syndrome (DS) and congenital transient myeloproliferative syndrome (TMD) or acute megakaryocytic leukemia (AMKL, M7-ANLL). The mutations have also been detected in umbilical cord blood of DS patients and in fetal liver of aborted DS embryos. The mutations occur in-utero probably during fetal liver hematopoiesis. They consist of insertions, deletions and base substitution in exon 2 and vicinity and all result in elimination of the full length GATA1 protein with preservation of the GATA1s isoform. The presence of GATA1s in the absence of full length GATA1 blocks megakaryocytic differentiation and promote proliferation of megakaryoblasts. The genes on chromosome 21 that promote this abnormality are unknown. GATA1 mutations are almost always associated with the M7 leukemia in DS although they were also described in a pair of twins with acquired trisomy 21 and in one adult non DS patient with M7. The down-regulations of genes regulated by GATA1 may explain the exquisite sensitivity of DS leukemic blasts to ACA-C.

Legend: Example to the distribution of the mutations in children with M7 and DS described in Rainis et al.

External links Nomenclature Hugo

GATA1


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GDB

GATA1

Entrez_Gene

GATA1 2623 GATA binding protein 1 (globin transcription factor 1) Cards

Atlas

GATA1ID40689chXp11

GeneCards

GATA1

Ensembl

GATA1

CancerGene

GATA1

Genatlas

GATA1

GeneLynx

GATA1

eGenome

GATA1

euGene

2623 Genomic and cartography

GoldenPath

GATA1 - Xp11.23 chrX:48401210-48408964 + Xp11.23 May_2004)

Ensembl

GATA1 - Xp11.23 [CytoView]

NCBI

Genes Cyto Gene Seq [Map View - NCBI]

OMIM

Disease map [OMIM]

HomoloGene

GATA1

(hg17-

Gene and transcription Genbank

AI057349 [ SRS ]

AI057349 [ ENTREZ ]

Genbank

BC009797 [ SRS ]

Genbank

M30601 [ SRS ]

M30601 [ ENTREZ ]

Genbank

X17254 [ SRS ]

X17254 [ ENTREZ ]

RefSeq

NM_002049 [ SRS ]

NM_002049 [ ENTREZ ]

RefSeq

NT_086942 [ SRS ]

NT_086942 [ ENTREZ ]

AceView

GATA1 AceView - NCBI

TRASER

GATA1 Traser - Stanford

Unigene

Hs.765 [ SRS ]

BC009797 [ ENTREZ ]

Hs.765 [ NCBI ]

HS765 [ spliceNest ]

Protein : pattern, domain, 3D structure SwissProt

P15976 [ SRS]

P15976 [ EXPASY ]

P15976 [ INTERPRO ]

Prosite

PS00344 GATA_ZN_FINGER_1 [ SRS ] GATA_ZN_FINGER_1 [ Expasy ]

PS00344

Prosite

PS50114 GATA_ZN_FINGER_2 [ SRS ] GATA_ZN_FINGER_2 [ Expasy ]

PS50114

Interpro

IPR000679 Znf_GATA [ SRS ]

CluSTr

P15976

Pfam

PF00320 GATA [ SRS ]

Blocks

P15976

IPR000679 Znf_GATA [ EBI ]

PF00320 GATA [ Sanger ]

pfam00320 [ NCBI-CDD ]

Polymorphism : SNP, mutations, diseases Atlas Genet Cytogenet Oncol Haematol 2005; 2

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OMIM

305371

[ map ]

GENECLINICS 305371 SNP

GATA1 [dbSNP-NCBI]

SNP

NM_002049 [SNP-NCI]

SNP

GATA1 [GeneSNPs - Utah] GATA1 [SNP - CSHL] GATA1] [HGBASE - SRS] General knowledge

Family Browser

GATA1 [UCSC Family Browser]

SOURCE

NM_002049

SMD

Hs.765

SAGE

Hs.765

Amigo

process|development

Amigo

component|nucleus

Amigo

component|nucleus

Amigo

process|regulation of transcription from Pol II promoter

Amigo

process|regulation of transcription, DNA-dependent

Amigo

function|transcription factor activity

Amigo


BIOCARTA

Hemoglobin's Chaperone

PubGene

GATA1 Other databases Probes

Probe

GATA1 Related clones (RZPD - Berlin) PubMed

PubMed

37 Pubmed reference(s) in LocusLink

Bibliography ADDIN EN.REFLIST Familial dyserythropoietic anaemia and thrombocytopenia due to an inherited mutation in G Nichols KE, Crispino JD, Poncz M, White JG, Orkin SH, Maris JM and Weiss MJ Nat Genet 2000; 24: 266-270. Medline 10700180 Different substitutions at residue D218 of the X-linked transcription factor GATA1 lead to altered clinical severity of macrothrombocytopenia and anemia and are associated with variable skewed X inactivation Freson K, Matthijs G, Thys C, Marien P, Hoylaerts MF, Vermylen J and Van Geet C Hum Mol Genet 2002; 11:147-152. Medline 11809723 A leukemogenic twist for GATA1


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Look AT Nat Genet 2002; 32: 83-84. (REVIEW) Medline 12172549 Acquired mutations in GATA1 in the megakaryoblastic leukemia of Down syndrome Wechsler J, Greene M, McDevitt MA, Anastasi J, Karp JE, Le Beau MM and Crispino JD Nat Genet 2002; 32: 148-152. Medline 12172547 Acquired mutations in GATA1 in neonates with Down's syndrome with transient myeloid disorder Groet J, McElwaine S, Spinelli M, Rinaldi A, Burtscher I, Mulligan C, Mensah A, Cavani S, Dagna-Bricarelli F, Basso G, Cotter FE and Nizetic D Lancet 2003; 361: 1617-1620. Medline 12747884 GATA1 mutations in transient leukemia and acute megakaryoblastic leukemia of Down syndrome Hitzler JK, Cheung J, Li Y, Scherer SW, Zipursky A Blood. 2003; 101: 4301-4304. Medline 12586620 Mutagenesis of GATA1 is an initiating event in Down syndrome leukemogenesis Mundschau G, Gurbuxani S, Gamis AS, Greene ME, Arceci RJ and Crispino JD Blood 2003; Medline 12560215 Mutations in exon 2 of GATA1 are early events in megakaryocytic malignancies associated with trisomy 21 Rainis L, Bercovich D, Strehl S, Teigler-Schlegel A, Stark B, Trka J, Amariglio N, Biondi A, Muler I, Rechavi G, Kempski H, Haas OA and Izraeli S Blood 2003; 102: 981-986. Medline 12649131 Natural history of GATA1 mutations in Down syndrome Ahmed M, Sternberg A, Hall G, Thomas A, Smith O, O'Marcaigh A, Wynn R, Stevens R, Addison M, King D, Stewart B, Gibson B, Roberts I and Vyas P Blood 2004; 103: 2480-2489. Medline 14656875 The role of cytidine deaminase and GATA1 mutations in the increased cytosine arabinoside sensitivity of Down syndrome myeloblasts and leukemia cell lines Ge Y, Jensen TL, Stout ML, Flatley RM, Grohar PJ, Ravindranath Y, Matherly LH


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and Taub JW Cancer Res 2004; 64: 728-735. Medline 14744791 Recent insights into the mechanisms of myeloid leukemogenesis in Down syndrome Gurbuxani S, Vyas P and Crispino JD Blood 2004; 103: 399-406. (REVIEW) Medline 14512321 The GATA1 mutation in an adult patient with acute megakaryoblastic leukemia not accompanying Down syndrome Harigae H, Xu G, Sugawara T, Ishikawa I, Toki T and Ito E Blood 2004; 103: 3242-3243. Medline 15070711 Leukaemia -- a developmental perspective Izraeli S Br J Haematol 2004; 126: 3-10. (REVIEW) Medline 15198727 Microarray transcript profiling distinguishes the transient from the acute type of megakaryoblastic leukaemia (M7) in Down's syndrome, revealing PRAME as a specific discriminating marker McElwaine S, Mulligan C, Groet J, Spinelli M, Rinaldi A, Denyer G, Mensah A, Cavani S, Baldo C, Dagna-Bricarelli F, Hann I, Basso G, Cotter FE and Nizetic D Br J Haematol 2004; 125; 729-742. Medline 15180862 Prenatal origin of GATA1 mutations may be an initiating step in the development of megakaryocytic leukemia in Down syndrome Taub JW, Mundschau G, Ge Y, Poulik JM, Qureshi F, Jensen T, James SJ, Matherly LH, Wechsler J and Crispino JD Blood 2004; 104; 1588-1589. Medline 15317736 Origins of leukaemia in children with Down syndrome Hitzler, JK and Zipursky A Nat Rev Cancer 2005; 5: 11-20. (REVIEW) Medline 15630411 REVIEW articles Last year publications

automatic search in PubMed automatic search in PubMed

BiblioGene - INIST


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Contributor(s) Written

022005

Shai Izraeli

Citation This paper should be referenced as such : Izraeli S . GATA1 (GATA binding protein 1 (globin transcription factor1)). Atlas Genet Cytogenet Oncol Haematol. February 2005 . URL : http://www.infobiogen.fr/services/chromcancer/Genes/GATA1ID40689chXp11.html © Atlas of Genetics and Cytogenetics in Oncology and Haematology


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LTA (Lymphotoxin-A) Identity Other names

TNFb Tumor Necrosis Factor-b TNFSF1 TNF Superfamily member 1

Hugo

LTA

Location

6p21.3

DNA/RNA Description The human TNFb gene is located next to HLA-C and HLA-B loci in chromosome 6 (6p21.3). The gene spans 2005bp with 4 exons, which transcribes a TNFb mRNA with size of 1386nt.

Protein

Description The human TNFb protein contains 205 amino acids. The soluble form of TNFb is usually a homotrimer with a relative molecular mass of 60 to 70 kDa, whereas the membrane form of TNFb is a heteromeric complex with lymphotoxin b (TNFc, LTb, TNFSF3). The human TNFb shares 35% identity and 50% homology in amino acid sequence with the human TNFa. The biological function of TNFb is mediated largely by TNFa receptor 1 and TNFa receptor 2. Recent studies suggested that TNFb can also recognize LIGHT ( TNFSF14) receptor. Expression The main cellular source of TNFb is the activated lymphocytes in immune response. Localisation Cell membrane, extracellular soluble form, blood stream, and biological fluids. Function

The human TNFb is an important cytokine involved in the development of secondary lymphoid organs and inflammatory responses.

Implicated in Disease

The polymorphism of TNFb gene in either the coding region or the promoter region has been associated with Crohn disease and myocardial infarction.

External links Atlas Genet Cytogenet Oncol Haematol 2005; 2

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Nomenclature Hugo

LTA

GDB

LTA

Entrez_Gene

LTA 4049 lymphotoxin alpha (TNF superfamily, member 1) Cards

Atlas

LTAID41209ch6p21

GeneCards

LTA

Ensembl

LTA

CancerGene

LT

Genatlas

LTA

GeneLynx

LTA

eGenome

LTA

euGene


GoldenPath

LTA - 6p21.3 chr6:31648072-31650077 + 6p21.33 May_2004)

Ensembl

LTA - 6p21.33 [CytoView]

NCBI


OMIM

Disease map [OMIM]

HomoloGene

LTA

(hg17-


AB088112 [ SRS ]

AB088112 [ ENTREZ ]

Genbank

AF129756 [ SRS ]

AF129756 [ ENTREZ ]

Genbank

AL662801 [ SRS ]

AL662801 [ ENTREZ ]

Genbank

AL929587 [ SRS ]

AL929587 [ ENTREZ ]

Genbank

AY070490 [ SRS ]

AY070490 [ ENTREZ ]

RefSeq

NM_000595 [ SRS ]


RefSeq

NT_086688 [ SRS ]


AceView

LTA AceView - NCBI

TRASER

LTA Traser - Stanford

Unigene

Hs.36 [ SRS ]

Hs.36 [ NCBI ]

HS36 [ spliceNest ]


P01374 [ SRS]

P01374 [ EXPASY ]

Prosite

PS00251 TNF_1 [ SRS ]

PS00251 TNF_1 [ Expasy ]

Prosite

PS50049 TNF_2 [ SRS ]

PS50049 TNF_2 [ Expasy ]

Interpro

IPR006053 TNF_abc [ SRS ]

Interpro

IPR006052 TNF_family [ SRS ]

Interpro

IPR008983 TNF_like [ SRS ]


P01374 [ INTERPRO ]

IPR006053 TNF_abc [ EBI ] IPR006052 TNF_family [ EBI ] IPR008983 TNF_like [ EBI ]

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Interpro

IPR003636 TNF_subf [ SRS ]

CluSTr

P01374

Pfam

PF00229 TNF [ SRS ]

Smart

SM00207 TNF [EMBL]

Prodom

PD002012 TNF_subf[INRA-Toulouse]

Prodom

IPR003636 TNF_subf [ EBI ]

PF00229 TNF [ Sanger ]


P01374 TNFB_HUMAN [ Domain structure ] P01374 TNFB_HUMAN

[

sequences sharing at least 1 domain ]

Blocks

P01374

PDB

1TNR [ SRS ]

1TNR [ PdbSum ], 1TNR [ IMB ]

Polymorphism : SNP, mutations, diseases OMIM

153440

[ map ]


LTA [dbSNP-NCBI]

SNP

NM_000595 [SNP-NCI]

SNP

LTA [GeneSNPs - Utah] LTA [SNP - CSHL] LTA] [HGBASE - SRS] General knowledge

Family Browser

LTA [UCSC Family Browser]

SOURCE

NM_000595

SMD

Hs.36

SAGE

Hs.36

Amigo

process|cell-cell signaling

Amigo

process|immune response

Amigo

process|induction of apoptosis

Amigo

component|membrane

Amigo

process|signal transduction

Amigo

function|tumor necrosis factor receptor binding

BIOCARTA

Cytokine Network

BIOCARTA

Cytokines and Inflammatory Response

BIOCARTA

TNF/Stress Related Signaling

BIOCARTA

TNFR2 Signaling Pathway

PubGene

LTA Other databases Probes

Probe

LTA Related clones (RZPD - Berlin) PubMed

PubMed


Bibliography


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Signalling pathways of the TNF superfamily: a double-edged sword Aggarwal BB Nat Rev Immunol 2003; 3(9): 745-756. Medline 12949498 Lymphotoxin/LIGHT, lymphoid microenvironments and autoimmune disease. Gommerman JL and Browning JL Nat Rev Immunol 2003; 3(8): 642-655. Medline 12974479 automatic search in PubMed REVIEW articles Last year automatic search in PubMed publications BiblioGene - INIST


022005

Fei Chen

Citation This paper should be referenced as such : Chen F . LTA (Lymphotoxin-A). Atlas Genet Cytogenet Oncol Haematol. February 2005 . URL : http://www.infobiogen.fr/services/chromcancer/Genes/LTAID41209ch6p21.html © Atlas of Genetics and Cytogenetics in Oncology and Haematology


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MLH1 (human mutL homolog 1) Identity Other names

COCA2 FCC2 hMLH1 HNPCC2

Hugo

MLH1

Location

3p21.3 Between the KIAA0342 and LRRFIP2 genes

DNA/RNA

Diagram of the MLH1 gene. Exons are represented by boxes (in scale) transcribed and untranscribed sequences in blue and yellow, with exon numbers on top and number of base pairs at the bottom. Introns are represented by black bars (not in scale) and the number of base pairs indicated. The arrows show the ATG and the stop codons respectively.

Description

The MLH1 gene is composed of 19 exons spanning in a region of 57360 bp.

Transcription The transcribed mRNA has 2524 bp

Protein


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Diagram of the MLH1 protein in scale. Numbers inside the blue boxes indicate the exon from which is translated each part of the protein. The three boxes inside represent the ATPase domain, the MutS homologs interaction domain and the PMS2/MLH3/PMS1 interaction domain; C: Carboxyl-terminal; N: Amino-terminal

Description Aminoacids: 756. Molecular Weight: 84.6 kDa. MLH1 is a protein involved in the mismatch repair process after DNA replication. It contains an ATPase domain and two interaction domains, one for MutS homologs (MSH2, MSH3, MSH6) and the other for PMS2, MLH3 or PMS1. Localisation Nuclear Function

MLH1 has no known enzymatic activity. MLH1 forms a heterodimer with PMS2 known as MutLa, although it can also bind to PMS1 or MLH3. This heterodimeric complex binds to the heteroduplexes MutSa (composed of MSH2 and MSH6) or MutSb (composed of MSH2 and MSH3), which recognize DNA lesions. The heterodimer formed by MLH1 is responsible for the recruitment of the proteins needed for the excision and repair synthesis.

Homology

MLH1 is homologue to the bacterial MutL gene, specially in the Nterminal region, and MLH1 homologues are also present in eukaryotes (for example in Mus musculus, Drosophila melanogaster, Caenorhabditis elegans or Saccharomyces cerevisae)

Mutations Germinal

There are over 300 MLH1 germline mutations described all along the gene that cause hereditary non-polyposis colorectal cancer (HNPCC, see below). This mutations are not present in any particular hotspot or zone of the gene and include either nucleotide substitutions (missense, nonsense or splicing errors) or insertions/deletions (gross or small). In most of these mutations the resulting protein is truncated. There are also founding mutations which account for a high proportion of the HNPCC tumours in some specific populations (for example there are two Finnish mutations that delete the exons 16 or 6). Some germline genetic changes have also been described in both exons and introns as non pathogenic.

Somatic

There are described some sporadic mismatch repair deficiency cases (sporadic MSI) with somatic MLH1 mutations, although most of them have MLH1 promoter hypermetilation.


HNPCC (Hereditary Non Polyposis Colorectal Cancer)

Disease

Predisposition to develop cancer, preferentially colorectal, but also in endometrium, ovary, urinary tract, stomach, small bowel, biliary tract and brain.

Oncogenesis MLH1 mutations in HNPCC account for about 25% of the total cases approximately.


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Entity

MSI (MicroSatellite Instability)

Note

Tumours in which the molecular feature that leads to cancer is the lost of the mismatch repair (MMR) system.

Disease

This phenotype is present in 15% of colorectal, gastric and endometrial cancer, and with lower incidence in some other tissues.

Prognosis

MSI tumours have better prognosis than the MicroSatellite Stable (MSS).

Oncogenesis Sporadic MSI cases are mostly due to a biallelic hypermetilation of the MLH1 promotor and therefore lack of MLH1 protein expression. Few sporadic cases and about 25% of the HNPCC are due to different mutations in MLH1. These mutations are germline in HNPCC. Entity

Muir-Torre syndrome

Disease

Coincidence of at least one sebaceous adenoma, epithelioma or carcinoma and one internal malignancy.

Oncogenesis Inherited MLH1 mutations can cause Muir-Torre syndrome (although MSH2 mutations are more present).


MLH1

GDB

MLH1

Entrez_Gene

MLH1 4292 mutL homolog 1, colon cancer, nonpolyposis type 2 (E. coli) Cards

Atlas

MLH1ID149ch3p21

GeneCards

MLH1

Ensembl

MLH1

CancerGene

MLH1

Genatlas

MLH1

GeneLynx

MLH1

eGenome

MLH1

euGene


GoldenPath

MLH1 - 3p21.3 chr3:37009983-37067341 + 3p22.3 May_2004)

Ensembl

MLH1 - 3p22.3 [CytoView]

NCBI


OMIM

Disease map [OMIM]

HomoloGene

MLH1


(hg17-

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AY217549 [ SRS ]

AY217549 [ ENTREZ ]

Genbank

AY344475 [ SRS ]

AY344475 [ ENTREZ ]

Genbank

AY706914 [ SRS ]

AY706914 [ ENTREZ ]

Genbank

U17839 [ SRS ]

U17839 [ ENTREZ ]

Genbank

U17840 [ SRS ]

U17840 [ ENTREZ ]

RefSeq

NM_000249 [ SRS ]


RefSeq

NT_086636 [ SRS ]


AceView

MLH1 AceView - NCBI

TRASER

MLH1 Traser - Stanford

Unigene

Hs.195364 [ SRS ]

Hs.195364 [ NCBI ]



P40692 [ SRS]

Prosite

PS00058 DNA_MISMATCH_REPAIR_1 [ SRS ] DNA_MISMATCH_REPAIR_1 [ Expasy ]

Interpro

P40692 [ EXPASY ]

P40692 [ INTERPRO ]

IPR003594 ATPbind_ATPase [ SRS ]

IPR003594 ATPbind_ATPase [

EBI ]

Interpro

IPR002099 DNA_mis_repair [ SRS ]

Interpro

IPR011186 MLH1 [ SRS ]

CluSTr

P40692

Pfam

PS00058

IPR002099 DNA_mis_repair [ EBI ]

IPR011186 MLH1 [ EBI ]

PF01119 DNA_mis_repair [ SRS ] pfam01119 [ NCBI-CDD ]

PF01119 DNA_mis_repair [ Sanger

]

Pfam

PF02518 HATPase_c [ SRS ] ] pfam02518 [ NCBI-CDD ]

Blocks

P40692

PF02518 HATPase_c [ Sanger


120436

[ map ]


MLH1 [dbSNP-NCBI]

SNP

NM_000249 [SNP-NCI]

SNP

MLH1 [GeneSNPs - Utah] MLH1 [SNP - CSHL] MLH1] [HGBASE - SRS] General knowledge

Family Browser

MLH1 [UCSC Family Browser]

SOURCE

NM_000249

SMD

Hs.195364

SAGE

Hs.195364

Amigo

function|ATP binding

Amigo

process|mismatch repair


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Amigo

process|negative regulation of cell cycle

Amigo

component|nucleus

PubGene

MLH1 Other databases Probes

Probe

MLH1 Related clones (RZPD - Berlin) PubMed

PubMed


Bibliography Mutation in the DNA mismatch repair gene homologue hMLH 1 is associated with hereditary non-polyposis colon cancer Bronner CE, Baker SM, Morrison PT, Warren G, Smith LG, Lescoe MK, Kane M, Earabino C, Lipford J, Lindblom A, Tannergard P, Bollag RJ, Godwin AR, Ward DC, Nordenskjld M, Fishel R, Kolodner R, Liskay RM Nature 1994; 368: 258-261. Medline 8145827 Microsatellite instability in inherited and sporadic neoplasms. Eshleman JR, Markowitz SD. Curr Opin Oncol 1995; 7: 83-89. (REVIEW). Medline 7696368 The genetic basis of Muir-Torre syndrome includes the hMLH1 locus. Bapat B, Xia L, Madlensky L, Mitri A, Tonin P, Narod SA, Gallinger S. Am J Hum Genet 1996; 59: 736-739. Medline 8751876 Biallelic inactivation of hMLH1 by epigenetic gene silencing, a novel mechanism causing human MSI cancers. Veigl ML, Kasturi L, Olechnowicz J, Ma AH, Lutterbaugh JD, Periyasamy S, Li GM, Drummond J, Modrich PL, Sedwick WD, Markowitz SD. Proc Natl Acad Sci USA 1998; 95: 8698-8702. Medline 9671741 hMLH1 promoter methylation and lack of hMLH1 expression in sporadic gastric carcinomas with high-frequency microsatellite instability. Leung SY, Yuen ST, Chung LP, Chu KM, Chan AS, Ho JC. Cancer Res 1999; 59: 159-164. Medline 9892201 DNA mismatch repair defects: role in colorectal carcinogenesis. Jacob S, Praz F. Biochimie 2002; 84: 27-47. (REVIEW) Medline 11900875


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DNA mismatch repair and mutation avoidance pathways. Marti TM, Kunz C, Fleck O. J Cell Physiol 2002; 191: 28-41. (REVIEW). Medline 11920679 Mismatch repair genes hMLH1 and hMSH2 and colorectal cancer: a HuGE review. Mitchell RJ, Farrington SM, Dunlop MG, Campbell H. Am J Epidemiol 2002; 156: 885-902. (REVIEW Medline 12419761 Low levels of microsatellite instability characterize MLH1 and MSH2 HNPCC carriers before tumor diagnosis. Alazzouzi H, Domingo E, Gonzalez S, Blanco I, Armengol M, Espin E, Plaja A, Schwartz S, Capella G, Schwartz S Jr. Hum Mol Genet 2005; 14: 235-239. Medline 15563510 automatic search in PubMed REVIEW articles Last year automatic search in PubMed publications BiblioGene - INIST


022005

Enrico Domingo, Simo Schwartz Jr

Citation This paper should be referenced as such : Domingo E, Schwartz S Jr . MLH1 (human mutL homolog 1). Atlas Genet Cytogenet Oncol Haematol. February 2005 . URL : http://www.infobiogen.fr/services/chromcancer/Genes/MLH1ID149ch3p21.html © Atlas of Genetics and Cytogenetics in Oncology and Haematology


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PTPN11 (Protein tyrosine phosphatase, non-receptor type, 11) Identity Other names

SHP-2 SH-PTP2 (Src homology 2 domain-containing protein tyrosine phosphatase, 2) PTP2C (Protein tyrosine phosphatase 2C) BPTP3

Hugo

PTPN11

Location

12q24.1 centromere - FLJ34154 - RPL6 - PTPN11 - RPH3A - OAS1 - telomere

DNA/RNA Description

The PTPN11 gene is divided in 16 exons. Exon 1 contains the 5' untranslated region and the translation initiation ATG, and a few additional codons. Exon 15 contains the stop codon and exon 16 contains a major portion of the 3' untranslated region. Other features of the PTPN11 gene, such as the promoter region and enhancer elements have not been delineated.

Transcription A 7.0-kb transcript is detected in several tissues (heart, brain, lung, liver, skeletal muscle, kidney, and pancreas) with highest steady-state levels in heart and skeletal muscle. The predominant human PTPN11 mRNA contains an open reading frame of 1,779 bases, resulting in a predicted protein of 593 amino acid residues. A second mRNA containing 12 additional base pairs (exon 11) has been identified. Little additional information is available about this alternative transcript. Pseudogene A number of PTPN11-related processed pseudogenes, i.e. with no apparent exon structure, have been documented in the human genome. All the pseudogenes share >92% nucleotide identity with the PTPN11 cDNA (including the 5'-UTR and 3'-UTR), but harbour frameshift mutations and multiple stop codons. Three of the five pseudogenes appear to be expressed with distinct tissue distributions and expression levels.

Protein


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PTPN11 genomic organization and SHP-2 domain structure: Figure 1 : (A) The PTPN11 gene and SHP-2 domain characterization. The coding exons are shown as numbered filled boxes. The functional domains of the protein, comprising two tandemly arranged SH2 domains at the N terminus (N-SH2 and CSH2) followed by a protein tyrosine phosphatase (PTP) domain, are shown below. Numbers below the domain structure indicate the amino-acid boundaries of those domains. (B) Three-dimensional structure of SHP-2 in its catalytically inactive conformation, as determined by Hof et al. (1998). Residues involved in catalysis are shown (space fill). Figure 2 : Location of SHP-2 mutated residues in human disease. (A) Noonan syndrome and LEOPARD syndrome (germ-line origin; N=224); (B) Noonan syndrome with juvenile myelomonocytic leukemia (germ-line origin; N=11); (C) hematologic malignancies, including juvenile myelomonocytic leukemia, acute myeloid leukemia, acute lymphoblastic leukemia, myelodysplastic syndromes and chronic myelomonocytic leukemia (somatic origin; N=97). The pictures show the C trace of SHP-2 in its catalytically inactive conformation. Affected residues are indicated with their side chains as black sticks.

Description SHP-2 is a member of a small subfamily of cytoplasmic Src homology 2 (SH2) domain-containing protein tyrosine phosphatases. Both the NSH2 and C-SH2 domains selectively bind to short amino acid motifs containing a phosphotyrosyl residue and promote SHP-2 association with activated receptors and other signaling partners. Crystallographic data indicate that the N-SH2 domain also interacts with the PTP domain using a separate site. As these subdomains show negative cooperativity, the N-SH2 domain functions as an intramolecular switch controlling SHP-2 catalytic activation. Specifically, the N-SH2 domain interacts with the PTP domain basally, blocking the catalytic site.


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Binding of the N-SH2 phosphopeptide-binding site to the phosphotyrosyl ligand promotes a conformational change of the domain that weakens the auto-inhibiting intramolecular interaction, making the catalytic site available to substrate, thereby activating the phosphatase. Expression Widely expressed in both embryonic and adult tissues. Localisation Cytoplasmic. It binds to activated cell surface receptors, cell adhesion molecules and scaffolding adapters. Function

SHP-2 functions as an intracellular signal transducer. It positively modulates signal flow in most circumstances, but can also function as negative regulator depending upon its binding partner and interactions with downstream signaling networks. SHP-2 positively controls the activation of the RAS/MAPK cascade induced by several growth factors, and negatively regulates JAK/STAT signaling. In most cases, SHP-2's function in intracellular signaling appears to be immediately proximal to activated receptors and upstream to RAS. The mechanisms of SHP-2's action and its physiological substrates are still poorly defined. However, both membrane translocation and PTPase activity are required for SHP2 function. SHP-2 is required during development. Embryos nullizygous for Shp-2 have defects in gastrulation and mesodermal patterning resulting in severe abnormalities in axial and paraxial mesodermal structures. Shp-2 function is also required for development of terminal and skeletal structures, semilunar valvulogenesis in the heart, and hematopoiesis.

Homology

PTPN6 (protein tyrosine phosphatase, non-receptor type, 6) previously known as SHP1 or SHP-1 (Src homology 2 domain-containing protein tyrosine phosphatase, 1).

Mutations Note

At least two distinct classes of PTPN11 mutations have been identified in humans. The first group, which has germ-line origin, causes Noonan syndrome and closely related developmental disorders. The second group, acquired as a somatic event, has been documented in a heterogeneous group of hematologic malignancies and pre-leukemic disorders, and rarely in certain solid tumors. The vast majority of mutations affect residues residing at or close to the interface between the N-SH2 and PTP domains. Increasing evidence supports that both germ-line and somatic mutations promote SHP-2 gain-of-function by destabilizing the catalytically inactive conformation of the protein, and prolong signal flux through the RAS/MAPK pathway in a ligand-dependent manner. A mouse model bearing the NS-causative D61G mutation in the Ptpn11 gene has been recently generated and characterized. The Ptpn11D61G/D61G genotype is embryonic lethal. At day E13.5, these embryos are grossly edematous and hemorrhagic, have diffuse liver necrosis and severe cardiac defects. Heterozygous embryos exhibit cardiac defects, proportionate growth failure and perturbed craniofacial development. Hematologic anomalies include a mild myeloproliferative disease. Ptpn11D61G/+ embryonic fibroblasts exhibit a three-fold


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increased Shp-2 activity and increased association of Shp-2 with Gab1 after stimulation with EGF. Cell culture and whole embryo studies reveal that increased RAS/MAPK signaling is variably present, appearing to be cell-context specific. Germinal

Selection: 124A>G (T42A), 179-181delGTG (delGly60), 181-183delGAT (delAsp61), 182A>G (D61G), 184T>G (Y62D), 188A>G (Y63C), 214G>T (A72S), 215C>G (A72G), 218C>T (T73I), 228G>T,C (E76D), 236A>G (N79R), 317A>C (D106A), 836A>G (Y279C), 922A>G (N308D), 1403C>T (T468M), 1510A>G (M504V).

Somatic

Selection: 181G>T (D61Y), 182A>T (D61V), 205G>A (E69K), 211213TTT>AAA (F71K), 214G>A (A72T), 215C>T (A72V), 226G>A (E76K), 226G>C (E76Q), 227A>T (E76V), 227A>G (E76G), 227A>C (E76A), 1471C>T (P491S), 1472C>T (P491L), 1504T>C (S502P), 1504T>G (S502A), 1520C>A (T507K), 1528C>A (Q510K).


Noonan syndrome, Noonan-like/multiple giant cell lesion syndrome and LEOPARD syndrome.

Note

Germ-line origin. Gain-of-function mutations. Increased basal protein tyrosine phosphatase activity. Prolonged ligand-dependent activation of the RAS/MAPK cascade.

Disease

Noonan syndrome is a genetically heterogeneous and clinically variable developmental disorder defined by short stature, facial dysmorphism and a wide spectrum of congenital heart defects. The distinctive facial features consist of a broad forehead, hypertelorism, down-slanting palpebral fissures, ptosis, high-arched palate and lowset, posteriorly rotated ears. Cardiovascular abnormalities, primarily pulmonic stenosis and hypertrophic cardiomyopathy, are present in up to 85% of affected individuals. Additional relatively frequent features are multiple skeletal defects, webbed neck, mental retardation, cryptorchidism and bleeding diathesis. Children with Noonan syndrome are predisposed to a spectrum of hematologic abnormalities, including transient monocytosis, thrombocytopenia and rarely juvenile myelomonocytic leukemia and acute leukemia.

Entity

Juvenile myelomonocytic leukemia, acute myeloid leukemia, acute lymphoblastic leukemia, myelodysplastic syndromes, chronic myelomonocytic leukemia, melanoma, neuroblastoma, lung adenocarcinoma, colon cancer.

Note

Somatic origin.

Prognosis

No data are currently available.

Oncogenesis Gain-of-function mutations. Increased basal protein tyrosine phosphatase activity. Prolonged ligand-dependent activation of the RAS/MAPK cascade.

External links


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Nomenclature Hugo

PTPN11

GDB

PTPN11

Entrez_Gene

PTPN11 5781 protein tyrosine phosphatase, non-receptor type 11 (Noonan syndrome 1) Cards

Atlas

PTPN11ID41910ch12q24

GeneCards

PTPN11

Ensembl

PTPN11

CancerGene

PTPN11

Genatlas

PTPN11

GeneLynx

PTPN11

eGenome

PTPN11

euGene


GoldenPath

PTPN11 - 12q24.1 chr12:111319256-111410436 + 12q24.13 (hg17-May_2004)

Ensembl

PTPN11 - 12q24.13 [CytoView]

NCBI


OMIM

Disease map [OMIM]

HomoloGene

PTPN11 Gene and transcription

Genbank

AU123593 [ SRS ]

AU123593 [ ENTREZ ]

Genbank

BC007869 [ SRS ]

BC007869 [ ENTREZ ]

Genbank

BC008692 [ SRS ]

BC008692 [ ENTREZ ]

Genbank

BC025181 [ SRS ]

BC025181 [ ENTREZ ]

Genbank

BC030949 [ SRS ]

BC030949 [ ENTREZ ]

RefSeq

NM_002834 [ SRS ]


RefSeq

NT_086796 [ SRS ]


AceView

PTPN11 AceView - NCBI

TRASER

PTPN11 Traser - Stanford

Unigene

Hs.506852 [ SRS ]

Hs.506852 [ NCBI ]



Q06124 [ SRS]

Q06124 [ EXPASY ]

Q06124 [ INTERPRO ]

Prosite

PS50001 SH2 [ SRS ]

Prosite

PS00383 TYR_PHOSPHATASE_1 [ SRS ] TYR_PHOSPHATASE_1 [ Expasy ]

PS00383

Prosite

PS50056 TYR_PHOSPHATASE_2 [ SRS ] TYR_PHOSPHATASE_2 [ Expasy ]

PS50056

PS50001 SH2 [ Expasy ]


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Prosite

PS50055 TYR_PHOSPHATASE_PTP [ SRS ] TYR_PHOSPHATASE_PTP [ Expasy ]

Interpro

IPR000980 SH2 [ SRS ]

Interpro

IPR000387 TYR_phosphatase [ SRS ]

Interpro

IPR000242 Tyr_PP [ SRS ]

CluSTr

Q06124

Pfam

PF00017 SH2 [ SRS ]

Pfam

IPR000980 SH2 [ EBI ] IPR000387 TYR_phosphatase

[ EBI ]

IPR000242 Tyr_PP [ EBI ]

PF00017 SH2 [ Sanger ]

PF00102 Y_phosphatase [ SRS ] pfam00102 [ NCBI-CDD ]


PF00102 Y_phosphatase [ Sanger

]

Smart

SM00194 PTPc [EMBL]

Smart

SM00252 SH2 [EMBL]

Prodom

PD000093 SH2[INRA-Toulouse]

Prodom

PS50055

Q06124 PTNB_HUMAN [ Domain structure ] Q06124 PTNB_HUMAN

[


Blocks

Q06124

PDB

2SHP [ SRS ]

2SHP [ PdbSum ], 2SHP [ IMB ]


176876

[ map ]


PTPN11 [dbSNP-NCBI]

SNP

NM_002834 [SNP-NCI]

SNP

PTPN11 [GeneSNPs - Utah] PTPN11 [SNP - CSHL] PTPN11] [HGBASE - SRS] General knowledge

Family Browser

PTPN11 [UCSC Family Browser]

SOURCE

NM_002834

SMD

Hs.506852

SAGE

Hs.506852

Enzyme

3.1.3.48 [ Enzyme-SRS ] 3.1.3.48 [ Brenda-SRS ] 3.1.3.48 [ KEGG ] 3.1.3.48 [

Amigo

function|hydrolase activity

Amigo

process|intracellular signaling cascade

Amigo

function|non-membrane spanning protein tyrosine phosphatase activity

Amigo

process|perception of sound

Amigo

process|protein amino acid dephosphorylation

Amigo

function|protein binding

BIOCARTA

The Co-Stimulatory Signal During T-cell Activation

BIOCARTA

IGF-1 Signaling Pathway

WIT ]


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BIOCARTA

IL 6 signaling pathway

BIOCARTA

Insulin Signaling Pathway

BIOCARTA

Signaling of Hepatocyte Growth Factor Receptor

KEGG

Phosphatidylinositol Signaling System

PubGene

PTPN11 Other databases Probes

Probe

PTPN11 Related clones (RZPD - Berlin) PubMed

PubMed


Bibliography A widely expressed human protein-tyrosine phosphatase containing src homology 2 domains. Ahmad S, Banville D, Zhao Z, Fischer EH, Shen SH. Proc Natl Acad Sci USA 1993; 90: 2197-2201. Medline 7681589 Crystal structure of the tyrosine phosphatase SHP-2. Hof P, Pluskey S, Dhe-Paganon S, Eck MJ, Shoelson SE. Cell 1998; 92: 441-444. Medline 9491886 Mutations in PTPN11, encoding the protein tyrosine phosphatase SHP-2, cause Noonan syndrome. Tartaglia M, Mehler EL, Goldberg R, Zampino G, Brunner HG, Kremer H, van der Burgt I, Crosby AH, Ion A, Jeffery S, Kalidas K, Patton MA, Kucherlapati RS, Gelb BD. Nat Genet 2001; 29: 465-468. Medline 11704759 Grouping of Multiple-Lentigines/LEOPARD and Noonan Syndromes on the PTPN11 Gene. Digilio MC, Conti E, Sarkozy A, Mingarelli R, Dottorini T, Marino B, Pizzuti A, Dallapiccola B. Am J Hum Genet 2002; 71: 389-394. Medline 12058348 PTPN11 mutations in LEOPARD syndrome. Legius E, Schrander-Stumpel C, Schollen E, Pulles-Heintzberger C, Gewillig M, Fryns JP. J Med Genet 2002; 39: 571-574. Medline 12161596 PTPN11 mutations in Noonan syndrome: molecular spectrum, genotypeAtlas Genet Cytogenet Oncol Haematol 2005; 2

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phenotype correlation, and phenotypic heterogeneity Tartaglia M, Kalidas K, Shaw A, Song X, Musat DL, van der Burgt I, Brunner HG, Bertola DR, Crosby A, Ion A, Kucherlapati RS, Jeffery S, Patton MA, Gelb BD. Am J Hum Genet 2002; 70: 1555-1563. Medline 11992261 The 'Shp'ing news: SH2 domain-containing tyrosine phosphatases in cell signaling. Neel BG, Gu H, Pao L. Trends Biochem Sci 2003; 28: 284-293. Medline 12826400 Somatic mutations in PTPN11 in juvenile myelomonocytic leukemia, myelodysplastic syndromes and acute myeloid leukemia. Tartaglia M, Niemeyer CM, Fragale A. Song X, Buechner J, Jung A, Hahlen K, Hasle H, Licht JD, Gelb BD. Nat Genet 2003; 34: 148-150. Medline 12717436 A genomic perspective on protein tyrosine phosphatases: gene structure, pseudogenes, and genetic disease linkage. Andersen JN, Jansen PG, Echwald SM, Mortensen OH, Fukada T, Del Vecchio R, Tonks NK, Moller NP. FASEB J 2004; 18: 8-30. Medline 14718383 Mouse model of Noonan syndrome reveals cell type- and gene dosagedependent effects of Ptpn11 mutation. Araki T, Mohi MG, Ismat FA, Bronson RT, Williams IR, Kutok JL, Yang W, Pao LI, Gilliland DG, Epstein JA, Neel BG. Nat Med 2004; 10: 849-857. Medline 15273746 Activating mutations of the Noonan syndrome-associated SHP2/PTPN11 gene in human solid tumors and adult acute myelogenous leukemia. Bentires-Alj M, Paez JG, David FS, Keilhack H, Halmos B, Naoki K, Maris JM, Richardson A, Bardelli A, Sugarbaker DJ, Richards WG, Du J, Girard L, Minna JD, Loh ML, Fisher DE, Velculescu VE, Vogelstein B, Meyerson M, Sellers WR, Neel BG. Cancer Res 2004; 64: 8816-8820. Medline 15604238 Noonan syndrome-associated SHP2/PTPN11 mutants cause EGF-dependent prolonged GAB1 binding and sustained ERK2/MAPK1 activation. Fragale A, Tartaglia M, Wu J, Gelb BD. Hum Mutat 2004; 23: 267-277. Medline 14974085


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PTPN11 mutations in pediatric patients with acute myeloid leukemia: results from the Children's Cancer Group. Loh ML, Reynolds MG, Vattikuti S, Gerbing RB, Alonzo TA, Carlson E, Cheng JW, Lee CM, Lange BJ, Meshinchi S. Leukemia 2004; 18: 1831-1834. Medline 15385933 Mutations in PTPN11 implicate the SHP-2 phosphatase in leukemogenesis. Loh ML, Vattikuti S, Schubbert S, Reynolds MG, Carlson E, Lieuw KH, Cheng JW, Lee CM, Stokoe D, Bonifas JM, Curtiss NP, Gotlib J, Meshinchi S, Le Beau MM, Emanuel PD, Shannon KM. Blood 2004; 103: 2325-2331 Medline 14644997. Paternal germline origin and sex-ratio distortion in transmission of PTPN11 mutations in Noonan syndrome. Tartaglia M, Cordeddu V, Chang H, Shaw A, Kalidas K, Crosby A, Patton MA, Sorcini M, van der Burgt I, Jeffery S, Gelb BD. Am J Hum Genet 2004; 75: 492-497. Medline 15248152 Genetic evidence for lineage- and differentiation stage-related contribution of somatic PTPN11 mutations to leukemogenesis in childhood acute leukemia. Tartaglia M, Martinelli S, Cazzaniga G, Cordeddu V, Iavarone I, Spinelli M, Palmi C, Carta C, Pession A, Arico M, Masera G, Basso G, Sorcini M, Gelb BD, Biondi A. Blood 2004; 104: 307-313. Medline 14982869 SHP-2 and myeloid malignancies. Tartaglia M, Niemeyer CM, Shannon KM, Loh ML. Curr Opin Hematol 2004;11: 44-50. Review. Medline 14676626 Genotype-phenotype correlations in Noonan syndrome. Zenker M, Buheitel G, Rauch R, Koenig R, Bosse K, Kress W, Tietze HU, Doerr HG, Hofbeck M, Singer H, Reis A, Rauch A. J Pediatr 2004; 144: 368-374. Medline 15001945 Germ-line and somatic PTPN11 mutations in human disease. Tartaglia M, Gelb BD. Eur J Med Genet 2005; 1: in press. Review. REVIEW articles Last year



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publications BiblioGene - INIST


022005

Marco Tartaglia, Bruce D Gelb

Citation This paper should be referenced as such : Tartaglia M, Gelb BD . PTPN11 (Protein tyrosine phosphatase, non-receptor type, 11). Atlas Genet Cytogenet Oncol Haematol. February 2005 . URL : http://www.infobiogen.fr/services/chromcancer/Genes/PTPN11ID41910ch12q24.html © Atlas of Genetics and Cytogenetics in Oncology and Haematology


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ACTB (Actin, beta) Identity Note

Other names

Six actin isoforms are known: two sarcomeric (a-skeletal and a-cardiac), two smooth muscle actins (a and g), and two non-muscle, cytoskeletal actins (b and g). Beta cytoskeletal actin Beta actin

Hugo

ACTB

Location

7p22.

DNA/RNA

Genomic organization of the ACTB gene.

Description

Six exons, spans approximately 3.4 kb of genomic DNA in the centromere-to-telomere orientation. The translation initiation codon ATG is located in exon 2, and the stop codon in exon 6.

Transcription mRNA of approximately 1.8 kb. Pseudogene At least 19 processed, non-expressed, pseudogenes are dispersed throughout the genome.

Protein Description The open reading frame encodes a 374 amino acid protein, with an estimated molecular weight of approximately 41.7 kDa. Expression Abundantly expressed in all mammalian and avian non-muscle cells. Localisation Cytoplasm Function

Component (together with cytoplasmic g actin) of the cytoskeletal microfilaments. Involved in the transport of chromosomes and organelles as well as in cell motility.

Homology

The ACTB proteins are evolutionary conserved. Mammalian


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cytoplasmic actins (actin g and b) are remarkably similar to each other, but differ in at least 25 residues from the muscle actins.

Mutations Somatic

ACTB is interrupted by the t(7;12)(p22;q13) detected in pericytoma with t(7;12).


Pericytoma with t(7;12)

Prognosis

Benign or low-malignant

Cytogenetics

t(7;12)(p22;q13)

Representative G-banded partial karyotype of the t(7;12)(p22;q13).

Hybrid/Mutated ACTB-GLI1 fusion gene. The breakpoints reported so far have been Gene located to introns 1, 2 or 3 within the ACTB gene, and to introns 5 or 6 or to exon 7 within the GLI1 gene. Reciprocal GLI1-ACTB gene fusions have also been detected. The breakpoints have been located to introns 5 or 7 within the GLI1 gene, and to intron 3 of the ACTB gene. Abnormal Protein

The ACTB-GLI1 fusion protein contains the N-terminal of ACTB and the C-terminal of GLI1, including the DNA-binding zink finger motifs (encoded by exons 7-10) and transactivating motifs (exon 12).

Oncogenesis

It is suggested that the strong ACTB promoter causes an overexpression of GLI1 sequences important for transcriptional activation of downstream target genes, akin to the oncogenic mechanisms of the COL1A1-PDGFB fusion gene detected in dermatofibrosarcoma protuberans.

External links


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Nomenclature Hugo

ACTB

GDB

ACTB

Entrez_Gene

ACTB 60 actin, beta Cards

Atlas

ACTBID42959ch7p22

GeneCards

ACTB

Ensembl

ACTB

Genatlas

ACTB

GeneLynx

ACTB

eGenome

ACTB

euGene


GoldenPath

ACTB - 7p22. chr7:5340027-5343462 - 7p22.1 May_2004)

Ensembl

ACTB - 7p22.1 [CytoView]

NCBI


OMIM

Disease map [OMIM]

HomoloGene

ACTB

(hg17-


AC006483 [ SRS ]

AC006483 [ ENTREZ ]

Genbank

AY582799 [ SRS ]

AY582799 [ ENTREZ ]

Genbank

M10277 [ SRS ]

Genbank

AK025375 [ SRS ]

AK025375 [ ENTREZ ]

Genbank

AK058019 [ SRS ]

AK058019 [ ENTREZ ]

RefSeq

NM_001101 [ SRS ]


RefSeq

NT_086701 [ SRS ]


AceView

ACTB AceView - NCBI

TRASER

ACTB Traser - Stanford

Unigene

Hs.520640 [ SRS ]

M10277 [ ENTREZ ]

Hs.520640 [ NCBI ]


Protein : pattern, domain, 3D structure Polymorphism : SNP, mutations, diseases OMIM

102630

[ map ]


ACTB [dbSNP-NCBI]

SNP

NM_001101 [SNP-NCI]

SNP

ACTB [GeneSNPs - Utah] ACTB [SNP - CSHL] ACTB] [HGBASE - SRS] General knowledge


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Family Browser

ACTB [UCSC Family Browser]

SOURCE

NM_001101

SMD

Hs.520640

SAGE

Hs.520640

Amigo

component|TIP60 histone acetyltransferase complex

Amigo

component|actin filament

Amigo

component|cytoskeleton

Amigo

function|motor activity

Amigo


Amigo

function|structural constituent of cytoskeleton

BIOCARTA

Chromatin Remodeling by hSWI/SNF ATP-dependent Complexes

PubGene

ACTB Other databases Probes

Probe

probes RP11-1275H24 (AC092171; substantially larger than the 85 kb reported by the NCBI) and RP11-93G19 (BAC ends: AQ321651, AQ321650)

Probe

ACTB Related clones (RZPD - Berlin) PubMed

PubMed


Bibliography Mammalian cytoplasmic actins are the products of at least two genes and differ in primary structure in at least 25 identified positions from skeletal muscle actins. Vandekerckhove J, Weber K. Proc Natl Acad Sci USA 1978; 75: 1106-1110. Medline 11001584 The human b-actin multigene family. Kedes L, Ng SY, Lin CS, Gunning P, Eddy R, Shows T, Leavitt J. Trans Assoc Am Phys 1985; 98: 42-45. Medline 3842206 Molecular structure of the human cytoplasmic ?-actin gene: interspecies homology of sequences in the introns. Nakajima-Iijima S, Hamada H, Reddy P, Kakunaga T. Proc Natl Acad Sci USA 1985; 82: 6133-6137. Medline 2994062 Evolution of the functional human b-actin gene and its multi-pseudogene family: conservation of noncoding regions and chromosomal dispersion of


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pseudogenes. Ng SY, Gunning P, Eddy R, Ponte P, Leavitt J, Shows T, Kedes L. Mol Cell Biol 1985; 5: 2720-2732. Medline 3837182 FISH localization of human cytoplasmic actin genes ACTB to 7p22 and ACTG1 to 17q25 and characterization of related pseudogenes. Ueyama H, Inazawa J, Nishino H, Ohkubo I, Miwa T. Cytogenet Cell Genet 1996; 74(3): 221-224. Medline 8941379 Deregulation of the platelet-derived growth factor B-chain gene via fusion with collagen gene COL1A1 in dermatofibrosarcoma protuberans and giant cell fibroblastoma. Simon MP, Pedeutour F, Sirvent N, Grosgeorge J, Minoletti F, Coindre J-M, TerrierLacombe MJ, Mandahl N, Craver RD, Blin N, Sozzi G, Turc-Carel C, O«Brien K, Kedra D, Fransson I, Guilbaud C, Dumanski JP. Nat Genet 1997; 15: 95-98. Medline 8988177 Activation of the GLI oncogene through fusion with the beta-actin (ACTB) gene in a group of distinctive pericytic neoplasms: Òpericytoma with t(7;12)Ó. DahlŽn A, Fletcher CDM, Mertens F, Fletcher JA, Perez-Atayde AR, Hicks MJ, Debiec-Rychter M, Sciot R, Wejde J, Wedin R, Mandahl N, Panagopoulos I. Am J Pathol 2004; 164: 1645-1653. Medline 15111311 Molecular genetic characterization of the ACTB-GLI fusion in pericytoma with t(7;12). DahlŽn A, Mertens F, Mandahl N, Panagopoulos I. Biochem Biophys Res Commun 2004; 325:1318-1323. Medline 15555571 REVIEW articles Last year publications


BiblioGene - INIST


032005

Anna Dahlén, Fredrik Mertens, Nils Mandahl, Ioannis Panagopoulos

Citation


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This paper should be referenced as such : Dahlén A, Mertens F, Mandahl N, Panagopoulos I . ACTB (Actin, beta). Atlas Genet Cytogenet Oncol Haematol. March 2005 . URL : http://www.infobiogen.fr/services/chromcancer/Genes/ACTBID42959ch7p22.html © Atlas of Genetics and Cytogenetics in Oncology and Haematology


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ADD3 (adducin 3) Identity Other names

ADDL Adducin-like adducin 3 (gamma) gamma adducin (adducin-like protein 70)

Hugo

ADD3

Location

10q25.1-q25.2 MXI1 (MAX-interacting protein 1) is more telomeric. XPNPEP1 (Xprolylaminopeptidase 1) is more telomeric.

DNA/RNA

Genomic structure of ADD3. Black boxes indicate exons.

Description

15 exons spanning 129.52 Kb on 10q25.1-10q25.2. Transcription is from centromere to telomere.

Transcription 2 alternative transcripts : Variant 1 includes an in-frame alternate coding exon and encodes a longer protein isoform (isoform a) compared to transcript variant 2. Variant 2 lacks an in-frame alternate coding exon and exon 13 and encodes a shorter protein (isoform b) compared to transcript variant 1. 3 alternative transcripts corresponding to variant 1 and 2.

Protein


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Schematic representation of ADD3. AldolaseII-N: domain belonging to aldolase class I family, adducin subfamily N-terminal, Coils: coiled-coil domain, Bipartite NLS: Bipartite nuclear localization signal.

Note

adducin 3 (adducin-like)

Description is membrane-cytoskeleton-associated protein that promotes the assembly of the spectrin-actin network and binds to calmodulin. Adducins are heteromeric proteins composed of different subunits referred to as adducin alpha, beta and gamma encoded by distinct genes and belong to a family of membrane skeletal proteins involved in the assembly of spectrin-actin network in erythrocytes and at sites of cell-cell contact in epithelial tissues. Structurally, each subunit is comprised of two distinct domains. The amino-terminal region is protease resistant and globular in shape, while the carboxy-terminal region is protease sensitive. The latter contains multiple phosphorylation sites for protein kinase C, the binding site for calmodulin, and is required for association with spectrin and actin. Alternatively spliced adducin gamma transcripts encoding different isoforms have been described. The functions of the different isoforms are not known. Expression Ubiquitous. Heart only expresses isoform 1 or a. Localisation Membrane skeleton. Function

Adducins are membrane skeletal proteins involved in the assembly of spectrin-actin network in erythrocytes and at sites of cell-cell contact in epithelial tissues. Adducin is a heterodimeric cytoskeleton protein and consists of an [alpha]-subunit (Mr 103 kDa) and either a [beta]- (Mr 97 kDa) or [gamma]-subunit (Mr 90kDa). Three genes (ADD1, ADD2, and ADD3, respectively) that map to different chromosomes encode these subunits. Adducin promotes the organization of the spectrin-actin lattice by favoring the spectrin-actin binding and controlling the rate of actin polymerization as an end-capping actin protein. Its function is calciumand calmodulin-dependent. It is phosphorylated by protein kinases A and C, tyrosine, and [rho]-kinases.10 It is a member of the myristoylated alanine-rich C kinase substrate protein family, which is involved in signal transduction, cell-to-cell contact formation, and cell migration. Non-silent polymorphisms resulting in subunits alpha and beta have been associated with the regulation of blood pressure in an animal model of hypertension.

Homology

It presents homology in various species. It also belongs to ADDUCIN protein family (3 members ADD1, ADD2 and ADD3).

Mutations Germinal

It has been shown that the interaction of ADD1 and ADD3 gene variants in humans is statistically associated with variation in blood pressure, suggesting the presence of epistatic effects among these loci.

Somatic

t(10;11)(q25;p15) 5' NUP98-ADD3 3' fusion in a T-cell acute lymphoblastic leukemia with biphenotipic characteristics (T/myeloid).


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t(10;11)(q25;p15)

Disease

T-cell acute lymphoblastic leukemia with biphenotipic characteristics (T/myeloid)

Prognosis

bad

Cytogenetics

t(10;11)(q25;p15) (cryptic)

Hybrid/Mutated 5' NUP98-ADD3 3' Gene Abnormal Protein

NUP98-ADD3

Schematic representation of the fusion NUP98-ADD3 consecuence of the t(10;11)(q25;p15) in a T-cell acute lymphoblastic leukemia with biphenotipic characteristics. From up to down: ADD3, NUP98 and the putative chimeric NUP98-ADD3 structure. FGrepeats, phenilalanine-glycine repeats; bipartite NLS, bipartite nuclear localization signal. Coiled coil domains on ADD3 and NUP98-ADD3 are indicated with asterisks.


ADD3

GDB

ADD3

Entrez_Gene

ADD3 120 adducin 3 (gamma)


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Cards Atlas

ADD3ID520ch10q25

GeneCards

ADD3

Ensembl

ADD3

CancerGene

ADD3

Genatlas

ADD3

GeneLynx

ADD3

eGenome

ADD3

euGene


GoldenPath

ADD3 - chr10:111757708-111885313 + 10q25.1 May_2004)

Ensembl

ADD3 - 10q25.1 [CytoView]

NCBI


OMIM

Disease map [OMIM]

HomoloGene

ADD3

(hg17-


Y14372 [ SRS ]

Y14372 [ ENTREZ ]

Genbank

BC021694 [ SRS ]

BC021694 [ ENTREZ ]

Genbank

BC057285 [ SRS ]

BC057285 [ ENTREZ ]

Genbank

BC062559 [ SRS ]

BC062559 [ ENTREZ ]

Genbank

BI544596 [ SRS ]

RefSeq

NM_016824 [ SRS ]


RefSeq

NM_019903 [ SRS ]


RefSeq

NT_086775 [ SRS ]


AceView

ADD3 AceView - NCBI

TRASER

ADD3 Traser - Stanford

Unigene

Hs.501012 [ SRS ]

BI544596 [ ENTREZ ]

Hs.501012 [ NCBI ]



Q9UEY8 [ SRS]

Interpro

IPR001303 Aldolase_II_N [ SRS ]

CluSTr

Q9UEY8

Pfam Blocks

Q9UEY8 [ EXPASY ]

PF00596 Aldolase_II [ SRS ] pfam00596 [ NCBI-CDD ]

Q9UEY8 [ INTERPRO ] IPR001303 Aldolase_II_N [ EBI ]

PF00596 Aldolase_II [ Sanger

]

Q9UEY8 Polymorphism : SNP, mutations, diseases

OMIM

601568

[ map ]

GENECLINICS 601568


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SNP

ADD3 [dbSNP-NCBI]

SNP

NM_016824 [SNP-NCI]

SNP

NM_019903 [SNP-NCI]

SNP

ADD3 [GeneSNPs - Utah] ADD3 [SNP - CSHL] ADD3] [HGBASE - SRS] General knowledge

Family Browser

ADD3 [UCSC Family Browser]

SOURCE

NM_016824

SOURCE

NM_019903

SMD

Hs.501012

SAGE

Hs.501012

Amigo

function|calmodulin binding

Amigo

component|cytoskeleton

Amigo

component|membrane

Amigo

function|structural constituent of cytoskeleton

PubGene

ADD3 Other databases Probes

Probe

ADD3 Related clones (RZPD - Berlin) PubMed

PubMed


Bibliography Cloning, expression and chromosome mapping of adducin-like 70 (ADDL), a human cDNA highly homologous to human erythrocyte adducin. Katagiri T, Ozaki K, Fujiwara T, Shimizu F, Kawai A, Okuno S, Suzuki M, Nakamura Y, Takahashi E, Hirai Y. Cytogenet Cell Genet 1996; 74: 90-95. Medline 8893809 A new function for adducin. Calcium/calmodulin-regulated capping of the barbed ends of actin filaments. Kuhlman PA, Hughes CA, Bennett V, Fowler VM. J Biol Chem 1996; 271(14): 7986-7991. Medline 8626479 Genomic organization of the human gamma adducin gene. Citterio L, Azzani T, Duga S, Bianchi G. Biochem Biophys Res Commun 1999; 266(1): 110-114. Medline 10581174 Adducin: structure, function and regulation.


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Matsuoka Y, Li X, Bennett V. Cell Mol Life Sci 2000; 57(6): 884-895. Medline 10950304 Hypertension-linked decrease in the expression of brain gamma-adducin. Yang H, Francis SC, Sellers K, DeBarros M, Sun C, Sumners C, Ferrario CM, Katovich MJ, Muro AF, Raizada MK. Circ Res 2002; 91(7): 633-639. Medline 12364392 NUP98 is fused to adducin 3 in a patient with T-cell acute lymphoblastic leukemia and myeloid markers, with a new translocation t(10;11)(q25;p15). Lahortiga I, Vizmanos JL, Agirre X, Vazquez I, Cigudosa JC, Larrayoz MJ, Sala F, Gorosquieta A, Perez-Equiza K, Calasanz MJ, Odero MD. Cancer Res 2003; 63(12): 3079-3083. Medline 12810632 Decrease in hypothalamic gamma adducin in rat models of hypertension. Yang H, Reaves PY, Katovich MJ, Raizada MK. Hypertension 2004; 43(2): 324-328. Medline 14732736 Adducin polymorphism: detection and impact on hypertension and related disorders. Bianchi G, Ferrari P, Staessen JA. Hypertension 2005; 45(3): 331-340. Medline 15699449 Role of the adducin family genes in human essential hypertension. Lanzani C, Citterio L, Jankaricova M, Sciarrone MT, Barlassina C, Fattori S, Messaggio E, Serio CD, Zagato L, Cusi D, Hamlyn JM, Stella A, Bianchi G, Manunta P. J Hypertens 2005; 23(3): 543-549. Medline 15716695 automatic search in PubMed REVIEW articles Last year automatic search in PubMed publications BiblioGene - INIST


032005

José Luis Vizmanos

Citation This paper should be referenced as such : Vizmanos JL . ADD3 (adducin 3). Atlas Genet Cytogenet Oncol Haematol. March Atlas Genet Cytogenet Oncol Haematol 2005; 2

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2005 . URL : http://www.infobiogen.fr/services/chromcancer/Genes/ADD3ID520ch10q25.html © Atlas of Genetics and Cytogenetics in Oncology and Haematology


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APC (adenomatous polyposis coli) Identity Hugo

APC

Location

5q21

APC (5q21) - Courtesy Mariano Rocchi, Resources for Molecular Cytogenetics. Laboratories willing to validate the probes are welcome : contact [email protected]

DNA/RNA Description

15 exons (with a particularly large 15th exon).

Transcription 9.0 kb mRNA; 8538 bp open reading frame.

Protein Description 2843 amino acids; 310 kDa. Function

APC is a classical tumour suppressor protein. The APC gene product indirectly regulates transcription of a number of critical cell proliferation genes, through its interaction with the transcription factor beta catenin. APC binding to beta catenin leads to ubiquitin-mediated beta catenin destruction; loss of APC function increases transcription of beta catenin targets. These targets include cyclin D, C-myc, ephrins and caspases. APC also interacts with numerous actin and microtubule associated proteins. APC itself stabilizes microtubules. Homozygous APC truncation has been shown to affect chromosome attachment in cultured cells. Roles for APC in cell migration have been demonstrated in vitro and in mouse models.

Mutations Germinal

Germline mutations of APC cause a spectrum of diseases under the broad category of familial adenomatous polyposis (FAP).


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Mutations typically cluster in or just distal to the armadillo repeat region and truncate the protein near its middle. It is not known which is pathophysiologic - absence of the full-length protein or presence of the truncated version; evidence exists for both. The second hit creates another truncation or gene deletion. There is some evidence that the position of the first hit in the gene determines the pattern of the second hit. Rare hypomorphic mutations cause attenuated polyposis. Somatic

Both copies of the APC gene are mutated in 80% of sporadic colorectal tumours.


Sporadic colorectal cancer.

Disease

Somatic mutation of the APC gene is found in the majority of colorectal adenocarcinomas. Sporadic colorectal cancer is the third most frequent cancer in the world.

Prognosis

The prognosis depends on the stage of the disease. Stage I lesions are usually cured by surgery . There is controversy about the use of chemotherapy in Stage II disease. In Stage III disease, chemotherapy improves the five year survival from ~50% to ~60%.

Oncogenesis Loss of normal APC function is known to be an early event in both familial and sporadic colon cancer pathogenesis, occurring at the preadenoma stage. Current discussion is focused on whether loss of APC function precedes, follows, or is entwined with chromosomal instability. Later events include abnormalities of K-ras and p53. Generally colon cancers show either chromosomal instability (CIN), which correlates with loss of APC function, or microsatellite instability (MIN), which correlates with loss of mismatch repair function, but not both.


APC

GDB

APC

Entrez_Gene

APC 324 adenomatosis polyposis coli Cards

Atlas

APC118

GeneCards

APC

Ensembl

APC

CancerGene

APC

Genatlas

APC

GeneLynx

APC

eGenome

APC


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euGene


GoldenPath

APC - 5q21 chr5:112101483-112209834 + 5q22.2 May_2004)

Ensembl

APC - 5q22.2 [CytoView]

NCBI


OMIM

Disease map [OMIM]

HomoloGene

APC

(hg17-


AF127506 [ SRS ]

AF127506 [ ENTREZ ]

Genbank

AF297219 [ SRS ]

AF297219 [ ENTREZ ]

Genbank

AY682982 [ SRS ]

AY682982 [ ENTREZ ]

Genbank

S78214 [ SRS ]

Genbank

BC056268 [ SRS ]

RefSeq

NM_000038 [ SRS ]


RefSeq

NT_086678 [ SRS ]


AceView

APC AceView - NCBI

TRASER

APC Traser - Stanford

Unigene

Hs.158932 [ SRS ]

S78214 [ ENTREZ ] BC056268 [ ENTREZ ]

Hs.158932 [ NCBI ]



P25054 [ SRS]

Prosite

PS50176 ARM_REPEAT [ SRS ]

Interpro

IPR009240 APC_15aa [ SRS ]

IPR009240 APC_15aa [ EBI ]

Interpro

IPR009234 APC_basic [ SRS ]

IPR009234 APC_basic [ EBI ]

Interpro

IPR009223 APC_crr [ SRS ]

Interpro

IPR008938 ARM [ SRS ]

Interpro

IPR000225 Armadillo [ SRS ]

Interpro

IPR009232 EB1_binding [ SRS ]

Interpro

IPR009224 SAMP [ SRS ]

CluSTr

P25054

Pfam

PF05972 APC_15aa [ SRS ] ] pfam05972 [ NCBI-CDD ]

PF05972 APC_15aa [ Sanger

PF05956 APC_basic [ SRS ] pfam05956 [ NCBI-CDD ]

PF05956 APC_basic [ Sanger

Pfam Pfam

P25054 [ EXPASY ]

P25054 [ INTERPRO ] PS50176 ARM_REPEAT [ Expasy ]

IPR009223 APC_crr [ EBI ]

IPR008938 ARM [ EBI ] IPR000225 Armadillo [ EBI ] IPR009232 EB1_binding [ EBI ]

IPR009224 SAMP [ EBI ]

]

PF05923 APC_crr [ SRS ]

PF05923 APC_crr [ Sanger ]

pfam05923 [

NCBI-CDD ]

Pfam

PF00514 Arm [ SRS ]

PF00514 Arm [ Sanger ]

Pfam

PF05937 EB1_binding [ SRS ] pfam05937 [ NCBI-CDD ] ]



PF05937 EB1_binding [ Sanger

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Pfam

PF05924 SAMP [ SRS ]

PF05924 SAMP [ Sanger ]

pfam05924 [ NCBI-CDD

]

Blocks

P25054

PDB

1DEB [ SRS ]

1DEB [ PdbSum ], 1DEB [ IMB ]

PDB

1EMU [ SRS ]

1EMU [ PdbSum ], 1EMU [ IMB ]

PDB

1JPP [ SRS ]

1JPP [ PdbSum ], 1JPP [ IMB ]

PDB

1M5I [ SRS ]

1M5I [ PdbSum ], 1M5I [ IMB ]


175100

[ map ]


APC [dbSNP-NCBI]

SNP

NM_000038 [SNP-NCI]

SNP

APC [GeneSNPs - Utah] APC [SNP - CSHL] APC] [HGBASE - SRS] General knowledge

Family Browser

APC [UCSC Family Browser]

SOURCE

NM_000038

SMD

Hs.158932

SAGE

Hs.158932

Amigo

process|Wnt receptor signaling pathway

Amigo

function|beta-catenin binding

Amigo

process|cell adhesion

Amigo

function|microtubule binding

Amigo

process|negative regulation of cell cycle

Amigo

process|protein complex assembly

Amigo


BIOCARTA

ALK in cardiac myocytes

BIOCARTA

Inactivation of Gsk3 by AKT causes accumulation of b-catenin in Alveolar Macrophages

BIOCARTA

Multi-step Regulation of Transcription by Pitx2

BIOCARTA

Presenilin action in Notch and Wnt signaling

BIOCARTA

TGF beta signaling pathway

BIOCARTA

WNT Signaling Pathway

PubGene

APC Other databases Probes

Probe

Cancer Cytogenetics (Bari)

Probe

APC Related clones (RZPD - Berlin) PubMed


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PubMed


Bibliography Identification and characterization of theTITLE familial adenomatous polyposis coli gene. Groden J, Thliveris A, Samowitz W, Carlson M, Gelbert L, Albertsen H, Joslyn G, Stevens J, Spirio L, Robertson M, Sargeant L, Krapcho K, Wolff E, Burt R, Hughes JP, Warrington J, McPherson J, Wasmuth J, Le Paslier D, Abderrahim H, Cohen D, Leppert M, White R. Cell 1991; 66: 589-600. Medline 91330306 Mutations of chromosome 5q21 genes in FAP and colorectal cancer patients. Nishisho I, Nakamura Y, Miyoshi Y, Miki Y, Ando H, Horii A, Koyama K, Utsunomiya J, Baba S, Hedge P, Markham A, Krush AJ, Petersen G, Hamilton SR, Nilbert MC, Levy DB, Bryan TM, Preisinger AC, Smith KJ, Su LK, Kinzler KW, Vogelstein B. Science 1991; 253: 665-669. Medline 91335211 APC mutations occur early during colorectal tumorigenesis. Powell SM, Zilz N, Beazer-Barclay Y, Bryan TM, Hamilton SR, Thibodeau SN, Vogelstein B, Kinzler KW. Nature 1992; 359: 235-237. Medline 92408778 Lessons from hereditary colorectal cancer. Kinzler KW, Vogelstein B. Cell 1996; 87: 159-170. Medline 97015071 Biology of the Adenomatous Polyposis Suppressor. Goss KH, Groden J. J Clin Oncol 2000; 18(9): 1967-1979. Medline 10784639 The adenomatous polyposis coli protein: the Achilles heel of the gut epithelium. Nathke IS. Annu Rev Cell Dev Biol 2004;20:337-366. Medline 15473844 automatic search in PubMed REVIEW articles Last year automatic search in PubMed publications BiblioGene - INIST

Contributor(s)


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Written

041998

Richard Hamelin

Updated

032005

Jennifer Tirnauer

Citation This paper should be referenced as such : Hamelin P . APC (adenomatous polyposis coli). Atlas Genet Cytogenet Oncol Haematol. April 1998 . URL : http://www.infobiogen.fr/services/chromcancer/Genes/APC118.html Tirnauer J . APC (adenomatous polyposis coli). Atlas Genet Cytogenet Oncol Haematol. March 2005 . URL : http://www.infobiogen.fr/services/chromcancer/Genes/APC118.html © Atlas of Genetics and Cytogenetics in Oncology and Haematology


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GLI1 (glioma-associated oncogene homolog 1) Identity Note

Other names

GLI1 was the first human member of the KrŸppel zinc finger proteins to be identified, and constitutes the archetype of this family of human genes. Other members are GLI2 (2q14) and GLI3 (7p13). GLI4/HKR4 (8q24) was misclassified as member of the human GLI gene family. GLI Zinc finger protein GLI1 (glioma-associated oncogene) Oncogene GLI Glioma-associated oncogene homolog 1

Hugo

GLI1

Location

12q13.2-14.1. Telomeric to the ATF1 gene; centromeric to the OS-9, SAS and CDK4 genes.

DNA/RNA

Genomic organization of the GLI1 gene.

Description

12 exons, spans approximately 12 kb of genomic DNA in the centromere-totelomere orientation. The translation initiation codon is located to exon 2, and the stop codon to exon 12.

Transcription mRNA of 3.6 kb

Protein Description The open reading frame encodes a 1106 amino acid protein, with an estimated molecular weight of approximately 118 kDa. The protein contains five DNA-binding zinc fingers between amino acids 235 and 393 (encoded by exons 7-10), and a transactivating domain constituted by amino acids 1020-1091 (encoded by exon 12).


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Expression GLI proteins function as direct effectors of sonic hedgehog-signaling during embryogenesis. GLI1 (also GLI2 and GLI3) are therefore likely to be involved in the tissue-specific proliferation of the central nervous system, the zones of polarizing activity in the developing limb, and of the gut. In the adult human, GLI1 expression has been demonstrated in the testes, myometrium and Fallopian tubes. Localisation Nuclear. Might be fluctuating between the cytoplasm and the nucleus. Function

DNA-binding transcription factor

Mutations Germinal

An abnormal activity of GLI, caused by mutations affecting upstream components of the sonic hedgehog-signaling pathway (sonic hedgehog, patched or smoothened) are associated with developmental disorders.

Somatic

Various tumors of mesenchymal and lymphocytic origin.

Implicated in Note

Rearrangement and fusion of the GLI1 gene.

Disease


Prognosis

Benign or low-malignant

Cytogenetics

t(7;12)(p22;q13)

Representative G-banded partial karyotype of the t(7;12)(p22;q13).

Hybrid/Mutated ACTB-GLI1 fusion gene. The breakpoints reported so far have been Gene located to introns 1, 2 or 3 within the ACTB gene, and to introns 5 or 6 or to exon 7 within the GLI1 gene. Reciprocal GLI1-ACTB gene fusions have also been detected. The breakpoints have been located to introns 5 or 7 within the GLI1 gene, and to intron 3 of the ACTB gene. Abnormal Protein

The ACTB-GLI1 fusion protein contains the N-terminal of ACTB and the C-terminal of GLI1, including the DNA-binding zinc finger motifs


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(encoded by exons 7-10) and transactivating motifs (exon 12). Oncogenesis

It is suggested that the strong ACTB promoter causes an overexpression of GLI1 sequences important for transcriptional activation of downstream target genes, akin to the oncogenic mechanisms of the COL1A1-PDGFB fusion gene detected in dermatofibrosarcoma protuberans.

Note

Amplification of the GLI1 gene

Disease

Glioma, B-cell lymphoma, sarcoma

Prognosis

Depends on tumor type

Oncogenesis

Overexpression of GLI1 sequences. Might be of prognostic importance.


GLI1

GDB

GLI1

Entrez_Gene

GLI1 2735 glioma-associated oncogene homolog 1 (zinc finger protein) Cards

Atlas

GLIID310ch12q13

GeneCards

GLI1

Ensembl

GLI1

Genatlas

GLI1

GeneLynx

GLI1

eGenome

GLI1

euGene


GoldenPath

GLI1 -

chr12:56140201-56152312 + 12q13.3

Ensembl

GLI1 - 12q13.3 [CytoView]

NCBI


OMIM

Disease map [OMIM]

HomoloGene

GLI1

(hg17-May_2004)


AF316573 [ SRS ]

AF316573 [ ENTREZ ]

Genbank

BC013000 [ SRS ]

BC013000 [ ENTREZ ]

Genbank

X07384 [ SRS ]

RefSeq

NM_005269 [ SRS ]


RefSeq

NT_086796 [ SRS ]


X07384 [ ENTREZ ]


-241-

AceView

GLI1 AceView - NCBI

TRASER

GLI1 Traser - Stanford

Unigene

Hs.436288 [ SRS ]

Hs.436288 [ NCBI ]



P08151 [ SRS]

Prosite

PS00028 ZINC_FINGER_C2H2_1 [ SRS ] ZINC_FINGER_C2H2_1 [ Expasy ]

PS00028

Prosite

PS50157 ZINC_FINGER_C2H2_2 [ SRS ] ZINC_FINGER_C2H2_2 [ Expasy ]

PS50157

Interpro

IPR007087 Znf_C2H2 [ SRS ]

CluSTr

P08151

Pfam

P08151 [ EXPASY ]

PF00096 zf-C2H2 [ SRS ]

P08151 [ INTERPRO ]

IPR007087 Znf_C2H2 [ EBI ]

PF00096 zf-C2H2 [ Sanger ]

pfam00096 [

NCBI-CDD ]

Smart

SM00355 ZnF_C2H2 [EMBL]

Prodom

PD000003 Znf_C2H2[INRA-Toulouse]

Prodom

P08151 GLI1_HUMAN [ Domain structure ] P08151 GLI1_HUMAN

Blocks

P08151

PDB

2GLI [ SRS ]

[ sequences

sharing at least 1 domain ]

2GLI [ PdbSum ], 2GLI [ IMB ]


165220

[ map ]


GLI1 [dbSNP-NCBI]

SNP

NM_005269 [SNP-NCI]

SNP

GLI1 [GeneSNPs - Utah] GLI1 [SNP - CSHL] GLI1] [HGBASE - SRS] General knowledge

Family Browser

GLI1 [UCSC Family Browser]

SOURCE

NM_005269

SMD

Hs.436288

SAGE

Hs.436288

Amigo

function|DNA binding

Amigo

function|RNA polymerase II transcription factor activity

Amigo

process|development

Amigo

component|nucleus

Amigo

process|regulation of smoothened signaling pathway

Amigo

process|regulation of transcription from Pol II promoter

Amigo


Amigo

function|zinc ion binding

BIOCARTA

Sonic Hedgehog (Shh) Pathway


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PubGene

GLI1 Other databases Probes

Probe

probes 181L23 (AC022506) and 772E1 (AC063917) spanning the GLI1 locus.

Probe

GLI1 Related clones (RZPD - Berlin) PubMed

PubMed


Bibliography Identification of an amplified, highly expressed gene in a human glioma. Kinzler KW, Bigner SH, Bigner DD, Trent JM, Law ML, O'Brien SJ, Wong AJ, Vogelstein B. Science 1987; 236: 70-73. Medline 3563490 The GLI gene is a member of the Kruppel family of zinc finger proteins. Kinzler KW, Ruppert JM, Bigner SH, Vogelstein B. Nature 1988; 332: 371-374. Medline 2832761 In situ hybridization localizes the human putative oncogene GLI to chromosome subbands 12q13.3-14.1. Arheden K, Ronne M, Mandahl N, Heim S, Kinzler KW, Vogelstein B, Mitelman F. Hum Genet 1989; 82: 1-2. Medline 2497059 Amplification of the gli gene in childhood sarcomas. Roberts WM, Douglass EC, Peiper SC, Houghton PJ, Look AT. Cancer Res 1989; 49: 5407-5413. Medline 2766305 The GLI gene encodes a nuclear protein which binds specific sequences in the human genome. Kinzler KW, Vogelstein B. Mol Cell Biol 1990; 10: 634-642. Medline 2105456 GLI3 encodes a 190-kilodalton protein with multiple regions of GLI similarity. Ruppert JM, Vogelstein B, Arheden K, Kinzler KW. Mol Cell Biol 1990; 10: 5408-5415. Medline 2118997 Assignment of the gene encoding human Kruppel-related zinc finger protein 4 (GLI4) to 8q24.3 by fluorescent in situ hybridization.


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Kas K, Wlodarska I, Meyen E, Van den Berghe H, Van de Ven WJ. Cytogenet Cell Genet 1996; 72: 297-298. Medline 8641133 Assignment of the human GLI2 gene to 2q14 by fluorescence in situ hybridization. Matsumoto N, Fujimoto M, Kato R, Niikawa N. Genomics 1996; 36: 220-221. Medline 8812445 Deregulation of the platelet-derived growth factor B-chain via fusion with the collagen gene COL1A1 in dermatofibrosarcoma protuberans. Simon MP, Pedeutour F, Sirvent N, Grosgeorge J, Minoletti F, Coindre J-M, TerrierLacombe MJ, Mandahl N, Craver RD, Blin N, Sozzi G, Turc-Carel C, O«Brien K, Kedra D, Fransson I, Guilbaud C, Dumanski JP. Nat Genet 1997; 15: 95-98 Medline 8988177 High-level DNA amplifications are common genetic aberrations in B-cell neoplasms. Werner CA, Dohner H, Joos S, Trumper LH, Baudis M, Barth TF, Ott G, Moller P, Lichter P, Bentz M. Am J Pathol 1997; 151: 335-342. Medline 9250147 Characterization of the promoter region and genomic organization of GLI, a member of the Sonic hedgehog-Patched signaling pathway. Liu CZ, Yang JT, Yoon JW, Villavicencio E, Pfendler K, Walterhouse D, Iannaccone P. Gene 1998; 209: 1-11. Medline 9524201 Expression of the Sonic hedgehog (SHH ) gene during early human development and phenotypic expression of new mutations causing holoprosencephaly. Odent S, Atti-Bitach T, Blayau M, Mathieu M, Aug J, Delezo de AL, Gall JY, Le Marec B, Munnich A, David V, Vekemans M. Hum Mol Genet 1999; 8: 1683-1689. Medline 10441331 The sonic hedgehog-patched-gli pathway in human development and disease. Villavicencio EH, Walterhouse DO, Iannaccone PM. Am J Hum Genet 2000; 67: 1047-1054. Medline 11001584 Activation of the GLI oncogene through fusion with the beta-actin (ACTB) gene


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in a group of distinctive pericytic neoplasms: Òpericytoma with t(7;12)Ó. DahlŽn A, Fletcher CDM, Mertens F, Fletcher JA, Perez-Atayde AR, Hicks MJ, Debiec-Rychter M, Sciot R, Wejde J, Wedin R, Mandahl N, Panagopoulos I. Am J Pathol 2004; 164: 1645-1653 Medline 15111311 Molecular genetic characterization of the ACTB-GLI fusion in pericytoma with t(7;12). DahlŽn A, Mertens F, Mandahl N, Panagopoulos I. Biochem Biophys Res Commun 2004; 325: 1318-1323. Medline 15555571 automatic search in PubMed REVIEW articles Last year automatic search in PubMed publications BiblioGene - INIST


032005


Citation This paper should be referenced as such : Dahlén A, Mertens F, Mandahl N, Panagopoulos I . GLI1 (glioma-associated oncogene homolog 1). Atlas Genet Cytogenet Oncol Haematol. March 2005 . URL : http://www.infobiogen.fr/services/chromcancer/Genes/GLIID310ch12q13.html © Atlas of Genetics and Cytogenetics in Oncology and Haematology


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NKX2-5 (NK2 transcription factor related, locus 5 (Drosophila). Identity Other names

CSX CSX1 NKX2E Hs.54473 NM_004387 cardiac-specific homeobox

Hugo

NKX2-5

Location

5q35.2 cen--- BNIP1---NKX2-5--- STC2---tel

DNA/RNA

The gene for NKX2-5 comprizes two exons of 510 and 1075 bp, respectively. The length of the intron is 1540 bp. Positions of start and stop codons are indicated. These data refer to ENSEMBL transcript

Description

The gene has two exons and one intron.

Transcription Transcription takes place in a telomere --> centromere orientation. The length of the processed mRNA is about 1500 bp. Pseudogene Not known

Protein


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Figure shows mutations causing various cardiac anomalies. NKX2-5 contains two exons encoding a 324-amino acid protein including a tinman domain (TN), homeodomain (black) and an NK2 domain. Truncation mutations are shown above, missense mutations below. ? indicates deletion of the intron 1 splice donor site. Note clustering of mutations within the homeobox itself.

Description 324 amino acids; 35-38 kDa, depending on phosphorylation status; contains one TN domain (residues 10-21), one homeodomain (residues 138-197), and one NK2 domain (residues 212-234). Expression Expression is mainly restricted to the heart. But during embryogenesis NKX2-5 expression has also been detected in spleen-precursor cells. Localisation Cytoplasmatic and nuclear, probably depending on phosphorylation status Function

Involved in differentiation processes in heart development and in homeostasis and survival of cardiac myocytes.

Homology

Homeodomain protein with membership of the NK2 / NKX family.

Mutations Note

Among vertebrates, NKX2-5 is the most highly conserved of the Drosophila tinman homologs and subject to transcriptional control via complex series of cis-regulatory elements both proximal and distal of the transcription unit.

Germinal

Haploinsufficiency due to loss-of-function mutations is associated with atrioventricular conduction defects and tetralogy of Fallot

Somatic

Recently identified in cardiac disease.


t(5;14)(q35;q32) in acute lymphoblastic leukaemia (ALL) and t(5;14)(q35;q11) in chronic lymphocytic leukaemia

Note

NKX2-5 lies circa 2 Mbp telomeric of TLX3 which is recurrently targeted for juxtaposition with BCL11B by t(5;14)(q35;q32) in a subset of patients (both pediatric and adult) in T-cell ALL. Studies performed on pediatric T-ALL cell lines have shown that visually identical t(5;14) rearrangements may target NKX2-5 or TLX3 . Initial data suggest that the t(5;14) variant targeting NKX2-5 is clinically rare . The clinical involvement t(5;14)/NKX2-5 has only been recently identified but has yet to be published. In addition to T-ALL, NKX2-5 rearrangement has been reported in a case


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of chronic lymphocytic leukaemia (CLL) with t(5;14)(q35;q11) where the activating partner at 14q11 is TCRA/TCRD. Prognosis

Unknown

Cytogenetics

The t(5;14) rearrangements respectively targeting NKX2-5 and TLX3 which lies about 2Mbp centromeric are cytogenetically indistinguishable in both conventionally banded and chromosome painting preparations. In addition, both sets of rearrangements are cryptic as equal and similarly banded material from chromosomes 5 and 14 are exchanged. Thus, analysis using sets of BAC clones covering both TLX3 and NKX2-5 loci is necessary to distinguish these rearrangements.

Figure shows FISH analysis of t(5;14) in the pediatric T-ALL cell line PEER using three RP11 library clones located immediately centromeric (779o18, labelled red), spanning (466h21, green) and telomeric (45g21, yellow) of NKX2-5. (See below for map.) The rearrangement may be a simple insertion or, a double translocation whereby chromosome 14 material is first translocated onto the der(5) and then returned by a nonreciprocal copying process to the der(14) accompanied by genomic material surrounding NKX2-5.


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Hybrid/Mutated No Gene Abnormal Protein Oncogenesis

No NKX2-5 is developmentally silenced in thymocytes. Formation of t(5;14) juxtaposes NKX2-5 with enhancer elements probably cognate with T-cell specific DNaseI hypersensitive sites present in the downstream regulatory region of BCL11B which plays a central role in thymic maturation. It is believed that both TLX3 and NKX2-5 are reactivated by similar mechanisms involving juxtaposition with T-cell specific regulatory regions. Structural similarities shared by NKX2-5, TLX1 and TLX3 add weight to this hypothesis.

Breakpoints

Figure shows breakpoints described in ALL cell lines with t(5;14)(q35.2;q32) which juxtaposes NKX2-5 with the downstream region of BCL11B - outer breakpoints; and in a case of CLL with t(5;14)(q35.2;q11) where the activating locus was TRD - middle breakpoint. Completion of sequencing data at the NKX2-5 locus has repositioned some of the BAC clones, allowing further refinement of the breakpoint assignments. It is now clear that known breakpoints tightly flank NKX2-5 without disrupting the transcription unit itself. Thus, NKX2-5 translocations may also involve disruption of cis-regulatory elements as has been shown for TLX1(HOX11) in t(10;14)(q24;q11) in T-ALL.


NKX2-5

GDB

NKX2-5

Entrez_Gene

NKX2-5 1482 NK2 transcription factor related, locus 5 (Drosophila) Cards

Atlas

NKX25ID42958ch5q35


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GeneCards

NKX2-5

Ensembl

NKX2-5

Genatlas

NKX2-5

GeneLynx

NKX2-5

eGenome

NKX2-5

euGene


GoldenPath

NKX2-5 - 5q35.2 chr5:172591744-172594868 - 5q35.1 May_2004)

Ensembl

NKX2-5 - 5q35.1 [CytoView]

NCBI


OMIM

Disease map [OMIM]

HomoloGene

NKX2-5

(hg17-


AB021133 [ SRS ]

AB021133 [ ENTREZ ]

Genbank

BC025711 [ SRS ]

BC025711 [ ENTREZ ]

Genbank

U34962 [ SRS ]

RefSeq

NM_004387 [ SRS ]


RefSeq

NT_086682 [ SRS ]


AceView

NKX2-5 AceView - NCBI

TRASER

NKX2-5 Traser - Stanford

Unigene

Hs.54473 [ SRS ]

U34962 [ ENTREZ ]

Hs.54473 [ NCBI ]



P52952 [ SRS]

Prosite

PS00027 HOMEOBOX_1 [ SRS ]

PS00027 HOMEOBOX_1 [ Expasy ]

Prosite

PS50071 HOMEOBOX_2 [ SRS ]

PS50071 HOMEOBOX_2 [ Expasy ]

Interpro

IPR001356 Homeobox [ SRS ]

Interpro

IPR009057 Homeodomain_like [ SRS ] Homeodomain_like [ EBI ]

CluSTr

P52952

Pfam

PF00046 Homeobox [ SRS ] ] pfam00046 [ NCBI-CDD ]

Prodom

PD000010 Homeobox[INRA-Toulouse]

Prodom Blocks

P52952 [ EXPASY ]

P52952 [ INTERPRO ]

IPR001356 Homeobox [ EBI ] IPR009057

PF00046 Homeobox [ Sanger

P52952 NKX25_HUMAN [ Domain structure ] P52952 NKX25_HUMAN

[


P52952 Polymorphism : SNP, mutations, diseases

OMIM

600584

[ map ]

GENECLINICS 600584


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SNP

NKX2-5 [dbSNP-NCBI]

SNP

NM_004387 [SNP-NCI]

SNP

NKX2-5 [GeneSNPs - Utah] NKX2-5 [SNP - CSHL] NKX2-5] [HGBASE - SRS] General knowledge

Family Browser

NKX2-5 [UCSC Family Browser]

SOURCE

NM_004387

SMD

Hs.54473

SAGE

Hs.54473

Amigo

process|development

Amigo

process|heart development

Amigo

process|negative regulation of transcription from RNA polymerase II promoter

Amigo

component|nucleus

Amigo


Amigo


Amigo

component|transcription factor complex

Amigo

function|transcriptional repressor activity

PubGene

NKX2-5 Other databases Probes

Probe

NKX2-5 Related clones (RZPD - Berlin) PubMed

PubMed


Bibliography Nkx-2.5: a novel murine homeobox gene expressed in early heart progenitor cells and their myogenic descendants. Lints TJ, Parsons LM, Hartley L, Lyons I, Harvey RP. Development 1993; 119: 419-431. Medline 7904557 NK-2 homeobox genes and heart development. Harvey RP. Dev Biol 1996; 178: 203-216 (REVIEW). Medline 8812123 Vertebrate homologs of tinman and bagpipe: roles of the homeobox genes in cardiovascular development. Tanaka M, Kasahara H, Bartunkova S, Schinke M, Komuro I, Inagaki H, Lee Y, Lyons GE, Izumo S. Dev Genet 1998; 22: 239-249


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Medline 9621431 Identification of the in vivo casein kinase II phosphorylation site within the homeodomain of the cardiac tisue-specifying homeobox gene product Csx/Nkx2.5. Kasahara H, Izumo S. Mol Cell Biol 1999; 19: 526-536. Medline 9858576 Building the heart piece by piece: modularity of cis-elements regulating Nkx2-5 transcription. Schwartz RJ, Olson EN. Development 1999; 26: 4187-4192 (REVIEW). Medline 10477287 Atrial form and function: lessons from human molecular genetics. Hatcher CJ, Kim MS, Basson CT. Trends Cardiovasc Med 2000; 10: 93-101. (REVIEW). Medline 11428001 Embryonic origins of spleen asymmetry. Patterson KD, Drysdale TA, Krieg PA. Development 2000; 127: 167-175. Medline 10654610 A new recurrent and specific cryptic translocation, t(5;14)(q35;q32), is associated with expression of the Hox11L2 gene in T acute lymphoblastic leukemia. Bernard OA, Busson-LeConiat M, Ballerini P, Mauchauffe M, Della Valle V, Monni R, Nguyen Khac F, Mercher T, Penard-Lacronique V, Pasturaud P, Gressin L, Heilig R, Daniel MT, Lessard M, Berger R. Leukemia 2001; 15: 1495-1504 Medline 11587205 t(5;14)/HOX11L2-positive T-cell acute lymphoblastic leukemia. A collaborative study of the Groupe Francais de Cytogenetique Hematologique (GFCH). Berger R, Dastugue N, Busson M, Van Den Akker J, Perot C, Ballerini P, Hagemeijer A, Michaux L, Charrin C, Pages MP, Mugneret F, Andrieux J, Talmant P, Helias C, Mauvieux L, Lafage-Pochitaloff M, Mozziconacci MJ, Cornillet-Lefebvre P, Radford I, Asnafi V, Bilhou-Nabera C, Nguyen Khac F, Leonard C, Speleman F, Poppe B, Bastard C, Taviaux S, Quilichini B, Herens C, Gregoire MJ, Cave H, Bernard OA; Groupe Francais de Cytogenetique Hematologique (GFCH). Leukemia 2003; 17: 1851-1857. Medline 12970786 Activation of HOX11L2 by juxtaposition with 3'-BCL11B in an acute lymphoblastic leukemia cell line (HPB-ALL) with t(5;14)(q35;q32.2). Atlas Genet Cytogenet Oncol Haematol 2005; 2

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MacLeod RAF, Nagel S, Kaufmann M, Janssen JW, Drexler HG. Genes Chromosomes Cancer 2003; 37: 84-91. Medline 12661009 The cardiac homeobox gene NKX2-5 is deregulated by juxtaposition with BCL11B in pediatric T-ALL cell lines via a novel t(5;14)(q35.1;q32.2). Nagel S, Kaufmann M, Drexler HG, MacLeod RAF. Cancer Res 2003; 63: 5329-5334 Medline 14500364 Bcl11b is required for differentiation and survival of alphabeta T lymphocytes. Wakabayashi Y, Watanabe H, Inoue J, Takeda N, Sakata J, Mishima Y, Hitomi J, Yamamoto T, Utsuyama M, Niwa O, Aizawa S, Kominami R. Nat Immunol 2003; 4: 533-539. Medline 12717433 The functional mapping of long-range transcription control elements of the HOX11 proto-oncogene. Brake RL, Chatterjee PK, Kees UR, Watt PM. Biochem Biophys Res Commun 2004; 313: 327-335. Medline 14684164 Identifying gene regulatory elements by genome-wide recovery of DNase hypersensitive sites. Crawford GE, Holt IE, Mullikin JC, Tai D, Blakesley R, Bouffard G, Young A, Masiello C, Green ED, Wolfsberg TG, Collins FS; National Institutes Of Health Intramural Sequencing Center. Crawford GE, Holt IE, Mullikin JC, Tai D, Blakesley R, Bouffard G, Young A, Masiello C, Green ED, Wolfsberg TG, Collins FS; National Institutes Of Health Intramural Sequencing Center. Proc Natl Acad Sci U S A 2004; 101: 992-997. Medline 14732688 Function follows form: cardiac conduction system defects in Nkx2-5 mutation. Jay PY, Harris BS, Buerger A, Rozhitskaya O, Maguire CT, Barbosky LA, McCusty E, Berul CI, O'brien TX, Gourdie RG, Izumo S. Anat Rec A Discov Mol Cell Evol Biol 2004; 280: 966-972. (REVIEW). Medline 15368343 BCL11B rearrangements probably target T-cell neoplasia rather than acute myelocytic leukemia. MacLeod RAF, Nagel S, Drexler H Cancer Genet Cytogenet 2004; 153: 88-89. Medline 15325104 Novel NKX2-5 mutations in diseased heart tissues of patients with cardiac malformations.


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Reamon-Buettner SM, Hecker H, Spanel-Borowski K, Craatz S, Kuenzel E, Borlak J Am J Pathol. 2004; 164: 2117-2125. Medline 15161646 Transcriptional activation of the cardiac homeobox gene CSX1/NKX2-5. Su X, Busson M, Delabessee E, Azgui Z, Berger R, Beral HM, Bernard OA. Blood 2004; 104: 152b.(MEETING ABSTRACT). Two dual-color split signal fluorescence in situ hybridization assays to detect t(5;14) involving HOX11L2 or CSX in T-cell acute lymphoblastic leukemia. van Zutven LJ, Velthuizen SC, Wolvers-Tettero IL, van Dongen JJ, Poulsen TS, MacLeod RA, Beverloo HB, Langerak AW. Haematologica 2004; 89: 671-678. Medline 15194534 automatic search in PubMed REVIEW articles Last year automatic search in PubMed publications BiblioGene - INIST


032005

Roderick MacLeod, Stefan Nagel

Citation This paper should be referenced as such : MacLeod R, Nagel S . NKX2-5 (NK2 transcription factor related, locus 5 (Drosophila).. Atlas Genet Cytogenet Oncol Haematol. March 2005 . URL : http://www.infobiogen.fr/services/chromcancer/Genes/NKX25ID42958ch5q35.html © Atlas of Genetics and Cytogenetics in Oncology and Haematology


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SS18L1 (synovial sarcoma translocation gene on chromosome 18-like 1) Identity Other names

CREST KIAA0693 MGC26711 SYT homolog 1

Hugo

SS18L1

Location

20q13.3 chr20:60,152,245-60,190,935 (UCSC latest release: May 2004)

DNA/RNA Note

Member of the SS18 family.

Description 11 exons with similar splice sites as SS18.The promoter region lacks CAAT and TATA boxes but contains CpG islands, suggesting that SS18L1 is a housekeeping gene. Pseudogene SS18L2 (3p21)

Protein Description 396 amino acids, 42990 Da. The SS18L1 protein, similarly to the SS18 protein, exhibits two domains: a SYT N-terminal homology domain found in a wide variety of species ranging from plants to humans and the QPGY domain at the COOH-terminal part, rich in glutamine, proline, glycine, and tyrosine. The QPGY domain of the SS18 protein may activate transcription when coupled to a DNA-binding domain. Expression Ubiquitous; with lowest levels in spleen. Localisation Nuclear? Function

Calcium-responsive transactivator: CREST is a SYT -related nuclear protein that interacts with CREB-binding protein (CBP) and is expressed in the developing brain.

Homology

SS18, SS18L2


Synovial sarcoma

Prognosis

Unknown


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Cytogenetics

t(X;20)(p11;q13.3)

Hybrid/Mutated In the SS18L1/ SSX1 transcript detected in the synovial sarcoma, the Gene exon 10 of SS18L1, which corresponds to exon 10 of SS18, was fused to exon 6 of SSX1 Abnormal Protein

In the putative SS18L1/SSX1 chimeric protein, the last 8 amino acid residues of the SS18L1 protein are replaced by 78 amino acids from the COOH-terminal part of SSX1. By analogy with what is presumed to be the case for the SS18/SSX fusion protein, SS18L1/SSX1 is likely to show an altered transcriptional pattern with the COOHterminal SSX domain, redirecting the SS18L1 activation domain to new target promoters.


SS18L1

GDB

SS18L1

Entrez_Gene

SS18L1 26039 synovial sarcoma translocation gene on chromosome 18-like 1 Cards

GeneCards

SS18L1

Ensembl

SS18L1

CancerGene

SS18L1

Genatlas

SS18L1

GeneLynx

SS18L1

eGenome

SS18L1

euGene


GoldenPath

SS18L1 - 20q13.3 chr20:60152217-60190961 + 20q13.33 (hg17-May_2004)

Ensembl

SS18L1 - 20q13.33 [CytoView]

NCBI


OMIM

Disease map [OMIM]

HomoloGene

SS18L1 Gene and transcription

Genbank

AL078633 [ SRS ]

AL078633 [ ENTREZ ]

Genbank

AB014593 [ SRS ]

AB014593 [ ENTREZ ]

Genbank

AK125656 [ SRS ]

AK125656 [ ENTREZ ]

Genbank

AY203931 [ SRS ]

AY203931 [ ENTREZ ]

Genbank

BC034494 [ SRS ]

BC034494 [ ENTREZ ]

RefSeq

NM_015558 [ SRS ]



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RefSeq

NM_198935 [ SRS ]


RefSeq

NT_086910 [ SRS ]


AceView

SS18L1 AceView - NCBI

TRASER

SS18L1 Traser - Stanford

Unigene

Hs.154429 [ SRS ]

Hs.154429 [ NCBI ]



O75177 [ SRS]

O75177 [ EXPASY ]

Interpro

IPR007726 SSXT [ SRS ]

CluSTr

O75177

Pfam

PF05030 SSXT [ SRS ]

Blocks

O75177

O75177 [ INTERPRO ]

IPR007726 SSXT [ EBI ] PF05030 SSXT [ Sanger ]



606472

[ map ]


SS18L1 [dbSNP-NCBI]

SNP

NM_015558 [SNP-NCI]

SNP

NM_198935 [SNP-NCI]

SNP

SS18L1 [GeneSNPs - Utah] SS18L1 [SNP - CSHL] SS18L1] [HGBASE - SRS] General knowledge

Family Browser

SS18L1 [UCSC Family Browser]

SOURCE

NM_015558

SOURCE

NM_198935

SMD

Hs.154429

SAGE

Hs.154429

PubGene

SS18L1 Other databases Probes

Probe

SS18L1 Related clones (RZPD - Berlin) PubMed

PubMed


Bibliography Prediction of the coding sequences of unidentified human genes. X. The complete sequences of 100 new cDNA clones from brain which can code for large proteins in vitro. Ishikawa K, Nagase T, Suyama M, Miyajima N, Tanaka A, Kotani H, Nomura N, Ohara O. DNA Res 1998; 5: 169-176. Medline 9734811


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Mapping and characterization of the mouse and human SS18 genes, two human SS18-like genes and a mouse Ss18 pseudogene. de Bruijn DR, Kater-Baats E, Eleveld M, Merkx G, Geurts Van Kessel A. Cytogenet Cell Genet 2001; 92: 310-319. Medline 11435705 Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences. Strausberg RL, Feingold EA, Grouse LH, Derge JG, Klausner RD, Collins FS, Wagner L, Shenmen CM, Schuler GD, Altschul SF, Zeeberg B, Buetow KH, Schaefer CF, Bhat NK, Hopkins RF, Jordan H, Moore T, Max SI, Wang J, Hsieh F, Diatchenko L, Marusina K, Farmer AA, Rubin GM, Hong L, Stapleton M, Soares MB, Bonaldo MF, Casavant TL, Scheetz TE, Brownstein MJ, Usdin TB, Toshiyuki S, Carninci P, Prange C, Raha SS, Loquellano NA, Peters GJ, Abramson RD, Mullahy SJ, Bosak SA, McEwan PJ, McKernan KJ, Malek JA, Gunaratne PH, Richards S, Worley KC, Hale S, Garcia AM, Gay LJ, Hulyk SW, Villalon DK, Muzny DM, Sodergren EJ, Lu X, Gibbs RA, Fahey J, Helton E, Ketteman M, Madan A, Rodrigues S, Sanchez A, Whiting M, Madan A, Young AC, Shevchenko Y, Bouffard GG, Blakesley RW, Touchman JW, Green ED, Dickson MC, Rodriguez AC, Grimwood J, Schmutz J, Myers RM, Butterfield YS, Krzywinski MI, Skalska U, Smailus DE, Schnerch A, Schein JE, Jones SJ, Marra MA; Mammalian Gene Collection Program Team Proc Natl Acad Sci U S A 2002; 9: 16899-16903. Epub 2002 Dec 11. Medline 12477932 A novel fusion gene, SS18L1/SSX1, in synovial sarcoma. Storlazzi CT, Mertens F, Mandahl N, Gisselsson D, Isaksson M, Gustafson P, Domanski HA, Panagopoulos I. Genes Chromosomes Cancer 2003; 37: 195-200. Medline 12696068 Dendrite development regulated by CREST, a calcium-regulated transcriptional activator. Aizawa H, Hu SC, Bobb K, Balakrishnan K, Ince G, Gurevich I, Cowan M, Ghosh A. Science 2004; 303: 197-202. Medline 14716005 automatic search in PubMed REVIEW articles Last year automatic search in PubMed publications BiblioGene - INIST


032005

Clelia Tiziana Storlazzi, Fredrik Mertens, Ioannis Panagopoulos

Citation This paper should be referenced as such :


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Storlazzi CT, Mertens F, Panagopoulos I . SS18L1 (synovial sarcoma translocation gene on chromosome 18-like 1). Atlas Genet Cytogenet Oncol Haematol. March 2005 . URL : http://www.infobiogen.fr/services/chromcancer/Genes/SS18L1ID474ch20q13.html © Atlas of Genetics and Cytogenetics in Oncology and Haematology


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WHSC1L1 (Wolf-Hirschhorn syndrome candidate 1 like gene 1) Identity Other names

NSD3 (Nuclear receptor-binding, su(var), enhancer-of-zeste and trithorax domain-containing protein 3).

Hugo

WHSC1L1

Location

8p11.2 WHSC1L1/NSD3 is 30 kb more telomeric than FGFR1 .

DNA/RNA Description

The gene spans 127 kb on minus strand.

Transcription 2 major transcripts: a short transcript ending after an alternative exon 10b (3995 bp), and a long form from exon 1 to 24 (5428 bp).

Protein Description The long transcript encodes a 1437 aminonacids protein (162 kDa) containing from N-term to C-term: a PWWP (proline-tryptophantryptophan-proline) domain, 4 PHD (plant-home domain)- type zinc finger motifs, a second PWWP domain, a SET associated cystein rich domain (SAC), a SET domain, a fifth PHD,and a Cys-His rich domain. The short transcript encodes a 645 amino acids protein (73 kDa) containing only the N-term t PWWP domain. Expression wide. Localisation putative nuclear location. Function

may have a regulatory role.

Homology

NSD1, WHSC1/NSD2 .

Mutations Somatic

a hybrid gene involving WHSC1L1/NSD3 was found in a rare leukemia subtype (see below); amplification of a region containing WHSC1L1/NSD3 was found in a subset of breast cancers (but it remains to be determined which gene, within an amplicon, is the critical gene).


t(8;11)(p11;p15) Acute non lymphocytic leukemia with WHSC1L1/NSD3 - NUP98 .

Prognosis

yet unknown: only 1 case with a proven hybrid gene 5' NUP98 - 3'


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NSD3; 2 other possible cases, but other genes may also be involved.

To be noted This region in 8p11.2 seems to be derived from a duplication of 4p16.3 with similar genes WHSC1L1, FGFR1, and TACC1 in 8p11 from pter, and TACC3, FGFR3, and WHSC1 in 4p16 from pter


WHSC1L1

GDB

WHSC1L1

Entrez_Gene

WHSC1L1 54904 Wolf-Hirschhorn syndrome candidate 1-like 1 Cards

Atlas

WHSC1L1NSD3ID42810ch8p11

GeneCards

WHSC1L1

Ensembl

WHSC1L1

CancerGene

WHSC1L1

Genatlas

WHSC1L1

GeneLynx

WHSC1L1

eGenome

WHSC1L1

euGene


GoldenPath

WHSC1L1 - 8p11.2 chr8:38293092-38358947 - 8p12 May_2004)

Ensembl

WHSC1L1 - 8p12 [CytoView]

NCBI


OMIM

Disease map [OMIM]

HomoloGene

WHSC1L1

(hg17-


AF255649 [ SRS ]

AF255649 [ ENTREZ ]

Genbank

AF318339 [ SRS ]

AF318339 [ ENTREZ ]

Genbank

AF332468 [ SRS ]

AF332468 [ ENTREZ ]

Genbank

AF332469 [ SRS ]

AF332469 [ ENTREZ ]

Genbank

AJ295990 [ SRS ]

AJ295990 [ ENTREZ ]

RefSeq

NM_017778 [ SRS ]


RefSeq

NM_023034 [ SRS ]


RefSeq

NT_086740 [ SRS ]


AceView

WHSC1L1 AceView - NCBI

TRASER

WHSC1L1 Traser - Stanford


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Unigene

Hs.32099 [ SRS ]

Hs.32099 [ NCBI ]



Q9BYU9 [ SRS]

Prosite

PS50868 POST_SET [ SRS ]

Prosite

PS50812 PWWP [ SRS ]

Prosite

PS50280 SET [ SRS ]

Prosite

PS01359 ZF_PHD_1 [ SRS ]

PS01359 ZF_PHD_1 [ Expasy ]

Prosite

PS50016 ZF_PHD_2 [ SRS ]

PS50016 ZF_PHD_2 [ Expasy ]

Interpro

IPR006560 AWS [ SRS ]

Interpro

IPR003616 PostSET [ SRS ]

Interpro

IPR000313 PWWP [ SRS ]

Interpro

IPR001214 SET [ SRS ]

Interpro

IPR001965 Znf_PHD [ SRS ]

Interpro

IPR001841 Znf_ring [ SRS ]

CluSTr

Q9BYU9

Pfam

PF00628 PHD [ SRS ]

Pfam

Q9BYU9 [ EXPASY ]

Q9BYU9 [ INTERPRO ]

PS50868 POST_SET [ Expasy ]

PS50812 PWWP [ Expasy ]

PS50280 SET [ Expasy ]

IPR006560 AWS [ EBI ] IPR003616 PostSET [ EBI ] IPR000313 PWWP [ EBI ]

IPR001214 SET [ EBI ] IPR001965 Znf_PHD [ EBI ] IPR001841 Znf_ring [ EBI ]

PF00628 PHD [ Sanger ]

PF00855 PWWP [ SRS ]


PF00855 PWWP [ Sanger ]

pfam00855 [ NCBI-

CDD ]

Pfam

PF00856 SET [ SRS ]

PF00856 SET [ Sanger ]

Smart

SM00570 AWS [EMBL]

Smart

SM00249 PHD [EMBL]

Smart

SM00508 PostSET [EMBL]

Smart

SM00293 PWWP [EMBL]

Smart

SM00184 RING [EMBL]

Smart

SM00317 SET [EMBL]

Blocks

Q9BYU9



607083

[ map ]


WHSC1L1 [dbSNP-NCBI]

SNP

NM_017778 [SNP-NCI]

SNP

NM_023034 [SNP-NCI]

SNP

WHSC1L1 [GeneSNPs - Utah] WHSC1L1 [SNP - CSHL] WHSC1L1] [HGBASE - SRS] General knowledge

Family Browser

WHSC1L1 [UCSC Family Browser]

SOURCE

NM_017778

SOURCE

NM_023034

SMD

Hs.32099


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SAGE

Hs.32099

Amigo

function|DNA binding

Amigo

process|cell differentiation

Amigo

process|cell growth

Amigo

component|nucleus

Amigo


Amigo

process|protein ubiquitination

Amigo

process|regulation of transcription, DNA-dependent

Amigo

component|ubiquitin ligase complex

Amigo

function|ubiquitin-protein ligase activity

Amigo

function|zinc ion binding

PubGene

WHSC1L1 Other databases Probes

Probe

WHSC1L1 Related clones (RZPD - Berlin) PubMed

PubMed


Bibliography NSD3, a new SET domain-containing gene, maps to 8p12 and is amplified in human breast cancer cell lines. Angrand PO, Apiou F, Stewart AF, Dutrillaux B, Losson R, Chambon P. Genomics 2001; 74: 79-88. Medline 11374904 WHSC1L1, on human chromosome 8p11.2, closely resembles WHSC1 and maps to a duplicated region shared with 4p16.3. Stec I, van Ommen GJ, den Dunnen JT. Genomics 2001; 76: 5-8. Medline 11549311 NUP98 is fused to the NSD3 gene in acute myeloid leukemia associated with t(8;11)(p11.2;p15). Rosati R, La Starza R, Veronese A, Aventin A, Schwienbacher C, Vallespi T, Negrini M, Martelli MF, Mecucci C. Blood. 2002; 99: 3857-3860. Medline 11986249 automatic search in PubMed REVIEW articles Last year automatic search in PubMed publications BiblioGene - INIST

Contributor(s) Atlas Genet Cytogenet Oncol Haematol 2005; 2

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Written

032005

Jean Loup Huret

Citation This paper should be referenced as such : Huret JL . WHSC1L1 (Wolf-Hirschhorn syndrome candidate 1 like gene 1). Atlas Genet Cytogenet Oncol Haematol. March 2005 . URL : http://www.infobiogen.fr/services/chromcancer/Genes/WHSC1L1NSD3ID42810ch8p11.html © Atlas of Genetics and Cytogenetics in Oncology and Haematology


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WISP3 (WNT-1 inducible signaling pathway protein 3) Identity Other names

PPD CCN6 LIBC PPAC Wnt1 signaling pathway protein 3

Hugo

WISP3

Location

6q22-q23

DNA/RNA Description

5 exons spanning 967kb of genomic

Transcription Alternative splicing generates at least three transcript variants, their sizes are 1212bp, 1307 bp and 1068 bp

Protein

Description WISP3 contains four conserved cysteine-rich domains: insulin-like growth factor-binding domain, von Willebrand factor type C module, thrombospondin domain and C-terminal cystine knot-like domain. It has three isoforms: 1) variant 1, 354 aa, 39292 Da; 2) variant 2, 331 aa, This variant differs from variant 1 in two regions. It has an alternate 5' end which results in a different N-terminus. It also uses two alternative donor and acceptor sites in the middle coding region which result in a few internal aa differences between variant 1 and 2. 3) variant 3, 372 aa, This variant differs in the 5' UTR and CDS, compared to variant 1. The resulting protein is longer and has a distinct N-terminus, compared to variant 1. Expression Predominant expression in adult kidney and testis and fetal kidney. Weaker expression found in placenta, ovary, prostate and small Atlas Genet Cytogenet Oncol Haematol 2005; 2

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intestine. Also expressed in skeletally-derived cells such as synoviocytes and articular cartilage chondrocytes. Localisation Secreted (Probable). Function

It is a member of the WNT1 inducible signaling pathway (WISP) protein subfamily, which belongs to the connective tissue growth factor (CTGF) family and may be downstream in the WNT1 signaling pathway that is relevant to malignant transformation. It is over-expressed in colon tumors. It is essential for normal postnatal skeletal growth and cartilage homeostasis. It acts as a putative growth regulator contributing to the inflammatory breast cancer by regulating tumor cell growth, invasion and angiogenesis.

Homology

Wnt1-inducible signaling proteins

Mutations Germinal

Various types of mutations have been described, dispersed throughout the gene, including nucleotide substitutions, small deletions and small insertions. There are patients who are compound heterozygous, heterozygous or homozygous. The mutations cause progressive pseudorheumatoid dysplasia.

Somatic

Somatic mutations that cause reading frameshifts at a polyadenosine tract within the WISP3 coding sequence have been observed at higherthan-expected rates in gastrointestinal tumors from patients with mutations in the mismatch repair pathway.


Arthropathy, progressive pseudorheumatoid, of childhood

Disease

Mutations in the WISP3 gene result in an arthropathy of childhood beginning at about age 3-8. Usually several joints were affected with pain and soft tissue swelling. The proximal interphalangeal joints of the hand were most commonly affected and the hips and elbows next most often involve

Entity

Inflammatory breast cancer

Oncogenesis Loss of WISP3 is one of the key genetic alterations in the development of IBC. Entity

Rheumatoid arthritis

Entity

Colon cancer

Oncogenesis Frameshifts, non-sense mutations and non-synonymous changes involving cysteines or affect a splice-donor site.

External links Nomenclature


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Hugo

WISP3

GDB

WISP3

Entrez_Gene

WISP3 8838 WNT1 inducible signaling pathway protein 3 Cards

GeneCards

WISP3

Ensembl

WISP3

CancerGene

WISP3

Genatlas

WISP3

GeneLynx

WISP3

eGenome

WISP3

euGene


GoldenPath

WISP3 -

chr6:112481971-112497584 + 6q21

Ensembl

WISP3 - 6q21 [CytoView]

NCBI


OMIM

Disease map [OMIM]

HomoloGene

WISP3

(hg17-May_2004)


AL512299 [ SRS ]

AL512299 [ ENTREZ ]

Genbank

AB075040 [ SRS ]

AB075040 [ ENTREZ ]

Genbank

AF100781 [ SRS ]

AF100781 [ ENTREZ ]

Genbank

AF143679 [ SRS ]

AF143679 [ ENTREZ ]

Genbank

AY358349 [ SRS ]

AY358349 [ ENTREZ ]

RefSeq

NM_003880 [ SRS ]


RefSeq

NM_130396 [ SRS ]


RefSeq

NM_198239 [ SRS ]


RefSeq

NT_086697 [ SRS ]


AceView

WISP3 AceView - NCBI

TRASER

WISP3 Traser - Stanford

Unigene

Hs.549081 [ SRS ]

Hs.549081 [ NCBI ]



O95389 [ SRS]

O95389 [ EXPASY ]

O95389 [ INTERPRO ]

Prosite

PS01185 CTCK_1 [ SRS ]

PS01185 CTCK_1 [ Expasy ]

Prosite

PS01225 CTCK_2 [ SRS ]

PS01225 CTCK_2 [ Expasy ]

Prosite

PS00222 IGF_BINDING [ SRS ]

Prosite

PS50092 TSP1 [ SRS ]

Interpro

IPR006208 Cys_knot [ SRS ]

Interpro

IPR006207 Cys_knot_C [ SRS ]

PS00222 IGF_BINDING [ Expasy ]

PS50092 TSP1 [ Expasy ]


IPR006208 Cys_knot [ EBI ] IPR006207 Cys_knot_C [ EBI ]

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Interpro

IPR000867 Insl_gro_fac_pr [ SRS ]

Interpro

IPR000884 TSP1 [ SRS ]

CluSTr

O95389

Pfam Pfam Pfam

IPR000867 Insl_gro_fac_pr [ EBI ]

IPR000884 TSP1 [ EBI ]

PF00007 Cys_knot [ SRS ]

PF00007 Cys_knot [ Sanger ]

pfam00007 [

NCBI-CDD ]

PF00219 IGFBP [ SRS ]

PF00219 IGFBP [ Sanger ]

pfam00219 [ NCBI-

PF00090 TSP_1 [ Sanger ]

pfam00090 [ NCBI-

CDD ]

PF00090 TSP_1 [ SRS ] CDD ]

Smart

SM00041 CT [EMBL]

Smart

SM00121 IB [EMBL]

Smart

SM00209 TSP1 [EMBL]

Blocks

O95389 Polymorphism : SNP, mutations, diseases

OMIM

603400

[ map ]


WISP3 [dbSNP-NCBI]

SNP

NM_003880 [SNP-NCI]

SNP

NM_130396 [SNP-NCI]

SNP

NM_198239 [SNP-NCI]

SNP

WISP3 [GeneSNPs - Utah] WISP3 [SNP - CSHL] WISP3] [HGBASE - SRS] General knowledge

Family Browser

WISP3 [UCSC Family Browser]

SOURCE

NM_003880

SOURCE

NM_130396

SOURCE

NM_198239

SMD

Hs.549081

SAGE

Hs.549081

Amigo

process|cell-cell signaling

Amigo

component|extracellular region

Amigo

function|growth factor activity

Amigo

function|insulin-like growth factor binding

Amigo

process|regulation of cell growth

Amigo


Amigo

component|soluble fraction

PubGene

WISP3 Other databases Probes

Probe

WISP3 Related clones (RZPD - Berlin)


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PubMed PubMed


Bibliography WISP genes are members of the connective tissue growth factor family that are up-regulated in wnt-1-transformed cells and aberrantly expressed in human colon tumors. Pennica D, Swanson TA, Welsh JW, Roy MA, Lawrence DA, Lee J, Brush J, Taneyhill LA, Deuel B, Lew M, Watanabe C, Cohen RL, Melhem MF, Finley GG, Quirke P, Goddard AD, Hillan KJ, Gurney AL, Botstein D, Levine AJ. Proc Natl Acad Sci USA 1998; 95: 14717-1422. Medline 9843955 Mutations in the CCN gene family member WISP3 cause progressive pseudorheumatoid dysplasia. Hurvitz JR, Suwairi WM, Van Hul W, El-Shanti H, Superti-Furga A, Roudier J, Holderbaum D, Pauli RM, Herd JK, Van Hul EV, Rezai-Delui H, Legius E, Le Merrer M, Al-Alami J, Bahabri SA, Warman ML. Nat Genet 1999; 23: 94-98. Medline 10471507 A novel putative low-affinity insulin-like growth factor-binding protein, LIBC (lost in inflammatory breast cancer), and RhoC GTPase correlate with the inflammatory breast cancer phenotype. van Golen KL, Davies S, Wu ZF, Wang Y, Bucana CD, Root H, Chandrasekharappa S, Strawderman M, Ethier SP, Merajver SD. Clin Cancer Res 1999; 5: 2511-2519. Medline 10499627 WNT1 inducible signaling pathway protein 3, WISP-3, a novel target gene in colorectal carcinomas with microsatellite instability. Thorstensen L, Diep CB, Meling GI, Aagesen TH, Ahrens CH, Rognum TO, Lothe RA. Gastroenterology 2001; 121: 1275-1280. Medline 11729105 WISP3 is a novel tumor suppressor gene of inflammatory breast cancer. Kleer CG, Zhang Y, Pan Q, van Golen KL, Wu ZF, Livant D, Merajver SD. Oncogene 2002; 21: 3172-3180. Medline 12082632 Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences. Strausberg RL, Feingold EA, Grouse LH, Derge JG, Klausner RD, Collins FS, Wagner L, Shenmen CM, Schuler GD, Altschul SF, Zeeberg B, Buetow KH, Schaefer CF, Bhat NK, Hopkins RF, Jordan H, Moore T, Max SI, Wang J, Hsieh F, Diatchenko L, Marusina K, Farmer AA, Rubin GM, Hong L, Stapleton M, Soares MB, Bonaldo


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MF, Casavant TL, Scheetz TE, Brownstein MJ, Usdin TB, Toshiyuki S, Carninci P, Prange C, Raha SS, Loquellano NA, Peters GJ, Abramson RD, Mullahy SJ, Bosak SA, McEwan PJ, McKernan KJ, Malek JA, Gunaratne PH, Richards S, Worley KC, Hale S, Garcia AM, Gay LJ, Hulyk SW, Villalon DK, Muzny DM, Sodergren EJ, Lu X, Gibbs RA, Fahey J, Helton E, Ketteman M, Madan A, Rodrigues S, Sanchez A, Whiting M, Madan A, Young AC, Shevchenko Y, Bouffard GG, Blakesley RW, Touchman JW, Green ED, Dickson MC, Rodriguez AC, Grimwood J, Schmutz J, Myers RM, Butterfield YS, Krzywinski MI, Skalska U, Smailus DE, Schnerch A, Schein JE, Jones SJ, Marra MA; Mammalian Gene Collection Program Team Proc Natl Acad Sci U S A. 2002; 99: 16899-16903. Medline 12477932 Variant WISPs as targets for gastrointestinal carcinomas. Tanaka S, Sugimachi K, Shimada M, Maehara Y, Sugimachi K. Gastroenterology 2002; 123: 392-393. Medline 12105881 The secreted protein discovery initiative (SPDI), a large-scale effort to identify novel human secreted and transmembrane proteins: a bioinformatics assessment. Clark HF, Gurney AL, Abaya E, Baker K, Baldwin D, Brush J, Chen J, Chow B, Chui C, Crowley C, Currell B, Deuel B, Dowd P, Eaton D, Foster J, Grimaldi C, Gu Q, Hass PE, Heldens S, Huang A, Kim HS, Klimowski L, Jin Y, Johnson S, Lee J, Lewis L, Liao D, Mark M, Robbie E, Sanchez C, Schoenfeld J, Seshagiri S, Simmons L, Singh J, Smith V, Stinson J, Vagts A, Vandlen R, Watanabe C, Wieand D, Woods K, Xie MH, Yansura D, Yi S, Yu G, Yuan J, Zhang M, Zhang Z, Goddard A, Wood WI, Godowski P, Gray A. Genome Res 2003; 13: 2265-2270. Erratum in: Genome Res 2003; 13: 2759. Medline 12975309 WISP3 (CCN6) is a secreted tumor-suppressor protein that modulates IGF signaling in inflammatory breast cancer. Kleer CG, Zhang Y, Pan Q, Merajver SD. Neoplasia 2004; 6: 179-185. Medline 15140407 WISP3-dependent regulation of type II collagen and aggrecan production in chondrocytes. Sen M, Cheng YH, Goldring MB, Lotz MK, Carson DA. Arthritis Rheum 2004; 50: 488-449 Medline 14872491 automatic search in PubMed REVIEW articles Last year automatic search in PubMed publications BiblioGene - INIST


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032005

Celina G Kleer, Lei Ding

Citation This paper should be referenced as such : Kleer CG, Ding L . WISP3 (WNT-1 inducible signaling pathway protein 3). Atlas Genet Cytogenet Oncol Haematol. March 2005 . URL : http://www.infobiogen.fr/services/chromcancer/Genes/WISP3ID469ch6q22.html © Atlas of Genetics and Cytogenetics in Oncology and Haematology


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i(5)(p10) in acute myeloid leukemia Identity Note

The isochromosome of the short arm of chromosome 5 - i(5)(p10) - has only been described in a few cases of myeloid leukemia. So far it has not been described as the sole abnormality. In four cases the i(5)(p10) was accompanied by trisomy 8, in three cases the i(5)(p10) occurred in addition to two normal chromosomes 5. An i(5)(p10) was also described in cases with a complex aberrant karyotype

i(5)(p10) G-banding - Claudia Schoch

Clinics and Pathology Phenotype / cell stem origin

Classified as AML, predominantly AML M5a

Etiology

Unclear

Epidemiology Mean age 40-50 yrs Clinics

Blood data WBC 8-40 x 109l, platelet counts 15-114 x 109l

Cytology

Typical cytomorphological features of AML M5a with more than 80% of bone marrow cells being monoblasts showing strong cytochemical reaction with nonspecific esterase. Expression of CD33 and CD65.

Treatment

According to AML protocols.

Prognosis

Unclear due to low number of cases, seems to be poor.

Cytogenetics Cytogenetics Isochromosome of the short arm of chromosome 5 Morphological Additional anomalies

trisomy 8, gain of chromosome 5

Genes involved and


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Proteins Note

Gene dosage effect of genes located on the short arm of chromosome 5?

External links Other database

i(5)(p10) in acute myeloid leukemia Mitelman database (CGAP - NCBI)

To be noted Additional cases are needed to delineate the epidemiology of this rare entity: you are welcome to submit a paper to our new Case Report section.

Bibliography Chromosomal breakpoints and changes in DNA copy number in refractory acute myeloid leukemia. El-Rifai W, Elonen E, Larramendy M, Ruutu T, Knuutila S. Leukemia 1997;11: 958-963. Medline 9204975 Cytogenetic analysis of de novo acute leukemia with trilineage myelodysplasia in comparison with myelodysplastic syndrome evolving to acute myeloid leukemia. Tamura S, Takemoto Y, Hashimoto-Tamaoki T, Mimura K, Sugahara Y, Senoh J, Furuyama J-I, Kakishita E. Int J Oncol 1998; 12:1259-1262. Medline 9592183 Lack of BCR/ABL reciprocal fusion in variant Philadelphia chromosome translocations: a use of double fusion signal FISH and spectral karyotyping. Markovic VD, Bouman D, Bayani J, Al-Maghrabi J, Kamel-Reid S, Squire JA. Leukemia 2000; 14: 1157-1160 Medline 10865986 Gain of an isochromosome 5p: a new recurrent chromosome abnormality in acute monoblastic leukemia. Schoch C, Bursch S, Kern W, Schnittger S, Hiddemann W, Haferlach T. Cancer Genet Cytogenet 2001; 127: 85-88. Medline 11408074


022005

Claudia Schoch


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Citation This paper should be referenced as such : Schoch C . i(5)(p10) in acute myeloid leukemia. Atlas Genet Cytogenet Oncol Haematol. February 2005 . URL : http://www.infobiogen.fr/services/chromcancer/Anomalies/i5pID1376.html © Atlas of Genetics and Cytogenetics in Oncology and Haematology


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Splenic lymphoma with villous lymphocytes (SLVL) Clinics and Pathology Phenotype / cell stem origin

Light chain restriction surface immunoglobulin. Most cases express IgM and IgD. B-cells express CD19+, CD20+, CD22+, CD24+, CD79b+, FMC7+ and DBA44+. Lack expression of CD5 (85%), CD10, CD23, CD103 and CD123.

Epidemiology In 1987, the term SLVL was introduced; 1-2% of non-Hodgkin lymphomas ; occurs in the elderly (med 70 yrs) ; sex ratio 2M/1F. Clinics

splenomegaly without hepatomegaly nor enlarged lymph nodes; monoclonal Ig in a third of cases, autoimmune phenomena in 10% of patients, transformation to high grade lymphoma in 10% of cases.

Peripheral blood lymphocytosis in 75% of patients and villous lymphocytes on peripheral blood smears (Fig 1).

Pathology

Spleen. Nodular replacement of the white pulp with a central core of small lymphocytes and larger cells in the peripheral marginal zone. Invasion of the splenic red pulp is inconstant. Bone marrow morphology showing intrasinusoidal lymphoma cells.

Treatment

Only in symptomatic patients : splenectomy or chemotherapy with purine analogues. Antiviral therapy (IFN) in patients with SLVL and hepatitis C.

Prognosis

Indolent B-cell malignancy with 5-yr survival : 80%; no consensus on adverse prognostic factors: WBC > 30 x 109/l, low lymphocyte count; cases treated with chemotherapy have shorter survival.


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Cytogenetics Cytogenetics A low mitotic activity is present in SLVL and most chromosomal Morphological banding analyses of SLVL have been based on cell cultures stimulated with different B-cell mitogens. The cytogenetic abnormalities are heterogeneous and often complex, with several recurrent abnormalities. The most common abnormalities are those involving structural abnormalities of chromosome 7q22-q32 [20-40% of cases] in the form of translocation, mainly unbalanced, and 7q deletion (see Fig 2). Some cases have been reported to show t(11;14)(q13;q32) [1015%]. Structural abnormalities, and microdeletion of 13q14 were found in 50% of cases. The 13q14 allelic loss at the RB1 locus deletion have been detected by interphase FISH. Other abnormalities, in particular trisomy 3 [10-15%], i(17)(q10), t(6;14)(p21;q32) and 2p11 translocations, t(2;7)(p12;q21) were also observed in a few cases. Immunoglobulin gene sequencing 43% of patients have an unmutated profile (>98% homology to the gem line sequence) and 57% of patients a mutated profile. Overuse of the VH1-2 gene segment is present in mutated and unmutaded cases.

t(11;14)(q13;q32) R-Banding (top left); del(7q) (top right); 13q14 allelic loss at the RB1 locus deletion detected by interphase FISH (bottom)

Genes involved and Proteins Note

del(7q): gene unknown t(11;14)(q13;q32)BCL1 in 11q13 and IgH in 14q32 are involved in 20% of cases, with or without visible (11;14); BCL1 encodes the cyclin


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D1; role in the cell cycle control (G1 progression and G1/S transition); 5' BCL1 translocated on chromosome 14 near JH, resulting in promoter exchange; the immunoglobulin gene enhancer stimulates the expression of BCL1, and overexpression of BCL1 which accelerates passage through the G1 phase. trisomy 3: gene unknown but region 3q13.q32-q29 over-represented. t(6;14)(p21;q32) cyclin D3 is located on 6p21 and, as CDK6, is implicated in the progression through the G1 phase of the cell cycle. t(2;7)(p12;q21). CDK6 is located on 7q21 and dysregulation of CDK6 gene expression could be contribute to the pathogenesis of SLVL and SMZL.

Bibliography Cytogenetic studies in splenic lymphoma with villous lymphocytes. Oscier DG, Matutes E, Gardiner A, Glide S, Mould S, Brito-Babapulle V, Ellis J, Catovsky D. Br J Haematol 1993 Nov;85(3):487-491 Medline 94183722 Splenic lymphoma with villous lymphocytes: clinical presentation, biology and prognostic factors in a series of 100 patients. Groupe Francais d'Hematologie Cellulaire (GFHC). Troussard X, Valensi F, Duchayne E, Garand R, Felman P, Tulliez M, Henry-Amar M, Bryon PA, Flandrin G Br J Haematol 1996 Jun;93(3):731-736 Medline 96240387 Molecular cytogenetic analysis in splenic lymphoma with villous lymphocytes: frequent allelic imbalance of the RB1 gene but not the D13S25 locus on chromosome 13q14. Garcia-Marco JA, Nouel A, Navarro B, Matutes E, Oscier D, Price CM, Catovsky D Cancer Res 1998 Apr 15;58(8):1736-1740 Medline 98222956 Analysis of the IgVH somatic mutations in splenic marginal zone lymphoma defines a group of unmutated cases with frequent 7q deletion and adverse clinical course. Algara P, Mateo MS, Sanchez-Beato M, Mollejo M, Navas IC, Romero L, Sole F, Salido M, Florensa L, Martinez P, Campo E, Piris MA. Blood 2002; 99: 1299-1304 Medline 11830479 Regression of splenic lymphoma with villous lymphocytes after treatment of hepatitis C virus infection. Hermine O, Lefrere F, Bronowicki JP, Mariette X, Jondeau K, Eclache-Saudreau V, Delmas B, Valensi F, Cacoub P, Brechot C, Varet B, Troussard X.


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N Engl J Med. 2002; 347(2): 89-94. Medline 12110736 Splenic marginal zone lymphoma. Oscier D, Owen R, Johnson S. Blood Reviews 2005; 19: 39-51. Medline 15572216


101998

Jean-Loup Huret, Hossain Mossafa

Updated

022005

Xavier Troussard, Hossain Mossafa

Citation This paper should be referenced as such : Huret JL, Mossafa H . Splenic lymphoma with villous lymphocytes (SLVL). Atlas Genet Cytogenet Oncol Haematol. October 1998 . URL : http://www.infobiogen.fr/services/chromcancer/Anomalies/splenvillousID2063.html Troussard X, Mossafa H . Splenic lymphoma with villous lymphocytes (SLVL). Atlas Genet Cytogenet Oncol Haematol. February 2005 . URL : http://www.infobiogen.fr/services/chromcancer/Anomalies/splenvillousID2063.html © Atlas of Genetics and Cytogenetics in Oncology and Haematology


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t(1;14)(q21;q32) FCGR2B/IGH Clinics and Pathology Disease

Follicular lymphoma in one CD10+ case, but without a t(14;18)(q32;q21), bcl2 negative, and with a t(1;14)(q21;q32); follicular lymphoma with FCGR2B rearrangement and dup(1)(q21q25)in another case .

Epidemiology These two cases with FCGR2B rearrangement were found among a panel of 76 non Hodgkin's lymphomas. Prognosis

May be associated with tumor progression.

Cytogenetics Cytogenetics One case with 46, XX, t(1;14)(q21;q32), t(8;9)(q24;q13); progression Morphological to a diffuse large cells lymphoma with a complexe caryotype. An another case with FCGR2B rearrangement in a follicular lymphoma: the karyotype was complexe with dup(1)(q21q25), t(14;18)(q32;q21).

Genes involved and Proteins Gene Name

FCGR2B

Location

1q22

Gene Name

IgH

Location

14q32

Result of the chromosomal anomaly The translocation juxtapose the 5' switch region og IGHG2 to a region Hybrid upstream of FCGR2B in the der(1) chromosome.FCGR2B is gene Description deregulated by this translocation and FCGR2B b2 mRNA isoform is overexpressed. Fusion No fusion protein. Protein Note Oncogenesis It is possible that alteration in the b2/b1 mRNA isoforms ratio in B-cells may promote B cell survival. This anomaly is bcl2 deregulationindependant because FCGR2B has been shown to be a tumorenhancing factor in non lymphoid cells in murine in vivo and in vitro


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models. Deregulation of FCGR2B expression can be considered as a second event which may impart additional growth advantage to the bcl2 deregulated B-cells.


t(1;14)(q21;q32) FCGR2B/IGH

Mitelman database (CGAP - NCBI)

Other database

t(1;14)(q21;q32) FCGR2B/IGH

CancerChromosomes (NCBI)


Bibliography Deregulation of FCGR2B expression by 1q21 rearrangements in follicular lymphomas. CHEN W, PALANISAMY N, SCHMIDT H, TERUYA-FELDSTEIN J, JHANWAR SC, ZELENETZ AD, HOULDSWORTH J, CHAGANTI RS. Oncogene 2001; 20: 7686-7693 Medline 11753646 Non-Hodgkin's Lymphoma. Molecular features of B Cell Lymphoma. MACINTYRE E, WILLEFORD D, MORRIS SW. Hematology (Am Soc Hematol Educ Program) 2000; 180-204. Medline Hematology The IgG Fc receptor, FcgammaRIIB, is a target for deregulation by chromosomal translocation in malignant lymphoma. CALLANAN MB, LE BACCON P, MOSSUZ P, DULEY S, BASTARD C, HAMOUDI R, DYER MJ, KLOBECK G, RIMOKH R, SOTTO JJ and LEROUX D Proc. Natl. Acad Sci USA 2000; 97: 309-314 Medline 10618414


022005

Jacques Boyer

Citation This paper should be referenced as such : Boyer J . t(1;14)(q21;q32) FCGR2B/IGH. Atlas Genet Cytogenet Oncol Haematol. February 2005 . URL : http://www.infobiogen.fr/services/chromcancer/Anomalies/t0114q21q32ID1341.html © Atlas of Genetics and Cytogenetics in Oncology and Haematology


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t(1;14)(q25;q32) Identity Note

Chromosome band 1q21-25 is one of the hotspots of chromosomal abnormalities in hematological malignancy. LHX4 gene at 1q25 is a novel gene coding for LIM proteins.

Clinics and Pathology Disease

Only two cases : Case 1: acute pre-B lymphoblastic leukemia (ALL); case 2: biphenotypic blast crisis of a chronic myelogenous leukemia(CML)

Epidemiology rare Clinics

Case 1: A 53-year-old woman with ALL; case 2: A 52-year-old in CML blast crisis

Cytogenetics Cytogenetics dup(1)(q21-25) is frequently detected in ALL of B-cell lineage Morphological Additional anomalies

case 1: associated with t(9;22)(q23 ?;q11) : the breakpoint at 9q23 reported in this paper needs to be confirmed; case 2: 46,XY,t(9;22)(q34;q11)/46, XY,t(1;14(q25;q32), del(20)(q11;q13.3) / 46,XY, t(1;14)(q25;q32) , add(19)(p13).


LHX4

Location

1q25.2

Note

Alias : Gsh-4. LHX4 gene is a member of the LIM-homeobox gene.

Dna / Rna

DNA : 44,66 kb and 6 exons. RNA : 1913 bp

Protein

LHX4 protein (40,8kDa, 390 aa) is very close to LHX3.The human LHX4 includes one tandem pair of zinc-finger LIM motifs and one adjacent homeodomain.

Gene Name

IgH

Location

14q32

Result of the chromosomal anomaly Atlas Genet Cytogenet Oncol Haematol 2005; 2

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case 1: the enhancer region of the IgH gene is fused to the 5¹ regulatory Hybrid region of the Lhx4 gene in a head-to-head configuration. LHX4 mRNA is gene Description expressed at high levels; case 2: the breakpoint fuses the J4 segment of IgH to sequences located 16kb from LHX4 Exon 1 in a head-to-head configuration. LHX4 mRNA is expressed at high levels. Fusion No fusion protein Protein Note Oncogenesis LHX4 homeodomain could play an important role as transcriptional regulators in cell regulation, but there is no report about the impairment of hematopoiesis in LHX4 deficient mice and human. There is no report about the transformation activity in the LHX4 gene. Overexpression of LXH2 has been reported in chronic myeloid leukemias and ALL.


t(1;14)(q25;q32)


Other database

t(1;14)(q25;q32)



Bibliography A novel chromosomal translocation t(1;14)(q25;q32) in pre-B acute lymphoblastic leukemia involves the LIM homeodomain protein gene, Lhx4. Kawamata N, Sakajiri S, Sugimoto K, Isobe Y, Kobayashi H, Oshimi K Oncogene 2002; 21: 4983-4991. Medline 12118377 Aberrant expression of the LHX4 LIM-homeobox gene caused by t(1;14)(q25;q32) in chronic myelogenous leukemia in biphenotypic blast crisis. Yamagushi M, Yamamoto K, Miura O Genes Chromosomes Cancer 2003; 38(3): 269-273. Medline 14506703


032005

Jacques Boyer

Citation This paper should be referenced as such : Boyer J . t(1;14)(q25;q32). Atlas Genet Cytogenet Oncol Haematol. March 2005 . URL : http://www.infobiogen.fr/services/chromcancer/Anomalies/t0114q25q32LHX4ID1352.html © Atlas of Genetics and Cytogenetics in Oncology and Haematology


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t(8;11)(p11;p15) Clinics and Pathology Disease

Acute non lymphocytic leukemia (ANLL)

Note

possibly heterogenous (see data on genes)

Epidemiology 3 cases to date: 1 M1-ANLL, 1 M4-ANLL and 1 case not otherwise specified; two male patients were aged 50 and 64 yrs Prognosis

one patient died during induction therapy, another one achieved complete remission and was alive at 19 mths+.

Cytogenetics Cytogenetics sole anomaly in 1 case, accompanied with del(9q) in another case. Morphological


In 8p11: WHSC1L1/NSD3 was proved to be implicated in the translocation in one case, while FGFR1 was (only) suspected to be involved in a second case; this case was analysed with two probes flanking FGFR1 over a distance of about 700 kb; the two probes were found to be split in FISH experiments, indicating that FGFR1 was possibly concerned by the break. However, NDS3 is 107 kb long, is at a distance of only 30 kb from FGFR1, and FGFR1 spans 56 kb; therefore, NDS3 is also a candidate in this case. In 11p15: NUP98 was found to be implicated in the translocation in one case; in the second case, probes flanking NUP98 over a distance of about 1 Mb were used; it is likely that NUP98 is also involved in this case, although the involvement of CARS, 600 kb more telomeric than NUP98, is not excluded.

Gene Name

WHSC1L1/NSD3

Location

8p11

Protein

suggested role in chromatin remodeling.

Gene Name

NUP98

Location

11p15

Protein

nuclear membrane localisation; nucleoporin: associated with the nuclear pore complex; role in nucleocytoplasmic transport processes


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Result of the chromosomal anomaly Hybrid gene Transcript

a 5' NUP98 - 3' NSD3 fusion transcript was detected; the reciprocal transcript was also expressed. The breakpoints occurred between exons 11 ad 12 of NUP98 and betweeen exons 3 and 4 in WHSC1L1/NSD3.


t(8;11)(p11;p15)


Other database

t(8;11)(p11;p15)



Bibliography The predictive value of initial cytogenetic studies in 148 adults with acute nonlymphocytic leukemia: a 12-year study (1970-1982). Larson RA, Le Beau MM, Vardiman JW, Testa JR, Golomb HM, Rowley JD. Cancer Genet Cytogenet 1983; 10: 219-236. Medline 6627222 Identification of four new translocations involving FGFR1 in myeloid disorders. Sohal J, Chase A, Mould S, Corcoran M, Oscier D, Iqbal S, Parker S, Welborn J, Harris RI, Martinelli G, Montefusco V, Sinclair P, Wilkins BS, van den Berg H, Vanstraelen D, Goldman JM, Cross NC. Genes Chromosomes Cancer 2001; 32: 155-163. Medline 11550283 NUP98 is fused to the NSD3 gene in acute myeloid leukemia associated with t(8;11)(p11.2;p15). Rosati R, La Starza R, Veronese A, Aventin A, Schwienbacher C, Vallespi T, Negrini M, Martelli MF, Mecucci C. Blood 2002; 99: 3857-3860. Medline 11986249


032005

Jean Loup Huret

Citation Atlas Genet Cytogenet Oncol Haematol 2005; 2

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This paper should be referenced as such : Huret JL . t(8;11)(p11;p15). Atlas Genet Cytogenet Oncol Haematol. March 2005 . URL : http://AtlasGeneticsOncology.org/Anomalies/t0811p11p15ID1200.html © Atlas of Genetics and Cytogenetics in Oncology and Haematology


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t(10;11)(q25;p15) Identity

G-band analysis. Partial karyotype showing the t(10;11)(q25;p15). Courtesy I Lahortiga, María J Calasanz and María D Odero. Department of Genetics, University of Navarra, Spain.


T-cell acute lymphoblastic leukemia with biphenotipic characteristics (T/myeloid).

Epidemiology Very rare, only one case described. Clinics

Adenopathies, moderate splenomegaly. Two different morphological populations detected by flow cytometry.

Treatment

Hematological and cytogenetic remission after induction therapy(AraC, Idarubicin, VP-16). Postremission therapy (two courses of Ida-Ara-C and mitoxantrone-Ara-C). Autologous transplantation. Relapse and exitus.

Evolution

Relapse and exitus.

Prognosis

Bad.

Cytogenetics


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FISH analyses. Left BAC RPCI-11 348A20 (red, covering NUP98) shows a split compatible with the molecular breakpoint found; RPCI-11 555F1 (green, 500 Kb telomeric to NUP98) labels normal chromosome 11 and der(10). Right BAC RPCI-11 252O7 (green, covering ADD3) shows a split compatible with the molecular breakpoint found; RPCI-11 348A20 shows the split in NUP98. Courtesy I Lahortiga, María J Calasanz and María D Odero. Department of Genetics, University of Navarra, Spain.

Additional sole anomaly anomalies Variants

no variants described


ADD3

Location

10q25.1-q25.2

Note

This gene is involved only in this translocation.

Dna / Rna

15 exons spanning 129.52 Kb on 10q25.1-10q25.2. Transcription is from centromere to telomere. 2-3 alternative transcripts.

Protein

Is membrane-cytoskeleton-associated protein that promotes the assembly of the spectrin-actin network and binds to calmodulin. Adducins are heteromeric proteins composed of different subunits referred to as adducin alpha, beta and gamma encoded by distinct genes and belong to a family of membrane skeletal proteins involved in the assembly of spectrin-actin network in erythrocytes and at sites of cell-cell contact in epithelial tissues. Structurally, each subunit is


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comprised of two distinct domains. The amino-terminal region is protease resistant and globular in shape, while the carboxy-terminal region is protease sensitive. The latter contains multiple phosphorylation sites for protein kinase C, the binding site for calmodulin, and is required for association with spectrin and actin. Alternatively spliced adducin gamma transcripts encoding different isoforms have been described. The functions of the different isoforms are not known. Gene Name

NUP98

Location

11p15

Dna / Rna

33 exons spanning 122.54 Kb on 11p15. Transcription is from centromere to telomere. 3-4 alternative transcripts.

Protein

Nup98 and Nup96 play a role in the bidirectional transport across the nucleoporin complex (NPC). The repeat domain in Nup98 has a direct role in the transport. Signal-mediated nuclear import and export proceed through the nuclear pore complex (NPC), which is comprised of approximately 50 unique proteins collectively known as nucleoporins. The 98 kD nucleoporin is generated through a biogenesis pathway that involves synthesis and proteolytic cleavage of a 186 kD precursor protein. This cleavage results in the 98 kD nucleoporin as well as a 96 kD nucleoporin, both of which are localized to the nucleoplasmic side of the NPC. The human gene has been shown to fuse to several genes following chromosome translocatons in acute myelogenous leukemia (AML) and T-cell acute lymphocytic leukemia (T-ALL). This gene is one of several genes located in the imprinted gene domain of 11p15.5, an important tumor-suppressor gene region. Alterations in this region have been associated with the Beckwith-Wiedemann syndrome, Wilms tumor, rhabdomyosarcoma, adrenocortical carcinoma, and lung, ovarian, and breast cancer. Alternative splicing of this gene results in several transcript variants; however, not all variants have been fully described.

Result of the chromosomal anomaly Fusion in-frame between NUP98 exon 10 and ADD3 exon 13 (transcript Hybrid variant 1) and between NUP98 exon 10 and ADD3 exon 14 (transcript gene Description variant 2)r Transcript

5' NUP98-ADD3 3'

Detection

ADD3-NUP98 was also detected at a lower level.


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Fusion Protein

Schematic representation of the fusion NUP98-ADD3 consecuence of the t(10;11)(q25;p15) in a T-cell acute lymphoblastic leukemia with biphenotipic characteristics. From up to down: ADD3, NUP98 and the putative chimeric NUP98-ADD3 structure. FGrepeats, phenilalanine-glycine repeats; bipartite NLS, bipartite nuclear localization signal. Coiled coil domains on ADD3 and NUP98-ADD3 are indicated with asterisks.

Description

The fusion gene is predicted to encode a NUP98-ADD3 protein of 566-598 aminoacids retaining the N-terminal FG repeat motif of NUP98 and the Cterminal phosphorilation sites and the calmodulin binding region of ADD3.

Oncogenesis In all the NUP98 fusions reported the FG-repeats are retained. In the NUP98 rearrangements involving the HOX family, the 3' region of these genes with the homodomain are retained so the fusion protein could act as an oncogenic transcription factor. In NUP98 fusions with non-HOX genes the partners have regions with a significant probability of adopting a coiledcoil conformation. In all cases the coiled-coil domain are retained in the chimeric protein. This domain could promote the oligomerization of the fusion protein activating its oncogenic potential.


t(10;11)(q25;p15)


Other database

t(10;11)(q25;p15)



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Bibliography NUP98 is fused to adducin 3 in a patient with T-cell acute lymphoblastic leukemia and myeloid markers, with a new translocation t(10;11)(q25;p15). Lahortiga I, Vizmanos JL, Agirre X, Vazquez I, Cigudosa JC, Larrayoz MJ, Sala F, Gorosquieta A, Perez-Equiza K, Calasanz MJ, Odero MD. Cancer Res. 2003;63(12):3079-3083. Medline 12810632


032005

José Luis Vizmanos

Citation This paper should be referenced as such : Vizmanos JL . t(10;11)(q25;p15). Atlas Genet Cytogenet Oncol Haematol. March 2005 . URL : http://www.infobiogen.fr/services/chromcancer/Anomalies/t1011q25p15ID1285.html © Atlas of Genetics and Cytogenetics in Oncology and Haematology


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t(11;20)(p15;q11) Identity

t(11;20)(p15;q11) G-banding..


Acute myelogenous leukemia, Therapy-related MDS (RAEB, RAEB-t)

Phenotype / cell stem myeloid, positive for CD34, 33, 13, HLA-DR. origin Etiology

either therapy-related or de novo


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Table 1

Leukemic cells have characteristics of type II myeloblasts with numerous granules. Several large nucleoli are seen in nuclei.(Wright-Giemmsa staining)(x 1,000)


NUP98

Location 11p15 Note

Gene Name

The NUP98 gene is fused to a number of genes through chromosomal translocation. The breakpoints in NUP98 gene span six introns (intron 914). Of particular notice, one type of translocation occurs in a specific intron. As for t(11;20), all four cases have the breakpoint in intron 13 of NUP98 gene.

TOP1


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Location 20q11

Protein Topoisomerase 1 is a ca.100 kDa protein with 765 amino acids; contains NLS in the N-term, a core domain which recognizes its binding sequences, a link domain which connects the core and catalytic domains, and the catalytic domain in the C-term.

Result of the chromosomal anomaly Fusion Protein

Structural diagrams of NUP98, TOP1, and fused chimeras. Fused protein has Nterminal of NUP98, which contains two FG repeats, and the core, link and catalytic domains of TOP1. Gene product of TOP1/NUP98 (150kD) has been demonstrated, but the fused protein of TOP1/NUP98 has not been examined.

Oncogenesis NUP98-TOP1 fusion protein has been proved to be leukemogenic in mice.


t(11;20)(p15;q11)


Other database

t(11;20)(p15;q11)




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Primer sets for RT-PCR and genomic PCR have been published in References.

Bibliography The t(11;20)(p15;q11) chromosomal translocation associated with therapyrelated myelodysplastic syndrome results in an NUP98-TOP1 fusion. Ahuja HG, Felix CA, Aplan PD Blood 1999 Nov 1; 94(9): 3258-3261. Medline 10556215 Potential role for DNA topoisomerase II poisons in the generation of t(11;20)(p15;q11) translocations. Ahuja HG, Felix CA, Aplan PD Genes Chromosomes Cancer 2000; 29: 96-105. Medline 10959088 Expression of NUP98/TOP1, but not of TOP1/NUP98, in a treatment-related myelodysplastic syndrome with t(10;20;11)(q24;q11;p15). Panagopoulos I, Fioretos T, Isaksson M, Larsson G, Billstrom R, Mitelman F, Johansson B Genes Chromosomes Cancer 2002 Jun; 34(2): 249-254. Medline 11979559 Generation of the NUP98-TOP1 fusion transcript by the t(11;20) (p15;q11) in a case of acute monocytic leukemia. Chen S, Xue Y, Chen Z, Guo Y, Wu Y, Pan J Cancer Genet Cytogenet 2003 Jan 15; 140(2): 153-156. Medline 12645654 Both NUP98/TOP1 and TOP1/NUP98 transcripts are detected in a de novo AML with t(11;20)(p15;q11). Iwase S, Akiyama N, Sekikawa T, Saito S, Arakawa Y, Horiguchi-Yamada J, Yamada H. Genes Chromosomes Cancer 2003 Sep; 38(1): 102-105. Medline 12874791 NUP98-topoisomerase I acute myeloid leukemia-associated fusion gene has potent leukemogenic activities independent of an engineered catalytic site mutation. Gurevich RM, Aplan PD, Humphries RK Blood 2004 Aug 15; 104(4): 1127-1136. Epub 2004 Apr 20. Medline 15100157 A t(11;20)(p15;q11) may identify a subset of nontherapy-related acute myelocytic leukemia. Potenza L, Sinigaglia B, Luppi M, Morselli M, Saviola A, Ferrari A, Riva G, Zucchini P, Giacobbi F, Emilia G, Temperani P, Torelli G Atlas Genet Cytogenet Oncol Haematol 2005; 2

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Cancer Genet Cytogenet 2004 Mar; 149(2): 164-168. Medline 15036893


032005

Tetsuaki Sekikawa, Junko Horiguchi-Yamada

Citation This paper should be referenced as such : Sekikawa T, Horiguchi-Yamada J . t(11;20)(p15;q11). Atlas Genet Cytogenet Oncol Haematol. March 2005 . URL : http://www.infobiogen.fr/services/chromcancer/Anomalies/t1120p15q11ID1155.html © Atlas of Genetics and Cytogenetics in Oncology and Haematology


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Adrenal cortical carcinoma Identity Note

Other names

Adrenocortical carcinoma is a rare malignant neoplasm of adrenal glands, which most often presents without any hormonal symptoms. The most common clinical presentation of patients with hormonesecreting adrenocortical carcinoma is that of CushingÕs syndrome. Other hormonal hypersecretion syndromes associated with adrenocortical carcinoma include virilization (from androgen-producing tumors), feminization (estrogen-producing tumors), and hyperaldosteronism. Multiple hormones may be produced by a single tumor, causing a mixed clinical picture. In children, virilization is more common because carcinomas have a greater tendency to be presented with a hormonal syndrome. Adrenocortical Carcinoma Adrenal Tumor

Clinics and Pathology Etiology

Adrenal cancer may present as part of rare hereditary syndromes such as Wiedemann-Beckwith syndrome (WBS) linked to 11p15.5 or the LiFraumeni syndrome (LFS), associated with germline mutations of the TP53 gene, on 17p. Sometimes carcinomas develop in children with congenital adrenal hyperplasia (CAH) that is caused most frequently by mutations in the CYP21B gene.

Epidemiology Adrenal cancer is a rare malignancy representing only 0.05% and 0.2% of all cancers worldwide. Women tend to develop functional adrenal cortical carcinomas more commonly than men. Men develop non-functional malignant adrenal tumors more often than women. There is a bimodal distribution in terms of age: young children less than 5 years old, and adults in their 30s and 40s. In Brazil, the incidence of carcinomas is three times more than the international rate Pathology

Grading and staging: Stage I: disease confined to the adrenal gland without local invasion or distant metastases and the greatest tumor dimension less than 5cm. Stage II: same as stage I but the greatest tumor dimension is greater than 5 cm. Stage III: local invasion that does not involve adjacent organs or regional lymph nodes. Stage IV: distant metastases or invasion into adjacent organs plus


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regional lymph nodes. Treatment

Treatment for adrenocortical carcinomas is complete surgical resection; these tumors do not respond well to chemotherapy. Mitotane may be used as a chronic treatment in non-cured cases or prophylactically. Other medications (e.g. ketoconazole, metyrapone, aminoglutethimide) may be given to reduce production of cortisol and other adrenal steroids that is responsible for many of symptoms.

Prognosis

Extremely poor prognosis, with a survival rate at 20% at five years for stage I-II disease.Poor prognostic indicators include: age at diagnosis, tumor size, distant metastases, invasion of vessels, capsule, or adjacent organs, and tumor necrosis. Pediatric patients with a hormonal syndrome are considered to have a better prognosis because the associated signs and symptoms can make the cancer diagnosis easier leading to earlier surgical intervention

Cytogenetics Cytogenetics Only a few karyotyping studies has been performed. Chromosomal Morphological analysis revealed a modal number of 61 with consistent structural abnormalities of add(3)(q11), add(9)(p11), and add(16)(ql1) in one case of adult carcinoma and the karyotype 46, XX, t(4;11)(q35;p13) in the another one. Karyotyping of short-term cultured cells from an 11cm adrenocortical carcinoma in a 3.5-year-old girl revealed the very complex karyotype 46,XX, inv(9)(p11q12)c/[2]/56-57,XX, +2, +4, +5, +7, +8, inv(9)c, +10, +add (13)(p11), +14, +15, +19, +20, +20, +mar[cp19]. Cytogenetics Fluorescent in situ hybridization (FISH) studies of carcinomas showed Molecular increasing genome instability in carcinoma progression. Loss of heterozygosity (LOH) studies identified allelic losses on chromosomes 11p, 11q, 13q, and 17p. The LOH on 2p16 is strongly associated with the malignant phenotype. Several studies were reported in carcinomas with comparative genomic hybridization (CGH). DNA sequence copy number gains were identified on chromosomes 4, 5, 9q, and 12q and losses on chromosomes 17p, 1p, 2q, 11q, and 9p. All studies showed that the number of genomic changes is closely correlated with tumor behavior. In adenomas, small tumors contain a small or zero number of chromosomal imbalances, and a number of changes increases in larger adenomas and then considerably increases in carcinomas. Of adenomas, the most common alterations were gains of 4q, 17p, 17q and 9q32-qter. Two CGH studies of childhood adrenal tumors showed extensive genetic alterations both in benign and malignant tumors. The copy number changes are distinctly different to those seen in adult tumors thus possibly reflecting different genetic background for these tumors. High-level amplification of 9q34 was very common.


A number of genes are implicated in tumor progression from adrenal adenoma to carcinoma; they include both oncogenes and tumor


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suppressor genes. Progression from adenoma to carcinoma involves a monoclonal proliferation of cells, which, together with other defects, have undergone rearrangements of the chromosomal locus 11p15.5 associated with IGF II hyperexpression and abrogation of expression of the CDKN1C and H19 genes. TP53 is involved in progression to carcinoma in a subset of patients. In childhood ADCC, 50% of children carried germline mutations of TP53. Deletions of the ACTH receptor gene have been recently found in undifferentiated adenomas and in aggressive adrenocortical carcinomas although the frequency of ACTH receptor deletion needs to be more fully examined. Other key oncogenes and tumor suppressor genes remain to be identified although the chromosomal loci that harbor them were identified at 17p, 1p, 2p16, 11q13, and 9p for tumor suppressor genes and chromosomes 4, 5, 9q, and 12 for oncogenes. The 11q13 region harbors the MEN1 gene, however mutations of the gene were not found in adrenal tumors.

Bibliography Genetic changes in human adrenocortical carcinomas. Yano T, Linehan M, Anglard P, Lerman MI, Daniel LN, Stein CA, Robertson CN, LaRocca R, Zbar B. J Natl Cancer Inst 1989; 81(7): 518-523. Medline 2564050 Tumor-specific loss of 11p15.5 alleles in del11p13 Wilms tumor and in familial adrenocortical carcinoma. Henry I, Grandjouan S, Couillin P, Barichard F, Huerre-Jeanpierre C, Glaser T, Philip T, Lenoir G, Chaussain JL, Junien C. Proc Natl Acad Sci USA 1989; 86(9): 3247-3251. Medline 2566168 Genetic aberrations in adrenocortical tumors detected using comparative genomic hybridization correlate with tumor size and malignancy. Kjellman M, Kallioniemi OP, Karhu R, Hoog A, Farnebo LO, Auer G, Larsson C, Backdahl M. Cancer Res 1996; 56(18): 4219-4223. Medline 8797595 Complex karyotype in a childhood adrenocortical carcinoma. Mertens F, Kullendorff CM, Moell C, Alumets J, Mandahl N. Cancer Genet Cytogenet 1998; 105(2): 190-192. Medline 9723041 Genotyping of adrenocortical tumors: very frequent deletions of the MEN1 locus in 11q13 and of a 1-centimorgan region in 2p16. Kjellman M, Roshani L, Teh BT, Kallioniemi OP, Hoog A, Gray S, Farnebo LO, Holst


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M, Backdahl M, Larsson C. J Clin Endocrinol Metab 1999; 84(2): 730-735. Medline 10022445 Analysis of genomic alterations in sporadic adrenocortical lesions. Gain of chromosome 17 is an early event in adrenocortical tumorigenesis. Zhao J, Speel EJ, Muletta-Feurer S, Rutimann K, Saremaslani P, Roth J, Heitz PU, Komminoth P. Am J Pathol 1999; 155(4): 1039-1045. Medline 10514385 Highly consistent genetic alterations in childhood adrenocortical tumours detected by comparative genomic hybridization. James LA, Kelsey AM, Birch JM, Varley JM. Br J Cancer 1999; 81(2): 300-304. Medline 10496356 Comparative genomic hybridization analysis of adrenocortical tumors of childhood. Figueiredo BC, Stratakis CA, Sandrini R, DeLacerda L, Pianovsky MA, Giatzakis C, Young HM, Haddad BR. J Clin Endocrinol Metab 1999; 84(3): 1116-1121. Medline 10084604 Increasing genome instability in adrenocortical carcinoma progression with involvement of chromosomes 3, 9 and X at the adenoma stage. Russell AJ, Sibbald J, Haak H, Keith WN, McNicol AM. Br J Cancer 1999 Oct; 81(4): 684-689. Medline 10574256 Adrenocortical carcinoma is characterized by a high frequency of chromosomal gains and high-level amplifications. Dohna M, Reincke M, Mincheva A, Allolio B, Solinas-Toldo S, Lichter P. Genes Chromosomes Cancer 2000 Jun; 28(2): 145-152. Medline 10824999 Adrenal Cancer. Stratakis CA, Chrousos GP. Endocrinol Metab Clin North Am 2000; 29(1): 15-25. Medline 10732261 Characterization of a newly established cell line derived from human adrenocortical carcinoma. Ueno M, Nakashima J, Akita M, Ban SI, Nakanoma T, Iida M, Deguchi N. Int J Urol 2001; 8(1): 17-22. Medline 11168692


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Adrenal cortical carcinoma. Boushey RP, Dackiw AP Curr Treat Options Oncol 2001; 2(4): 355-364. Medline 12057116 Combined comparative genomic hybridization and genomic microarray for detection of gene amplifications in pulmonary artery intimal sarcomas and adrenocortical tumors. Zhao J, Roth J, Bode-Lesniewska B, Pfaltz M, Heitz PU, Komminoth P. Genes Chromosomes Cancer 2002; 34(1): 48-57. Medline 11921282 Comparative genomic hybridization analysis of adrenocortical tumors. Sidhu S, Marsh DJ, Theodosopoulos G, Philips J, Bambach CP, Campbell P, Magarey CJ, Russell CF, Schulte KM, Roher HD, Delbridge L, Robinson BG. J Clin Endocrinol Metab 2002; 87(7): 3467-74. Medline 12107267 Adrenocortical Carcinoma: Diagnosis, Evaluation, and Treatment. Ng L, Liberton JM. Journal of Urology 2003; 169: 5-12. Medline 12478091 Androgen-Secreting Adrenal Tumors. Cordera F, Grant C, van Heerden J, Thompson G, Young W. Surgery 2003; 134: 874-880. Medline 14668717 Andrenocortical carcinomas: twelve-year prospective experience. Tauchmanova L, Colao A, Marzano LA, Sparano L, Camera L, Rossi A, Palmieri G, Marzano E, Salvatore M, Pettinato G, Lombardi G, Rossi R. World J Surg 2004; 28(9): 896-903. Medline 15593464 Adrenocortical carcinoma: a single institution experience. Gomez-Rivera F, Medina-Franco H, Arch-Ferrer JE, Heslin MJ. Am Surg 2005; 71(1): 90-94. Medline 15757066 REVIEW articles Last year publications



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032005

Constantine A Stratakis, Ludmila Matyakhina

Citation This paper should be referenced as such : Stratakis CA, Matyakhina L . Adrenal cortical carcinoma. Atlas Genet Cytogenet Oncol Haematol. March 2005 . URL : http://AtlasGeneticsOncology.org/Tumors/AdrenalCorticalCarcinID5088.html © Atlas of Genetics and Cytogenetics in Oncology and Haematology


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Bone tumors: an overview Identity Note

Primary skeletal neoplasms account for 0,2% of human tumors, whereas involvement of skeletal tissue by metastatic disease is much more common. Their soft tissue-related counterparts outnumber bone tumors by a margin of approximately 10:1. Because of their rarity, not much is known about the etiology and risk factors of bone tumors, although a difference in ethnical distribution has been observed. Bone tumors are mostly of mesenchymal origin, though for example Ewing sarcoma is thought to have neuroectodermal precursor cells. Classification of the World Health Organization will be followed in this overview. Grading of bone tumors is roughly based on the cellularity of the lesion compared to the amount of extracellulair matrix, nuclear features, the presence of mitotic figures and necrosis. Staging via the TNM system is normally not used, because metastases in lymph nodes are not frequent in these lesions. Therefore staging is based on degree of differentiation of the tumor tissue and local and distant spread of the tumor. Genetic information and references are provided for tumors investigated in more than a single case.

Classification Cartilage tumors Osteochondroma Chondromas Enchondroma Periosteal chondroma Chondroblastoma Chondromyxoid fibroma Chondrosarcoma Dedifferentiated Mesenchymal Clear cell Periosteal Osteogenic tumors Osteoid osteoma Osteoblastoma Osteosarcoma Conventional Teleangiectatic


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Small cell Low grade central Secondary Parosteal Periosteal High grade surface Fibrogenic tumors Desmoplastic fibroma of bone Fibrosarcoma of bone Fibrohistiocytic tumors Histiocytoma of bone Ewing sarcoma/Primitive neuroectodermal tumor Giant cell tumors Giant cell tumor Notochordal tumors Chordoma Vascular tumors Haemangioma and related lesions Angiosarcoma Myogenic, lipogenic, neural and epithelial tumors Leiomyosarcoma of bone Lipoma of bone Adamantinoma and osteofibrous dysplasia Tumors of undefined neoplastic nature Aneurysmal bone cyst Simple bone cyst Fibrous dysplasia Langerhans cell histiocytosis (LCH)

Clinics and Pathology Cytogenetics Cartilage tumors Osteochondroma Germ line mutations in the tumorsupressor genes Exostosin-1 (EXT-1) located at 8q24 and Exostosin-2 (EXT-2) located at 11p11-p12 have been found in hereditary multiple osteochondromas (MO). Somatic mutations are extremely rare in these tumors. In four tumors aberrations involving the region 1p13-p22 were shown. Chondromas Enchondroma By conventional cytogenetic analysis, abnormalities involving chromosome 6 and the long arm of chromosome 12 have been detected. o Periosteal chondroma This subtype has not been individually investigated. o

Chondroblastoma Atlas Genet Cytogenet Oncol Haematol 2005; 2

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Although a dozen of case reports have been published, no specific alterations were found in these rare benign tumors. Chondromyxoid fibroma Structural rearrangements of chromosome 6 are found to be nonrandom, particularly involving the long arm (q13 and q25) and p25 on the short arm. Chondrosarcoma In most genetic studies no difference is made between peripheral, central chondrosarcoma and other subtypes. CGH revealed extensive genetic aberrations; gains of whole chromosomes or chromosome arms at 20q (32-38%), 20p (24-31%), and 14q23-qter (24-28%). In a comparative study, 19 of 20 peripheral chondrosarcoma showed LOH at the loci for EXT, EXTL, 13q14, 17p14, 17p13, 9p21 and chromosome 10, while only 3 of 12 central chondrosarcoma did. In addition the ploidy status in peripheral chondrosarcoma showed wide variation (0,56-2,01), whereas central chondrosarcomas were predominantly periploid. Dedifferentiated In the cartilaginous, as well as in the dedifferentiated part of the tumor an identical somatic 6 bp deletion in exon 7 of p53 and loss of the same copy on chromosome 13 had been found. These findings provide evidence for a common origin of both parts. o Mesenchymal A Robertsonian (13;21) translocation, der(13;21)(q10;q10), was detected in two cases, together with loss of material from chromosome 8 and 20 and gain of material from chromosome 8. o Clear cell No specific alterations have been reported. o Periosteal No specific alterations have been reported. o

Cytogenetics Osteogenic tumors Osteoid osteoma Involvement of band 22q13 and loss of the distal part of arm 17q were detected in two out of three analyzed cases. Osteoblastoma No consistent aberrations have been detected in four cases, although clues are leading to deregulation of the cell cycle. No telomerase activity could be found. Osteosarcoma o

Conventional Although most osteosarcomas reveal complex


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o

o

o

o

o

o o

chromosomal aberrations, no specific alterations have been found. Amplification at 1q21-23 and 17p, together with co-amplification of 12q13-15 are frequently reported. In 14-27% of osteosarcomas, the MDM2 gene is amplified and in 41% the PRIM1 gene. Amplification of the CDK4 gene is found in aggressive lesions. Chromosome 12p is differently amplified in low- versus high-grade osteosarcomas. The MYC gene has been shown to be amplified in 44% of osteosarcoma (8q24). Teleangiectatic In contrast to the conventional osteosarcomas, no amplifications were detected in four cases. Complex chromosomal changes were found. Small cell No genetic alterations have been reported on this subtype of osteosarcoma. Low grade central The complex aberrations found in high-grade osteosarcomas could not be identified in these low-grade variants. Recurrent gains have been reported with minimal common regions at 12q13-14, 12p and 6p21. Secondary In tumors developing in bone after radiation, chromosomal losses are more frequently observed than gains. Especially 1p, which is lost in 3% of the conventional type, is lost in 57% of the radiationassociated type. In osteosarcomas secondary to Paget Disease of Bone (PDB) LOH is found at 18q, the locus for PDB. Parosteal Ring chromosomes are reported as the sole alteration in parosteal osteosarcoma. Using FISH techniques, the SAS, CDK4 and MDM2 genes are shown to be coamplified with a minimal common region at 12q13-15 in the ring chromosomes. Periosteal Complex chromosomal aberrations were reported. High grade surface These lesions have not been studied as a specific subtype.

Cytogenetics Fibrogenic tumors Desmoplastic fibroma of bone Like in desmoid tumors, trisomies 8 and 20 are commonly found. Fibrosarcoma of bone No cytogenetic investigations on fibrosarcoma have been published.


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Cytogenetics Fibrohistiocytic tumors Histiocytoma of bone Of the benign form of this tumor, no cytogenetic information is available. Its malignant counterpart shows LOH at chromosome 9p2122, which has also been shown by CGH before. Cytogenetics Ewing sarcoma/Primitive neuroectodermal tumor The most common rearrangement (85%) in this tumor is translocation t(11;22)(q24;q12). Consequently, this leads to the fusion protein EWS/FLI1. Other translocations found in the Ewing Sarcoma gene are listed below: fusion to translocation % of EWS FLI1 t(11;22)(q24;q12) 85 EWS ERG t(21;22)(q22;q12)

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EWS ETV1 t(7;22)(p22;q12) < 1 EWS FEV t(2;22)(q36;q12) < 1 EWS E1AF t(17;22)(q21;q12) < 1 Cytogenetics Giant cell tumors Giant cell tumor Reduction in length of the telomeres, as well as telomeric association, has been demonstrated in these tumors. Most commonly 11p, 13p, 14p, 15p, 19q, 20q and 21p are affected. Cytogenetics Notochordal tumors Chordoma Nine of sixteen investigated chordomas were hypodiploid with a chromosome number ranging from 33 to 44. Chromosomes 3, 4, 10, and 13 are most commonly lost, and in half of the cases the following segments are lost up to the telomere: 1p31, 3p21, 3q21, 9p24, 17q11. Because LOH is found at band 1p36, a tumor suppressor gene is thought to exist on distal 1p. Cytogenetics Vascular tumors Haemangioma and related lesions No cytogenetic investigations reported. Angiosarcoma An identical translocation of chromosomes 1 and 3 has been reported


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in two epithelioid haemangioendotheliomas. Cytogenetics Myogenic, lipogenic, neural and epithelial tumors Leiomyosarcoma of bone 5 Grade IIB tumors demonstrated a rate of genomic loss of 90%, whereas high micro satellite instability was not observed. Allelotyping revealed loss of pRb in the tumors. In addition, chromosomal loss was noticed in human telomerase subunit-linked markers. Lipoma of bone Only one case study is published about the benign form of this tumor. On its malignant counterpart, liposarcoma of bone, no genetic information has been published. Adamantinoma and osteofibrous dysplasia Cumulating evidence indicates that classic adamantinomas derive from their osteofibrous dysplasia (OFD)-like counterparts. OFD and adamantinoma show common cytogenetic abnormalities. In 15 cases of adamantinoma (n=11) and OFD (n=4) trisomies of chromosomes 7, 8, 12, 19 and 21 were detected. These findings further substantiate the clonal origin of OFD and the common histogenesis of OFD and adamantinoma. Cytogenetics Tumors of undefined neoplastic nature Aneurysmal bone cyst Aneurysmal bone cysts can be primary or secondary to other bone lesions. Chromosome bands 16q22 and/or 17p13 (USP6 gene) are non-randomly rearranged in ABC, regardless of tumor type (classic and solid) and of location (osseous and extraosseous). However, rearrangements are absent in secondary ABC. A recurrent t(16;17)(q22;p13) has been identified, but other chromosomal segments as translocation partner for each chromosome have been described. Simple bone cyst Only one case report describes structural rearrangements. Fibrous dysplasia Two fibrous dysplasia cases exhibited either a completely normal karyotype or single cell aberrations. Evidence that this lesion is neoplastic comes from the fact that clonal chromosomal aberrations have been found. In monostotic as well as polyostotic lesions activating GNAS1(20q13.2) mutations, known from the McCune-Albright syndrome, have been demonstrated. Langerhans cell histiocytosis (LCH) Studies of X-chromosome inactivation demonstrated that LCH is clonal. Cytogenetics Congenital and inherited syndromes


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Beckwith-Wiedemann syndrome This syndrome, which is caused by heterogenic genetic changes on 11q15, is subject to genomic imprinting. 3 Beckwith-Wiedemann syndrome chromosome regions (BWSCR) have been identified: BWSC1 near INS/IGF2, BWSC2 5 Mb proximal to BWSC1, and BWSC3 2 Mb even more proximal. Enchondromatosis: Ollier disease and Maffucci syndrome These syndromes are non-hereditary although a case of familial clustering has been reported. Mutations in the PTH receptor 1 have been found in two cases, but these results could not be confirmed in a larger series of 31 patients, suggesting that PTHR1 is not the culprit for enchondromatosis. McCune-Albright syndrome Mutations in the GNAS1 gene, located on 20q13, change the structure of the G-protein a-stimulatory subunit. Dysfunctions of the heterotrimeric G-protein complexes lead to this non-familial occurring disorder. Multiple osteochondromatosis(MO)/Hereditary Multiple Exostosis Mutations in one of the two exostosin (EXT) genes are responsible for this autosomal dominant syndrome. EXT1 is located at 8q24 and EXT2 at 11p11-p12. Most mutations are either nonsense, frame shift or splice-site mutations, leading to premature termination of the EXT proteins. This causes alteration of the gene products, which are functioning in the endoplasmatic reticulum as transmembrane glycoproteins, and will affect the biosynthesis of heparan sulphate proteoglycans, leading to altered growth factor signaling. Familial Paget Disease of Bone Familial Paget Disease of Bone (PDB) demonstrates linkage to chromosome 18q. Some cases (PDB type 2) are caused by mutations in the TNFRSF11A gene on chromosome 18q22.1, which encodes RANK, a protein essential in osteoclast formation. The phenotype linked to chromosome 5q35 (PDB type 3) is caused by mutations in the SQSTM1 gene, the product of which is associated with the RANK pathway.

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Biologic and clinical significance of cytogenetic and molecular cytogenetic abnormalities in benign and malignant cartilaginous lesions. Bridge JA, Bhatia PS, Anderson JR, and Neff JR. Cancer Genet Cytogenet 1993; 69: 79-90. Medline 8402563 Rearrangement of band q13 on both chromosomes 12 in a periosteal chondroma. Mandahl N, Willen H, Rydholm A, Heim S, and Mitelman F. Genes Chromosomes Cancer 1993; 6: 121-123 Medline 7680888 Clonal chromosomal abnormalities in osteofibrous dysplasia. Implications for histopathogenesis and its relationship with adamantinoma. Bridge JA, Dembinski A, De Boer J, Travis J, and Neff JR. Cancer 1994; 73: 1746-1752. Medline 8156503 Langerhans'-cell histiocytosis (histiocytosis X). A clonal proliferative disease. Willman C L, Busque L, Griffith BB, Favara BE, McClain KL, Duncan MH, and Gilliland DG. N Engl J Med 1994; 331: 154-160. Medline 8008029 Mesenchymal chondrosarcoma - A cytogenetic, immunohistochemical and ultrastructural study. Dobin SM, Donner LR, and Speights VO, Jr. Cancer Genet Cytogenet 1995; 83: 56-60. Medline 7656206 DNA aberrations in the epithelial cell component of adamantinoma of long bones. Hazelbag HM, Fleuren GJ, Cornelisse CJ, Van den Broek LJCM, Taminiau AHM, and Hogendoorn PCW. Am J Pathol 1995; 147: 1770-1779. Medline 7495301 Gains and losses of DNA sequences in osteosarcomas by comparative genomic hybridization. Tarkkanen M, Karhu R, Kallioniemi A, Elomaa I, Kivioja AH, Nevalainen J, Bohling T, Karaharju E, Hyytinen E, Knuutila S, and Kallioniemi O-P. Cancer Res 1995; 55: 1334-1338. Medline 7882332 Positional cloning of a gene involved in hereditary multiple exostoses. Wuyts W, Van Hul W, Wauters J, Nemtsova M, Reyniers E, Van Hul EV, De Boulle


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K, de Vries BB, Hendrickx J, Herrygers I, Bossuyt P, Balemans W, Fransen E, Vits L, Coucke P, Nowak NJ, Shows TB, Mallet L, van den Ouweland AM, McGaughran J, Halley DJ, Willems PJ. Hum Mol Genet 1996; 5: 1547-1557. Medline 8894688 Cytogenetic findings in 73 osteosarcoma specimens and a review of the literature. Bridge JA, Nelson M, McComb E, McGuire MH, Rosenthal H, Vergara G, Maale GE, Spanier S, and Neff J R. Cancer Genet Cytogenet 1997; 95: 74-87. Review. Medline 9140456 The pericentromeric inversion, inv (6)(p25q13), is a novel diagnostic marker in chondromyxoid fibroma. Granter SR, Renshaw AA, Kozakewich HP, and Fletcher JA. Mod Pathol 1998; 11: 1071-1074. Medline 9831204 Cytogenetic analysis of a scapular chondromyxoid fibroma. Halbert AR, Harrison WR, Hicks MJ, Davino N, and Cooley LD. Cancer Genet Cytogenet 1998; 104: 52-56. Medline 9648559 Evidence of an association between 6q13-21 chromosome aberrations and locally aggressive behavior in patients with cartilage tumors. Sawyer JR, Swanson CM, Lukacs JL, Nicholas RW, North PE, and Thomas JR. Cancer 1998; 82: 474-483. Medline 9452264 Significance of abnormalities of chromosomes 5 and 8 in chondroblastoma. Swarts SJ, Neff JR, Johansson SL, Nelson M, and Bridge JA. Clin Orthop 1998; 189-193. Medline 9584382 EXT-mutation analysis and loss of heterozygosity in sporadic and hereditary osteochondromas and secondary chondrosarcomas. Bovee JV, Cleton-Jansen AM, Wuyts W, Caethoven G, Taminiau AH, Bakker E, Van Hul W, Cornelisse CJ, Hogendoorn PC. Am J Hum Genet 1999; 65: 689-698. Medline 10502322 Loss of heterozygosity and DNA ploidy point to a diverging genetic mechanism in the origin of peripheral and central chondrosarcoma. Bovee JV, Cleton-Jansen AM, Kuipers-Dijkshoorn NJ, van den Broek LJ, Taminiau AH, Cornelisse CJ, Hogendoorn PC.


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Genes Chromosomes Cancer 1999; 26: 237-246. Medline 10502322 Molecular genetic characterization of both components of a dedifferentiated chondrosarcoma, with implications for its histogenesis. Bovee JV, Cleton-Jansen AM, Rosenberg C, Taminiau AH, Cornelisse CJ, Hogendoorn PC. J Pathol 1999; 189: 454-462. Medline 10629543 Recurrent chromosome aberrations in fibrous dysplasia of the bone: a report of the CHAMP study group. CHromosomes And MorPhology. Dal Cin P, Sciot R, Brys P, De, Wever I, Dorfman H, Fletcher CD, Jonsson K, Mandahl N, Mertens F, Mitelman F, Rosai J, Rydholm A, Samson I, Tallini G, Van Den Berghe H, Vanni R, and Willen H. Cancer Genet Cytogenet 2000; 122: 30-32. Medline 11104029 Clonal chromosome abnormalities in enchondromas and chondrosarcomas. Gunawan B, Weber M, Bergmann F, Wildberger J, Niethard F U, and Fuzesi L. Cancer Genet Cytogenet 2000; 120: 127-130. Medline 10942802 Molecular Cytogenetics in Ewing Tumors: Diagnostic and Prognostic Information. Hattinger CM, Zoubek A, and Ambros PF. Onkologie 2000; 23: 416-422. Medline 11441235 Malignant fibrous histiocytoma: inherited and sporadic forms have loss of heterozygosity at chromosome bands 9p21-22-evidence for a common genetic defect. Martignetti, JA, Gelb, BD, Pierce H, Picci P, and Desnick R J. Genes Chromosomes Cancer 2000; 27: 191-195. Medline 10612808 Recurrent anomalies of 6q25 in chondromyxoid fibroma. Safar A, Nelson M, Neff JR, Maale GE, Bayani J, Squire J, and Bridge JA. Hum Pathol 2000; 31: 306-311. Medline 10746672 Frequent loss of 9p21 (p16(INK4A)) and other genomic imbalances in human malignant fibrous histiocytoma. Simons A., Schepens M., Jeuken J., Sprenger S, van de Zande G, Bjerkehagen B, Forus A, Weibolt V, Molenaar I, van den Berg E, Myklebost O, Bridge J, van Kessel, AG, and Suijkerbuijk R.


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Cancer Genet Cytogenet 2000; 118: 89-98. Medline 10748288 EXT genes are differentially expressed in bone and cartilage during mouse embryogenesis. Stickens D, Brown D, Evans GA. Dev Dyn 2000; 218: 452-464. Medline 9232192 Analysis of the p16INK4, p14ARF, p15, TP53, and MDM2 genes and their prognostic implications in osteosarcoma and Ewing sarcoma. Tsuchiya T, Sekine K, Hinohara S, Namiki T, Nobori T, and Kaneko Y Cancer Genet Cytogenet 2000; 120: 91-98. Medline 10942797 Chromosome 9 alterations and trisomy 22 in central chondrosarcoma: a cytogenetic and DNA flow cytometric analysis of chondrosarcoma subtypes. Bovée JVMG, Sciot R, Dal Cin P, Debiec-Rychter M, Van Zelderen-Bhola SL, Cornelisse CJ, and Hogendoorn PCW. Diagn Mol Pathol 2001; 10: 228-236. Medline 11763313 Genome-wide analysis of sixteen chordomas by comparative genomic hybridization and cytogenetics of the first human chordoma cell line, U-CH1. Scheil S, Bruderlein S, Liehr T, Starke H, Herms J, Schulte M, and Moller P. Genes Chromosomes Cancer 2001; 32: 203-211. Medline 11579460 Cytogenetic and molecular cytogenetic evidence of recurrent 8q24.1 loss in osteochondroma. Feely MG, Boehm AK, Bridge RS, Krallman PA, Neff JR, Nelson M, Bridge JA. Cancer Genet Cytogenet 2002; 137: 102-107. Medline 12393280 WHO Classification of tumours. Pathology & Genetics. Tumours of Bone and Soft tissue. Fletcher CDM, Unni KK, and Mertens F. IARC Press: Lyon 2002. Translocation der(13;21)(q10;q10) in Skeletal and Extraskeletal Mesenchymal Chondrosarcoma. Naumann S, Krallman PA, Unni KK. Mod Pathol 2002; 15: 572-576 Medline 12011263 Recurring breakpoints of 1p13 approximately p22 in osteochondroma.


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Yvonne M Schrage, Judith VMG Bovée.

Citation This paper should be referenced as such : Schrage YM, Bovée JVMG . Bone tumors: an overview. Atlas Genet Cytogenet Oncol Haematol. March 2005 . URL : http://AtlasGeneticsOncology.org/Tumors/BoneTumorID5143.html © Atlas of Genetics and Cytogenetics in Oncology and Haematology


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Pericytoma with t(7;12) Clinics and Pathology Disease


Phenotype / cell stem origin

Unknown

Embryonic origin

The cellular origin is unknown, but it presumably derives from the mesoderm. The tumor cells display cytoarchitectural, immunohistochemical and ultrastructural features highly suggestive of pericytic differentiation, and it seems likely that these lesions fall within the spectrum of myopericytic neoplasms.

Etiology

Unknown.

Epidemiology Presumably rare, but differential diagnostic problems may have hampered the distinction of these tumors in the past. Tumors that fall within the differential diagnosis include cellular examples of solitary fibrous tumors (also known as hemangiopericytoma), myofibroma(tosis), monophasic synovial sarcoma, mesenchymal chondrosarcoma, and metastatic endometrial stromal sarcoma. Affects both men and woman of all ages. No familial cases are known. Clinics

Seems to present as a solitary pain-less nodule. The locations reported so far have been the tongue (3 cases), the stomach (1 case) and the calf (1 case).

Pathology

Pericytomas with t(7;12) display a multilobulated, infiltrative growth pattern, and are composed of uniform spindle-shaped pericytic cells that are consistently arranged around small, thin-walled arborizing vessels. The spindle cells present small amounts of eosinophilic cytoplasm, and ovoid-to-tapered nuclei with vesicular chromatin and often a single nucleolus. No significant atypia or pleomorphism is present, and mitotic figures are rare.

Treatment

Preoperative chemotherapy has not proven efficient. Surgical excision seems to be the treatment of choice.

Prognosis

Based on a limited follow-up (22-120 months), pericytomas with t(7;12) are seemingly benign or low-malignant tumors. No signs of recurrence or metastasis have been reported.

Cytogenetics Cytogenetics The recurrently observed t(7;12)(p22;q13) is a specific translocation Morphological characteristic for the tumor type.


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Representative G-banded partial karyotype of the t(7;12)(p22;q13)

Cytogenetics Metaphase FISH mapping analysis on one case revealed that the Molecular breakpoints were located to BAC probes RP11-1275H24, and RP1193G19 on 7p22, and to BAC probes 181L23, and 772E1 on 12q13. The probes gave split signals on the respective derivatives. On the normal chromosomes, intact signals were seen. Probes

BAC probes RP11-1275H24 (AC092171; substantially larger than the 85 kb reported by the NCBI), and RP11-93G19 (BAC ends: AQ321651, AQ321650) spanning the ACTB locus, and BAC probes 181L23 (AC022506), and 772E1 (AC063917) spanning the GLI1 locus.


The t(7;12)(p22;q13), fuses the ACTB gene in 7p22, to the GLI1 gene in 12q13.

Gene Name

ACTB

Location

7p22

Dna / Rna

Six exons, spans approximately 3.4 kb of genomic DNA in the centromere-to-teleomere orientation. The translation initiation codon ATG is located to exon 2, and the stop codon to exon 6. The ACTB mRNA is approximately 1.8 kb. ACTB is abundantly expressed in all mammalian and avian non-muscle cells.

Protein

The open reading frame encodes a 374 amino acid protein, with an estimated molecular weight of approximately 41.7 kDa. The ACTB protein is located in the cytoplasm where it is a component (together with actin g) of the cytoskeleton.


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Gene Name

GLI1

Location

12q13

Dna / Rna

Twelve exons, spans approximately 12 kb of genomic DNA in the centromere-to-telomere orientation. The translation initiation codon is located in exon 2, and the stop codon in exon 12. The GLI1 mRNA transcript is 3.6 kb. GLI proteins function as direct effectors of sonic hedgehog-signaling during embryogenesis. GLI1 (also GLI2 and GLI3) are therefore likely to be involved in the tissue-specific proliferation of the central nervous system, the zones of polarizing activity in the developing limb, and of the gut. In the adult human, GLI1 expression has been demonstrated in the testes, myometrium and Fallopian tubes.

Protein

The open reading frame encodes an 1106 amino acid protein, with an estimated molecular weight of approximately 118 kDa. The GLI protein is a DNA binding transcription factor, also the last known step in the sonic hedgehog-signaling pathway. The GLI1 protein contains five DNAbinding zinc fingers between amino acids 235 and 393 (encoded by exons 7-10), and a transactivating domain constituted by amino acids 1020-1091 (encoded by exon 12).

Result of the chromosomal anomaly Hybrid Gene Note

To date, five cases of pericytoma with t(7;12) have been reported. All of them expressed an ACTB-GLI1 transcript, and two of them also expressed a reciprocal GLI1-ACTB fusion transcript. The genomic breakpoints of these fusions have been characterized, revealing that the respective breakpoints shared short common oligomers.

Detection

A detailed description of a protocol for the detection of ACTB-GLI1 and GLI1-ACTB chimeras has been reported.

Fusion Protein Note

The function of the ACTB-GLI1 chimera is unknown, but it is suggested that the strong ACTB promoter causes an over-expression of GLI1 sequences important for transcriptional activation of downstream target genes.

Description The ACTB-GLI1 fusion protein contains the N-terminal of ACTB and the C-terminal of GLI1, including the DNA-binding zinc finger motifs (encoded by exons 7-10) and transactivating motifs (exon 12).

Bibliography


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The human b-actin multigene family. Kedes L, Ng S-Y, Lin C-S, Gunning P, Eddy R, Shows T, Leavitt J. Trans Assoc Am Phys 1985; 98: 42-45. Medline 3842206 Molecular structure of the human cytoplasmic b-actin gene: interspecies homology of sequences in the introns. Nakajima-Iijima S, Hamada H, Reddy P, Kakunaga T. Proc Natl Acad Sci USA 1985; 82: 6133-6137. Medline 2994062 Evolution of the functional human b-actin gene and its multi-pseudogene family: conservation of noncoding regions and chromosomal dispersion of pseudogenes. Ng SY, Gunning P, Eddy R, Ponte P, Leavitt J, Shows T, Kedes L. Mol Cell Biol 1985; 5: 2720-2732. Medline 3837182 The GLI gene is a member of the Kruppel family of zinc finger proteins. Kinzler KW, Ruppert JM, Bigner SH, Vogelstein B. Nature 1988; 332: 371-374. Medline 2832761 The GLI gene encodes a nuclear protein which binds specific sequences in the human genome. Kinzler KW, Vogelstein B. Mol Cell Biol 1990; 10: 634-642. Medline 2105456 Characterization of the promoter region and genomic organization of GLI, a member of the Sonic hedgehog-Patched signaling pathway. Liu CZ, Yang JT, Yoon JW, Villavicencio E, Pfendler K, Walterhouse D, Iannaccone P. Gene 1998; 209: 1-11. Medline 9524201 The sonic hedgehog-patched-gli pathway in human development and disease. Villavicencio EH, Walterhouse DO, Iannaccone PM. Am J Hum Genet 2000; 67: 1047-1054 (Review). Medline 11001584 Myopericytoma. McMenamin ME World Health Organization Classification of Tumours. Pathology and Genetics of Tumours of Soft Tissue and Bone, Fletcher CDM, Unni KK, Mertens F (eds). Lyon, IARC Press 2002; pp. 138-139.


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Activation of the GLI oncogene through fusion with the beta-actin (ACTB) gene in a group of distinctive pericytic neoplasms: Òpericytoma with t(7;12)Ó. DahlŽn A, Fletcher CDM, Mertens F, Fletcher JA, Perez-Atayde AR, Hicks MJ, Debiec-Rychter M, Sciot R, Wejde J, Wedin R, Mandahl N, Panagopoulos I. Am J Pathol 2004; 164: 1645-1653 Medline 15111311 Molecular genetic characterization of the ACTB-GLI fusion in pericytoma with t(7;12). DahlŽn A, Mertens F, Mandahl N, Panagopoulos I. Biochem Biophys Res Commun 2004; 325: 1318-1323. Medline 15555571 REVIEW articles Last year publications



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Citation This paper should be referenced as such : Dahlén A, Mertens F, Mandahl N, Panagopoulos I . Pericytoma with t(7;12). Atlas Genet Cytogenet Oncol Haematol. March 2005 . URL : http://AtlasGeneticsOncology.org/Tumors/Pericytomt0712ID5192.html © Atlas of Genetics and Cytogenetics in Oncology and Haematology


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Bloom syndrome Identity Inheritance autosomal recessive; frequency is about 2/105 newborns in Ashkenazi Jews and in the Japanese (founder effect: affected persons descent from a common ancestor); much rarer otherwise

micronuclei (left); sister chromatid exchange (right) in a normal subject (herein: 19 SCE, instead of the hundred found in Bloom, see below) - Editor

Clinics Note

168 cases have been registered in the Bloom's syndrome Registry by James German; BS patients are predisposed to all types of cancer observed in the general population; thus, BS is a model of initiation and promotion of cancer, and highligths internal causes/processes of cancers

Phenotype and clinics

- phenotypic spectrum variable. - growth : dwarfism: intrauterine growth retardation; birth weight: below 2.3 kg; mean length: 44 cm; adult length < 145 cm. - skin: hyperpigmented (cafÈ au lait) spots; hypopigmented areas; sun sensitive telangiectatic erythema; in butterfly configuration across the face: resembles lupus erythematous - head: microcephaly; dolichocephaly; narrow face; prominent nose


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and/or ears; characteristic high-pitched voice - normal intelligence - immune deficiency --> frequent infections (may be life-threatening) - other: myocardopathy; hypogonadism in male patients; hypertriglyceridemia Neoplastic risk

nearly half of patients have had at least one cancer (10% of whom having had more than one primary cancer, which is quite characteristic of Bloom's); mean age at first cancer onset: 25 yrs (range: 2-49 yrs) acute leukaemias (ALL and ANLL) in 15 % of cases; lymphomas in 15 % as well; these occur mainly before the thirties carcinomas (of a wide variety) occur in 30 % of cases, mainly after the age of 20 yrs benign tumours (10%)

Evolution

major medical complications apart from cancers are : chronic lung disease, and diabetes mellitus (in 10 %)

Prognosis

1/3 of patients are dead at mean age 24 yrs (oldest died at 49 yrs, youngest died before 1 yr) and the mean age of the 2/3 remaining alive patients is 22 yrs (range: 4-46 yrs)

Cytogenetics Inborn conditions

chromatid/chromosome breaks; triradial and quadriradial figures, in particular symetrical quadriradial configuration involving homologous chromosomes (Class I qr), which are pathognomonic and which may be due to a mitotic crossing-over; micronuclei . diagnosis is on the (pathognomonic) highly elevated spontaneous sister chromatid exchange rate (90 SCE per cell; more than 10 times what is normally found); in some persons a minor population of low SCE cells exists, suggesting a recombination event between maternal and paternal alleles (with different mutations), giving rise to a wild type functional gene; this allowed to localize the gene in a very elegant strategy. heterozygotes are not detectable by cytogenetic studies.


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sister chromatid exchange in a normal subject (left) and in a Bloom syndrome patient (right) (from: Mounira Amor-Guéret)

Other findings Note

slowing of the cell cycle (lenthening of the G1 and S phases) spontaneous mutation rate 10 times higher than normal cells

Genes involved and Proteins Complementation no complementation group groups Gene Name

BLM

Location

15q26.1

Protein Description 1417 amino acids; contains one ATP binding site, one DEAH box, and two putative nuclear localization signals Expression accumulates to high levels in S phase of the cell cycle, persists in G2/M and sharply declines in G1; hyperphoshorylated in mitosis Localisation nuclear (PML nuclear bodies and nucleolus) Function

3-5 DNA helicase; probable role in DNA replication and doublestrand break repair Preferred substrates: G-quadruplex DNA, D-loops structures and Xjunctions. Recombinant protein promotes ATP-dependent branch migration of Hollyday junctions. participates in a supercomplex of BRCA1-associated proteins named BASC (BRCA1-Associated genome Surveillance Complex) and in a complex named BRAFT (BLM, RPA, FA, Topoisomerase IIIalpha) containing five of the Fanconia Anemia (FA) complementation group proteins (FANCA, FANCG, FANCC, FANCE and FANCF). Interacts physically and/or functionally with p53, 53BP1,WRN, MLH1, RAD51, TRF2, ligase IV, FEN1 Associated with telomeres and ribosomal DNA repeats. Phosphorylated in mitotic cells through the cdc2 pathway, and in response to DNA damaging agents.

Homology

with the RecQ helicases

Mutations Germinal

five BLM mutations introducing amino acid substitutions and four BLM mutations introducing premature nonsense codons into the coding sequence have been described to date; one BLM mutation consisting in a 6 bp deletion accompanied by a 7 bp insertion at nucleic acid position 2281 is common in patients from Ashkenazi Jewish ancestry, leading to a truncated protein of 739 amino acids in length; two BLM mutations, 631delCAA and 1610insA were detected in japanese patients.


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External links GeneCards BLM GDB

BLM

OMIM

210900

Orphanet

Bloom syndrome

HGMD

135698

Bibliography Bloom's syndrome. I. Genetical and clinical observations in the first twenty seven patients. German J. Am J Hum Genet 1969; 2: 196-227. Syndromes of the head and neck. Gorlin RJ, Cohen MM, Levin LS. Oxford Monogr Med Genet 1990; 19: 297-300. The Bloom's syndome gene product is homologous to RecQ helicases. Ellis NA, Groden J, Ye TZ, Straughen J, Lennon DJ, Ciocci S, Proytcheva M, German J. Cell 1995; 83: 655-666. Medline 96069866 Molecular genetics of Bloom's syndrome. Ellis NA and German J. Hum Mol Genet 1996; 5 Spec No: 1457-1463 (REVIEW). Medline 97029240 Characterization of a new BLM mutation associated with a topoisomerase II alpha defect in a patient with Bloom's syndrom Foucault F, Vaury C, Barakat A, Thibout D, Planchon P, Jaulin C, Praz F, AmorGueret M. Hum Mol Genet 1997; 6: 1427-1434. Medline 97449163 Bloom's syndrome. XX. The first 100 cancers. German J Cancer Genet Cytogenet 1997; 93: 100-106. (REVIEW). Medline 9062585 BLM (the causative gene of Bloom syndrome) protein translocation into the nucleus by a nuclear localization signal. Kaneko H, Orii KO, Matsui E, Shimozawa N, Fukao T, Matsumoto T, Shimamoto A, Furuichi Y, Hayakawa S, Kasahara K, Kondo N


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Biochem Biophys Res Commun 1997; 240: 348-353. Medline 98049834 The Bloom's syndrome gene product is a 3'-5' DNA helicase. Karow JK, Chakraverty RK, Hickson ID. J Biol Chem 1997; 272: 30611-30614. Medline 98049515 The Bloom's syndrome helicase unwinds G4 DNA. Sun H, Karow JK, Hickson ID, Maizels N. J Biol Chem 1998; 273: 27587-27592 Medline 9765292 PML is critical for ND10 formation and recruits the PML-interacting protein daxx to this nuclear structure when modified by SUMO-1. Ishov AM, Sotnikov AG, Negorev D, Vladimirova OV, Neff N, Kamitani T, Yeh ET, Strauss JF 3rd, Maul GG. J Cell Biol 1999; 147: 221-234. Medline 10525530 ATM-dependent phosphorylation and accumulation of endogenous BLM protein in response to ionizing radiation. Ababou M, Dutertre S, Lecluse Y, Onclercq R, Chatton B, Amor-Gueret M. Oncogene 2000; 19: 5955-5963. Medline 11146546 Identification of a novel BLM missense mutation (2706T>C) in a moroccan patient with Bloom's syndrome. Barakat A, Ababou M, Onclercq R, Dutertre S, Chadli E, Hda N, Benslimane A, Amor-Gueret M. Hum Mutat 2000; 6: 584-585. Medline 20321320 Cell cycle regulation of the endogenous wild type Bloom's syndrome DNA helicase. Dutertre S, Ababou M, Onclercq R, Delic J, Chatton B, Jaulin C, Amor-Gueret M. Oncogene 2000; 19: 2731-2738. Medline 20309931 The Bloom's syndrome gene product promotes branch migration of holliday junctions. Karow JK, Constantinou A, Li JL, West SC, Hickson ID. Proc Natl Acad Sci U S A 2000; 97: 6504-6508. Medline 20300930 Binding and melting of D-loops by the Bloom syndrome helicase.


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van Brabant AJ, Ye T, Sanz M, German III JL, Ellis NA, Holloman WK. Biochemistry 2000; 39: 14617-14625 Medline 11087418 BASC, a super complex of BRCA1-associated proteins involved in the recognition and repair of aberrant DNA structures. Wang Y, Cortez D, Yazdi P, Neff N, Elledge SJ, Qin J. Genes Dev 2000; 14: 927-939. Medline 20245492 Nuclear structure in normal and Bloom syndrome cells. Yankiwski V, Marciniak RA, Guarente L, Neff NF. Proc Natl Acad Sci U S A 2000; 97: 5214-5219. Medline 10779560 Regulation and localization of the Bloom syndrome protein in response to DNA damage. Bischof O, Kim SH, Irving J, Beresten S, Ellis NA, Campisi J. J Cell Biol 2001; 153: 367-380. Medline 11309417 The Bloom syndrome protein interacts and cooperates with p53 in regulation of transcription and cell growth control. Garkavtsev IV, Kley N, Grigorian IA, Gudkov AV. Oncogene 2001; 20: 8276-828 Medline 11781842 The Bloom's syndrome protein (BLM) interacts with MLH1 but is not required for DNA mismatch repair. Langland G, Kordich J, Creaney J, Goss KH, Lillard-Wetherell K, Bebenek K, Kunkel TA, Groden J. J Biol Chem 2001; 276: 30031-30035. Medline 11325959 The Bloom's and Werner's syndrome proteins are DNA structure-specific helicases. Mohaghegh P, Karow JK, Brosh Jr RM Jr, Bohr VA, Hickson ID. Nucleic Acids Res 2001; 29: 2843-2849. Medline 11433031 Direct association of Bloom's syndrome gene product with the human mismatch repair protein MLH1. Pedrazzi G, Perrera C, Blaser H, Kuster P, Marra G, Davies SL, Ryu GH, Freire R, Hickson ID, Jiricny J, Stagljar I. Nucleic Acids Res 2001; 29: 4378-4386. Medline 11691925


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Functional interaction of p53 and BLM DNA helicase in apoptosis. Wang XW, Tseng A, Ellis NA, Spillare EA, Linke SP, Robles AI, Seker H, Yang Q, Hu P, Beresten S, Bemmels NA, Garfield S, Harris CC. J Biol Chem 2001; 276: 32948-32955. Medline 11399766 Potential role for the BLM helicase in recombinational repair via a conserved interaction with RAD51. Wu L, Davies SL, Levitt NC, Hickson ID. J Biol Chem 2001; 276: 19375-19381. Medline 11278509 Bloom's syndrome protein response to ultraviolet-C radiation and hydroxyurea-mediated DNA synthesis inhibition. Ababou M, Dumaire V, Lecluse Y, Amor-Gueret M. Oncogene 2002; 21: 2079-2088. Medline 11960380 Increased error-prone non homologous DNA end-joining--a proposed mechanism of chromosomal instability in Bloom's syndrome. Gaymes TJ, North PS, Brady N, Hickson ID, Mufti GJ, Rassool FV. Oncogene 2002; 21: 2525-2533 Medline 11971187 The BLM helicase is necessary for normal DNA double-strand break repair. Langland G, Elliott J, Li Y, Creaney J, Dixon K, Groden J. Cancer Res 2002; 62: 2766-2770. Medline 12019152 Telomere-binding protein TRF2 binds to and stimulates the Werner and Bloom syndrome helicases. Opresko PL, von Kobbe C, Laine JP, Harrigan J, Hickson ID, Bohr VA. J Biol Chem 2002; 277: 41110-41119. Medline 12181313 The Bloom syndrome helicase BLM interacts with TRF2 in ALT cells and promotes telomeric DNA synthesis. Stavropoulos DJ, Bradshaw PS, Li X, Pasic I, Truong K, Ikura M, Ungrin M, Meyn MS. Hum Mol Genet 2002; 11: 3135-3144. Medline 12444098 Colocalization, physical, and functional interaction between Werner and Bloom syndrome proteins. von Kobbe C, Karmakar P, Dawut L, Opresko P, Zeng X, Brosh RM Jr, Hickson ID,


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Bohr VA. J Biol Chem 2002; 277: 22035-22044. Medline 11919194 The processing of Holliday junctions by BLM and WRN helicases is regulated by p53. Yang Q, Zhang R, Wang XW, Spillare EA, Linke SP, Subramanian D, Griffith JD, Li JL, Hickson ID, Shen JC, Loeb LA, Mazur SJ, Appella E, Brosh RM Jr, Karmakar P, Bohr VA, Harris CC. J Biol Chem 2002; 277: 31980-31987. Medline 12080066 A multiprotein nuclear complex connects Fanconi anemia and Bloom syndrom Meetei AR, Sechi S, Wallisch M, Yang D, Young MK, Joenje H, Hoatlin ME, Wang W. Mol Cell Biol 2003; 23: 3417-2346. Medline 12724401 Possible anti-recombinogenic role of Bloom's syndrome helicase in doublestrand break processing. Onclercq-Delic R, Calsou P, Delteil C, Salles B, Papadopoulo D, Amor-Gueret M. Nucleic Acids Res 2003; 31: 6272-6782. Medline 14576316 BLM helicase-dependent transport of p53 to sites of stalled DNA replication forks modulates homologous recombination. Sengupta S, Linke SP, Pedeux R, Yang Q, Farnsworth J, Garfield SH, Valerie K, Shay JW, Ellis NA, Wasylyk B, Harris CC. EMBO J 2003; 22: 1210-1222. Medline 12606585 Telomere and ribosomal DNA repeats are chromosomal targets of the bloom syndrome DNA helicase. Schawalder J, Paric E, Neff NF. BMC Cell Biol 2003; 4: 15 Medline 14577841 Relatively common mutations of the Bloom syndrome gene in the Japanese population. Kaneko H, Isogai K, Fukao T, Matsui E, Kasahara K, Yachie A, Seki H, Koizumi S, Arai M, Utunomiya J, Miki Y, Kondo N. Int J Mol Med 2004; 14: 439-442. Medline 15289897 A major role for mitotic CDC2 kinase inactivation in the establishment of the mitotic DNA damage checkpoint. Bayart E, Grigorieva O, Leibovitch S, Onclercq-Delic R, Amor-Gueret M.


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Cancer Res 2004; 64: 8954-8959. Medline 15604258 Functional interaction between BLM helicase and 53BP1 in a Chk1-mediated pathway during S-phase arrest. Sengupta S, Robles AI, Linke SP, Sinogeeva NI, Zhang R, Pedeux R, Ward IM, Celeste A, Nussenzweig A, Chen J, Halazonetis TD, Harris CC. J Cell Biol 2004; 166: 801-813. Medline 15364958 Genetic interactions between BLM and DNA ligase IV in human cell So S, Adachi N, Lieber MR, Koyama H. J Biol Chem 2004; 279: 55433-55442. Medline 15509577 Human bloom protein stimulates flap endonuclease 1 activity by resolving DNA secondary structure. Wang W, Bambara RA. J Biol Chem. 2005; 280: 5391-5399 Medline 15579905 REVIEW articles Last year publications



021998

Jean-Loup Huret

Updated

092000

Mounira Amor-Guéret

Updated

022005

Mounira Amor-Guéret

Citation This paper should be referenced as such : Huret JL . Bloom syndrome. Atlas Genet Cytogenet Oncol Haematol. February 1998 . URL : http://AtlasGeneticsOncology.org/Kprones/BLO10002.html Amor-Guéret M . Bloom syndrome. Atlas Genet Cytogenet Oncol Haematol. September 2000 . URL : http://AtlasGeneticsOncology.org/Kprones/BLO10002.html Amor-Guéret M . Bloom syndrome. Atlas Genet Cytogenet Oncol Haematol. February 2005 . URL : http://AtlasGeneticsOncology.org/Kprones/BLO10002.html © Atlas of Genetics and Cytogenetics in Oncology and Haematology


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Waardenburg syndrome (WS) Identity Note

Other names

Waardenburg syndrome (WS) is an auditory-pigmentary syndrome caused by a deficiency of melanocytes and other neural crest-derived cells. The disease was named for Petrus Johannes Waardenburg, a Dutch ophthalmologist (1886-1979) who was the first to notice that people with two different coloured eyes frequently had hearing problems. Klein-Waardenburg syndrome (WS3) Waardenburg syndrome with upper limb anomalies (WS3) White forelock with malformations (WS3) Waardenburg-Hirschsprung disease (WS4) Waardenburg syndrome variant (WS4) Shan-Waardenburg syndrome (WS4) Hirschsprung disease with pigmentary anomaly (WS4)

Inheritance Inherited in an autosomal dominant manner with an incidence of 1 in 40 000 newborns. Almost 90% of patients have an affected parent but the symptoms in the parent can be quite different from those in the child.

Clinics Note

Waardenburg syndrome (WS) is a hereditary auditory-pigmentary syndrome, the major symptoms being congenital sensorineural hearing loss and pigmentary disturbance of eyes, hair and skin. Depending in additional symptoms, WS can be classified into four types: WS type I (WS1) is associated with facial deformity such as dystopia canthorum (lateral displacement of the inner canthi); WS2 has no other symptoms; WS3 is associated with upper limb deformity; and WS4, with megacolon.


Disease with variable penetrance and several know clinical types. Characteristics may include depigmentation of the hair and skin, congenital deafness, heterochromia iridis, medial eyebrow hyperplasia, hypertrophy of the nasal root, and especially dystopia canthorum. The underlying cause may be defective development of the neural crest (neurocristopathy). Waardenburg's syndrome may be closely related to piebaldism. Klein-Waardenburg syndrome refers to a disorder that also includes upper limb abnormalities.

Neoplastic risk Treatment

Slight increased risk for rhabdomyosarcoma. No specific treatment is available for Waardenburg syndrome. Attention must be paid to any hearing deficit and hearing aids and appropriate


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schooling may need to be provided. Type 4 patients with constipation require special attention to their diet and medications to keep their bowels moving. Prognosis

With correction of hearing deficits, affected people should be able to lead a normal life.


WS can be classified into for types. At least one gene responsible for each type of WS has been cloned and for these cloning procedures mice with pigmentation anomalies have contributed greatly. Six genes contributing to this syndrome- PAX3, SOX10, MITF, SLUG, EDN3 and EDNRB- have been cloned so far, all of them necessary for normal development of melanocytes. Table 1: Genes involved in Waardenburg syndrome (WS): GENE Syndrome Specific symptoms PAX3

WS1; WS3

Dysthopia canthorum, hypoplasia of limb muscle; contracture of elbows, fingers.

MITF

WS2

Main symptoms only (auditorypigmentary syndrome)

SLUG

WS2

Main symptoms only (auditorypigmentary syndrome)

EDNRB WS4

Hirschsprung´s disease

EDN3

WS4


SOX10 WS4


Gene Name

PAX3.

Location

2q35-q37

Note

PAX3 is an important gene in muscle development and muscleproducing neoplasms such as rhabdomyosarcomas.

DNA/RNA Description 10 exons Protein Description 206-215 residues Expression is expressed during embryonic development. Skeletal muscle, esophagus, cerebellum, pancreas, liver and stomach. Function

Transcription factor

Mutations Note

Mutations in PAX3, which encodes a paired homeodomain transcription factor, are responsible for Waardenburg syndrome 1 and 3. PAX3 was shown to bind and transactivate the MITF promoter, thereby demonstrating the role of PAX3 in the regulation of MITF expression.


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This observation supports an epistatic relationship between MITF and PAX3 and can explain the pigmentary disorders observed in WS1 and 3, because MITF controls melanocyte development. PAX3 defects affect neural crest cell derivatives, resulting in the presence of craneofacial malformations. Gene Name

SOX10

Location

22q13

DNA/RNA Description 5 exons Protein Note

SOX10, a protein that modulates other transcription factors (including PAX3) belongs to the high mobility group (HMG) box superfamily of DNA-binding proteins. It is first expressed during development in cells of the neural crest that contributes to the forming peripheral nervous system, and can be detected in the sensory, sympathetic and enteric ganglia and along nerves. SOX10 is also transiently expressed in melanoblast.

Description 466 residues Expression During development in cells of the neural crest. Function

Transcription factor.

Mutations Note

Mutations in Sox10 also result in WS4. How mutations in this gene lead to deafness and pigmentary abnormalities, shared by all the WS subtypes, was not elucidated. It was tempting to propose that the WS4 genes are directly or indirectly involved in the regulation of MITF expression that is crucial for melanocyte development. SOX10 binds and transactivates the MITF promoter, whereas Sox10 mutants found in WS4 patients failed to stimulate the MITF promoter. Thus, there is an epistatic relationship between SOX1 and MITF, thereby giving a molecular basis for the audio-pigmentary defect in patients with WS4. SOX10 joins Pax3, CREB and LEF1 in the list of transcription factors that control MITF expression.

Gene Name

MITF

Location

3p14.1-p12.3


Microphtalmia-associated transcription factor (MITF) is a basic helix-


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loop-helix, leucin zipper transcription factor that plays a pivotal role in survival and differentiation of melanocytes, the cells that produce melanin pigments. MITF has been demonstrated to up-regulate the expression of the genes involved in melanin synthesis, such as tyrosine, TRP1, and TRP2. Further MITF is thought to be a master gene in melanocyte differentiation, because its forced expression in fibroblast leads to the expression of melanocytes-specific enzymes required for melanin synthesis. Description 520 residues Expression in melanocytes Function

Transcription factor

Mutations Note

In humans, mutations, of MITF are responsible for Waardenburg syndrome (WS) type 2, characterized by pigmentation abnormalities and sensorineural deafness due to the absence of melanocytes from the stria vascularis of the inner ear. In mice, mutations in the microphthalmia gene cause pigmentation disorders because of the absence of melanocytes, supporting the involvement of MITF in melanocyte survival. Over 20 different Mitf mutations have been described in mice. They all result in a deficiency in skin or coat melanocytes ranging in severity from minor pigmentary defects with normal eyes to total lack of coat and eye pigmentation, small colobomatous eyes, deafness and in some instances osteopetrosis.

Gene Name

SLUG

Location

8q11.21


SLUG a zinc finger transcription factor is a marker of neural crest cells in Xenopus, zebrafish and chick embryos and probably has a functional role in formation of premigratory neural crest. In the mouse, the corresponding gene, Slugh, is expressed in migratory but not premigratory neural crest cells and is not essential for neural crest development.

Description 268 residues Expression Placenta, adult heart, pancreas, liver, kidney and skeletal muscle. Function

Transcriptional repressor.

Mutations Note

Mice lacking Slugh have patchy deficiency of melanocytes, a phenotype similar to human Waardenburg syndrome. It has been shown that some


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human patients with Waardenburg syndrome carry homozygous deletions of SLUG as their only detected genetic abnormality, thus defining a recesive form of type 2 WS. Preliminary investigations of the role of SLUG in melanocyte development show that it is a downstream target of MITF, which acts on an E-box sequence in the SLUG promoter. Gene Name

EDN3 (ENDOTHELIN 3)

Location

20q13.2-q13.3

DNA/RNA Description 5 exons Protein Description 230 residues Expression trophoblasts, placental stem villi vessels. Function

Peptide hormone.

Gene Name

EDNRB (ENDOTHELIN RECEPTOR, TYPE B)

Location

13q22

DNA/RNA Description 7 exons Protein Description 442 residues Expression lung, placenta, kidney and skeletal muscle. Function

G protein-coupled receptor.

Mutations Note

WS4 is also caused by mutations in endothelin B receptor or in endothelin 3. How mutations in these genes lead to deafness and pigmentary abnormalities, shared by all the WS subtypes, was not elucidated. It was tempting to propose that the WS4 genes are directly or indirectly involved in the regulation of MITF expression that is crucial for melanocyte development.

To be noted Mouse models Mutant mice with coat color anomalies were helpful in identifying these genes, although the phenotypes of these mice did not necessarily perfectly match those of the four types of WS. There are several mice with mutations of murine homologs of WS genes and verify their


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suitability as models for WS with special interest in the cochlear disorder. The mice include splotch (Sp), microphthalmia (mi), Slugh -/-, WS4, JF1, lethal-spotting (ls), and Dominant megacolon (Dom). splotch (Sp) mice as a model for WS1 The mouse Pax3 gene was identified as the gene responsible for splotch (Sp) mice. Sp mice exhibit a number of characteristic developmental anomalies which predominantly affect the neural tube and neural crest. Severe alleles in six types of homozygous Sp mice are fatal at the embryonic stage, and even splotch-retarded (Spd) mice, which have the least severe allele, encoding Pax3 with a substitution mutation at the paired domain, die at birth. Heterozygous Sp (Sp/+) mice survive after birth and have white belly spots, but curiously, showed no sign of auditory defects; WS1 patients are usually heterozygous at the PAX3 gene and yet many show auditory dysfunction. The phenotype of Spd mice varies depending on their genetic background, suggesting the existence of modifier genes. It has been estimated that at least two genes interact with Spd to influence the craniofacial features. microphthalmia (mi) mice as a model for WS2 Homozygous mi mice are microphthalmic due to the loss of retinal pigmentary epithelial (RPE) cells, white in coat color due to the loss of melanocytes, and deaf. 11 types of mi gene mutations, so far identified in mi mice, are transmitted in either a recesive or semi-dominant manner. In contrast, in humans is transmitted in a dominant manner. Slugh-/- mice as a model for WS2 Slugh-/- mice have diluted coat color, a white forehead blaze, and areas of depigmentation on the ventral body, tail and feet. Hearing function has not yet been assessed in Slugh-/- mice, but hyperactivity and circling behaviours observed in some Slugh-/- mice suggest a vestibulecochlear disorder. WS4 mice as a model for WS4 Homozygous WS4 mice showed pigmentation anomaly (white coat color with black eye), aganglionic megacolon and cochlear disorder. Exons 2 and 3, which encode transmembrane domains III and IV of the Ednrb G-protein-coupled receptor protein, were deleted in these mice. Cochlea of WS4 mice showed endolymphatic collapse, due to the lack of melanocytes (intermediate cells) in the stria vascularis. JF1 mice as a model for WS2 The JF1 mice are an inbred strain of mice derived from Japanese wild mice, which are often bred by Japanese laymen as fancy ³panda² mice because of their cute appearance with black eyes and white spotting on a black coat. JF1 mice are not lethal even in the homozygous state. This non-lethality of JF1 mice is probably due to the fact that the mutation in mice is an insertional mutation in intron 1 that creates a


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cryptic splicing acceptor site that results in decreased expression of wild-type Ednrb but does not cause aganglionic megacolon. As JF1 mice have pigmentation anomalies and hearing impairment- but not megacolon or dysmorphogenesis- they constitute a mouse model of WS2. These notions are consistent with the finding that WS2 is occasionally caused by mutations in EDNRB. lethal-spotted (ls) mice as a model for WS4 Homozygous mutations of the endothelin 3 (EDN3) gene cause coat spotting and aganglionic megacolon in ls mice and gene targeted edn3 null mice. Some of these mice can survive and mate; they are potentially a model for WS4, although cochlear disorders of these mice remain to be examined. Dominant megacolon (Dom) mice as a model for WS4 The Sox10 gene is mutated in the dominant megacolon (Dom) mouse, an animal model of neurocristopathy, whose phenotype is reminiscent of Waardenburg-Hirschsprung patients. The pigmentary phenotype also suggests that Sox10 expression is essential for melanocyte development. Homozygous Dom mice are lethal and their embryos lack neural crestderived cells expressing the melanocyte lineage markers. Heterozygous Dom mice show white spotting and some of them show megacolon. Dom mice not respond to sound. They did not show endolymphatic collapse, suggesting that their stria vascularis had intermediate cells (melanocytes) sufficient for normal production of endolymph. However, their organ of Corti was missing.

Bibliography The Sox10 (Dom) mouse: modeling the genetic variation of Waardenburg-Shah (WS4) syndrome. Southard-Smith EM, Angrist M, Ellison JS, Agarwala R, Baxevanis AD, Chakravarti A, Pavan WJ. Genome Res 1999 Mar; 9(3): 215-225. Medline 10077527 Interaction among SOX10, PAX3 and MITF, three genes altered in Waardenburg syndrome. Bondurand N, Pingault V, Goerich DE, Lemort N, Sock E, Caignec CL, Wegner M, Goossens M. Hum Mol Genet 2000 Aug 12; 9(13): 1907-1917. Medline 10942418 MITF: a stream flowing for pigment cells. Tachibana M. Pigment Cell Res 2000 Aug; 13(4): 230-240. Review. Medline 10952390


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Neurological phenotype in Waardenburg syndrome type 4 correlates with novel SOX10 truncating mutations and expression in developing brain. Touraine RL, Attie-Bitach T, Manceau E, Korsch E, Sarda P, Pingault V, EnchaRazavi F, Pelet A, Auge J, Nivelon-Chevallier A, Holschneider AM, Munnes M, Doerfler W, Goossens M, Munnich A, Vekemans M, Lyonnet S. Am J Hum Genet 2000 May; 66(5): 1496-1503. Epub 2000 Apr 04. Erratum in: Am J Hum Genet 2000 Jun; 66(6): 2020. Medline 10762540 Regulation of the microphthalmia-associated transcription factor gene by the Waardenburg syndrome type 4 gene, SOX10. Verastegui C, Bille K, Ortonne JP, Ballotti R. J Biol Chem 2000 Oct 6; 275(40): 30757-30760. Medline 10938265 EDNRB/EDN3 and Hirschsprung disease type II. McCallion AS, Chakravarti A. Pigment Cell Res 2001 Jun; 14(3): 161-169. Review. Medline 11434563 Waardenburg syndrome. Konno P, Silm H J Eur Acad Dermatol Venereol 2001 Jul; 15(4): 330-333. Medline 11730045 A mouse model of Waardenburg syndrome type 4 with a new spontaneous mutation of the endothelin-B receptor gene. Matsushima Y, Shinkai Y, Kobayashi Y, Sakamoto M, Kunieda T, Tachibana M. Mamm Genome 2002 Jan; 13(1): 30-35. Medline 11773966 SLUG (SNAI2) deletions in patients with Waardenburg disease. Sanchez-Martin M, Rodriguez-Garcia A, Perez-Losada J, Sagrera A, Read AP, Sanchez-Garcia I. Hum Mol Genet 2002 Dec 1; 11(25): 3231-3236. Medline 12444107 Mouse models for four types of Waardenburg syndrome. Tachibana M, Kobayashi Y, Matsushima Y. Pigment Cell Res 2003 Oct; 16(5): 448-454. Review. Medline 12950719 REVIEW articles Last year publications


Contributor(s) Atlas Genet Cytogenet Oncol Haematol 2005; 2

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Written

022005

Carolina Vicente-Duen˜as, Camino Bermejo-Rodríguez, María Pérez-Caro, Inés González-Herrero, Manuel Sánchez-Martín, Isidro Sánchez-García.

Citation This paper should be referenced as such : Vicente-Dueña;s C, Bermejo-Rodríguez C, Pérez-Caro M, González-Herrero I, Sánchez-Martín M, Sánchez-García I . Waardenburg syndrome (WS). Atlas Genet Cytogenet Oncol Haematol. February 2005 . URL : http://www.infobiogen.fr/services/chromcancer/Tumors/WaardenburgID10089.html © Atlas of Genetics and Cytogenetics in Oncology and Haematology


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Shwachman-Diamond Syndrome (SDS) Identity Inheritance Autosomal recessive inheritance. Male to female ratio 1.7 : 1

Clinics Note

Bone marrow failure syndrome with exocrine pancreatic dysfunction and growth retardation, many phenotypic features often present at birth.


Intermittent neutropenia is the most common haematological finding (85-100%); in addition aplastic anemia (80%), increased hemoglobin F levels (80%), thrombocytopenia (25-85%) and impaired neutrophil chemotaxis, B- and T-cell defects can be found. Fluctuating or persistent exocrine pancreatic dysfunction (with low serum amylase in 50-75%, low serum trypsinogen in 70-98% and abnormal pancreatic stimulation test in nearly 100%), Growth retardation (shortness 60%, weight 50%, microcephalus

adenomatous polyposis coli

adenomatous polyposis coli

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