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DISEASE OF THE MONTH EBERHARD RITZ, FEATURE EDITOR
Eye and Kidney: From Clinical Findings to Genetic Explanations HASSANE IZZEDINE,* BAHRAM BODAGHI,† VINCENT LAUNAY-VACHER,* and GILBERT DERAY* *Nephrology and †Ophthalmology Departments, Pitie-Salpetriere Hospital, Paris, France.
Although the study of embryonic eye and kidney development was first studied in the middle of the 19th century, three decades passed until scientists identified the molecular controls of both renal and eye organogenesis. Most of these advances have come from mouse and rodent gene manipulation. Translation of the mouse data to human congenital oculorenal disease has just begun. Examples of these genes include Pax2 and bone morphogenic protein 7 (BMP-7). Others factors that participate in mouse ocular and renal organogenesis, such as epithelial growth factor or integrins, may later be proven important in human eye and kidney development. A variety of human congenital syndromes affecting both organs have been described. An interesting pathophysiological classification scheme on kidney diseases has been very recently reported by Pohl et al (1). We propose a clinical diagnostic approach of oculorenal syndromes with their genetic’s links.
Renal Dysgenesis and Eye Abnormalities Pax and WT1 Gene Families Pax genes are a family of developmental control genes that encode nuclear transcription factors. They are characterized by the presence of the paired domain, a conserved amino acid motif with DNA-binding activity. Originally, paired-box-containing genes were detected in Drosophila melanogaster, where they exert multiple functions during embryogenesis. In vertebrates, Pax genes are also involved in embryogenesis. Mutations in four out nine characterized Pax genes have been associated with either congenital human diseases such as Waardenburg syndrome (Pax3), Aniridia (Pax6), Peter’s anomaly (Pax6), renal coloboma syndrome (Pax2), or spontaneous mouse mutants, which all show defects in development. Recently, analysis of spontaneous and transgenic mouse mutants has revealed that vertebrate pax genes are key regulators during organogenesis of kidney, eye, ear, nose, limb muscles, vertebral column, and brain (2).
Correspondence to Dr. Hassane Izzedine, Department of Nephrology, 47– 83 Boulevard de l’Hoˆpital, 75013 Paris France. Phone: ⫹33-0-1-42-17-72-26; Fax: ⫹33-0-1-42-17-72-32; E-mail:
[email protected] 1046-6673/1402-0516 Journal of the American Society of Nephrology Copyright © 2003 by the American Society of Nephrology DOI: 10.1097/01.ASN.0000051705.97966.AD
The expression pattern of Wilms’ tumor suppressor 1 (WT1) during embryogenesis is highly complex. WT1 has at least two functions during the first stage of kidney development. First, it may be required for the inductive signal that induces the outgrowth of the ureter from the mesonephros. Second, it seems to be involved in either survival or reception of the survival signal from the ureteric bud (3). In addition to its role in genitourinary formation, WT1 is required for the differentiation of ganglion cells in the developing retina (4). Wilms’ tumor gene was originally identified on the basis of its mutational inactivation in 10 to 15% of all Wilms’ tumors. A preliminary report on the expression of WT1 in the developing eye is remarkable because it points toward a possible role for WT1 in ocular development (5). Severe abnormalities were also found in the WT1⫺/⫺ retinas at later stages of development. Consistent with the expression of WT1 in the inner portion of the WT1⫹/⫹ retina, a significant fraction of cells was lost apoptosis in the developing retinal ganglion cells of mutant E18 embryos. Defects in the remaining ganglion cells in the WT1⫺/⫺ retinas are indicated by failure of these cells to give rise to normally growing optic nerve fiber bundles. This phenotype of the WT1⫺/⫺ retinas is reminiscent of the abnormalities seen in mice, which lack the POU-domain transcription factor Pou4f2 (also known as Brn-3b) (6). Coloboma. Typical isolated ocular coloboma is a congenital abnormality caused by defective closure of the embryonic fissure of the optic cup (Figure 1). The defect is typically located in the lower part of the iris. The association of a coloboma to urinary anomalies may evoke a papillorenal syndrome. However, among some patients with a ‘renal-coloboma‘ syndrome, Pax2 mutation was not found. A clinical analysis can nevertheless help the diagnostic orientation as shown in Figure 2. Renal-Coloboma Syndrome (OMIM 120330). The predominant abnormalities associated with renal-coloboma syndrome are bilateral optic nerve colobomas and renal hypoplasia, with or without renal failure. A significant degree of clinical variation is observed between family members who share the same mutation (7). Moreover, patients with renal-coloboma syndrome and Pax2 mutations may have additional congenital anomalies that occur with variable penetrance. These anomalies include vesico-ureteral reflux (VUR), auditory anomalies, CNS anomalies, and skin and joint anomalies (8).
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Figure 1. Fundus photograph showing a large coloboma involving the optic disc and the adjacent retina.
Figure 2. Coloboma with renal anomalies.
Patients with mutations in Pax2 have colobomatous eye defects. Developmental abnormalities of the optic fissure during optic cup and stalk development result in a group of defects, including orbital cysts, microphthalmia, optic disc dysplasia, and colobomas of the optic nerve and (9) All patients identified to have mutations in Pax2 have been observed to have colobomatous defects at the posterior pole of the globe
(8). Iris colobomas have not been observed in patients with mutations in Pax2. Sometimes the optic nerve colobomas in patients with renal-coloboma syndrome are described as morning glory syndrome (10). Patients with Pax2 mutations often exhibit small kidneys with reduction in size of both the renal pelvis and renal cortex. The renal disease in patients with Pax2 mutations is usually
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progressive and frequently necessitates renal transplantation after chronic renal failure (7,8), although patients with very minimal renal involvement have also been identified (3). Renal cortical biopsies have demonstrated mesangial fibrosis and glomerulosclerosis, involuting glomeruli, hyalinization of glomeruli, atrophic tubules, and hyperplastic gomeruli with an overall decreased number of glomeruli (7,8,11). Pathologic examination of kidneys revealed cortical thinning, hypoplastic papillae with low numbers of gomeruli, and collecting ducts in the cortex and the papilla, respectively, consistent with renal hypoplasia (8). VUR is an important factor when considering determinants of renal function loss in patients with renal-coloboma syndrome (12). It arises during development of the ureter in embryogenesis, and there is evidence that VUR can begin in utero. VUR can cause both renal failure and scarring. It has been observed in 5 of 19 patients with Pax2 mutations, although the frequency may be higher because VUR has a tendency to resolve with age (8,13). However, the more common, nonsyndromic form of VUR maps to 1p13 and is not linked to the PAX2 locus (14). The renal histology description associated with renal-coloboma syndrome includes interstitial fibrosis, glomerulosclerosis, and tubular atrophy and is similar to those observed in patients with VUR (12). In addition, later stages of reflux nephropathy in patients with VUR are associated with proteinuria and end-stage renal failure, which also occur in patients with renal-coloboma syndrome. The exact incidence of renal-coloboma syndrome (or of Pax2 mutations) in the population is unknown. During embryonic development, Pax2 expression (which gene localizes to human chromosome band 10q24.3-q25.1 [15]) occurs in the developping urogenital system (kidney, ureter, and genital tract), as well as the developing eye, ear, and central nervous system (CNS) (16). In the kidney, Pax2 expression occurs in the early stages of mesenchymal to epithelial differentiation, preceding formation of the glomerulus. Pax2 expression is also found in the ureteric bud and at low levels in epithelia such as collecting duct, renal pelvis, and ureter (16). In the developing eye, Pax2 expression starts in the optic placode and then continues in the optic vesicle. As the optic vesicle folds and becomes a bilayer optic cup, Pax2 expression is restricted to the optic fissure and along the length of the optic stalk (17). Renal-Coloboma Like Syndrome. Pax2 mutation was not found in some patients with renal-coloboma syndrome or a renal-coloboma-like syndrome (13). Other syndromes that involve renal and ocular anomalies and have similarities to renal-coloboma syndrome include Senior-Loken syndrome (SLS), CHARGE syndrome (colobomas, heart anomalies, choanal atresia, retardation, genitourinary anomalies, and ear anomalies), COACH syndrome (cerebellar vermis hypo/aplasia, oligophrenia, congenital ataxia, coloboma, hepatic fibrosis), Joubert syndrome, acrorenoocular syndrome, and bilateral macular coloboma with hypercalciuria syndrome. Senior-Loken Syndrome (OMIM 266900). SLS is an autosomal recessive disorder defined by the association of nephronophthisis and tapetoretinal degeneration. It occurs in approximately 18% of all cases of nephronophthisis (18).
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Nephronophthisis can also be associated with conditions affecting extrarenal organs, such as retinitis pigmentosa (SLS) and ocular motor apraxia (Cogan syndrome). Except for the ocular involvement, the pathologic and clinical features of SLS are virtually identical to those of isolated nephronophthisis, including course of renal disease. Affected individuals invariably progress to end-stage renal failure, usually before the age of 20 yr (18,19). They present a long-standing history of polyuria-polydipsia, nocturia, mild proteinuria, unremarkable urine sediment, and symmetrically reduced-size kidneys containing multiple small cysts. For nephronophthisis (NPHP), the primary genetic cause of chronic renal failure in young adults, three loci have been mapped, with forms on chromosomes 2q13 (NPHP1, juvenile form), 9q22 (NPHP2, infantile form), and 3q21-q22 (NPHP3, adolescent form). Localization of a SLS locus to the region of NPHP3 opens the possibilities of both diseases arising by mutations within the same pleiotropic gene or two adjacent genes (20). Recently, a second locus associated with the juvenile form of the disease, NPHP4, was mapped to chromosome 1p36 and constitutes a new locus for SLS associated with retinitis pigmentosa (21–23). CHARGE Syndrome (OMIM 302905). CHARGE syndrome is named from its six major clinical features: Coloboma of the eye, Heart defects, choanal Atresia, Retarded growth and development including CNS anomalies, Genital hypoplasia and/or urinary tract anomalies, and Ear anomalies and/or hearing loss (24). Ocular abnormalities were found in 44 of 50 patients diagnosed with CHARGE syndrome. The majority had retinochoroidal colobomata with optic nerve involvement, but only 13 patients had an iris defect. Two patients had atypical iris colobomata with normal fundi. Additional features were microphthalmos in 21 patients, optic nerve hypoplasia in 4, nystagmus in 12, and a vertical disorder of eye movement in 4 of the 22 cases with facial palsy (25). Of the 24 patients who underwent renal ultrasound, 10 (42%) were diagnosed with urinary tract anomalies, including a solitary kidney, hydronephrosis, renal hypoplasia and duplex kidneys. Further evaluation revealed vesicoureteral reflux, neurogenic bladder secondary to spinal dysraphism, nephrolithiasis, ureteropelvic junction obstruction, and a nonfunctioning upper pole in both duplex kidneys (26). COACH Syndrome (OMIM 216360). COACH syndrome is characterized by hypoplasia of cerebellar vermis, oligophrenia, congenital ataxia, coloboma, and hepatic fibrosis. The occurrence of multiple cases in single sibships suggests an autosomal recessive inheritance. Progressive renal insufficiency with fibrocystic changes on renal biopsy is found as a common manifestation of COACH syndrome (27). Nephronophtisis, fibrocystic renal disease, oligophrenia, and small medullar cysts have also been described. Aniridia. Aniridia is a severe eye disease characterized by iris hypoplasia. Both sporadic and familial cases with autosomal dominant inheritance have been reported. Mutations in the Pax6 gene have been shown to be the genetic cause of the disease (OMIM 106210). Other ocular findings include de-
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creased vision, cataract, glaucom, Peter’s anomaly (congenital anomaly of the anterior segment), and corneal clouding. Some of the sporadic cases are caused by large chromosomal deletions, some of which also include the Wilms tumor gene (WAGR syndrome), resulting in an increased risk of developing Wilms tumor (28). A variety of WT1 mutations induces renal development defects such as the dominant Wilms tumor/ aniridia/genital anomaly/mental retardation syndrome (WAGR syndrome; OMIM 194072), Denys-Drash syndrome (DDS; OMIM 194080), and Frasier syndrome (FS; OMIM 136680). Wilms tumor (nephroblastoma) is a childhood tumor of the kidney (1/10,000 live births) originating from the metanephric blastema. Patients with Wilms tumor are at an increased risk for developing ocular disorders, including aniridia and, less frequently, optic nerve hypoplasia resulting from inactivation of the aniridia gene Pax6, which lies telomeric of WT1 on chromosome 11p13 (29). Unlike the genetic mechanism leading to the development of retinoblastoma, an embryonal tumor of childhood affecting the retina, which only requires the inactivation of one single gene, the biological pathways leading to the development of Wilms tumor are complex and likely involve several genetic loci (30). Denys-Drash Syndrome. On 100 reports of intragenic WT1 mutations, the accompanying clinical phenotypes revealed 5% of sporadic Wilms tumours and ⬎90% of patients with the DDS (renal nephropathy, severe hypertension, a steroid-resistant nephrotic syndrome that rapidly progresses to end-stage renal disease before the age of 5 yr, male pseudohermaphrodism, predisposition to Wilms tumor [31]). Renal biopsy showed diffuse mesangial sclerosis and focal segmental sclerosis. Podocytes exhibit decreased or absent WT1 expression but persistent Pax2 expression. It is proposed that patients with early onset, rapidly progressive nephrotic syndrome and diffuse mesangial or focal segmental sclerosis should be tested for WT1 mutations to identify those at risk for developing Wilms tumor (32). Frasier Syndrome. FS includes a slowly progressing nephrotic syndrome attributable to minimal glomerular changes or focal segmental glomerulosclerosis and complete male or female gender reversal in 46 XY patients but no signs of Wilms tumor. In contrast to DDS, end-stage renal disease develops more slowly and at a later stage in life (3).
Eya1 Gene The Drosophila eyes absent gene (eya) is involved in the formation of compound eyes. Flies with loss-of-function mutations of this gene develop no eyes and form the ectopic eye in the antennae and the ventral zone of the head on target expression. A highly conserved homologous gene in various invertebrates and vertebrates has been shown to function in the formation of the eye. In contrast, a human homologue, EYA1, has been identified by positional cloning as a candidate gene for branchio-oto-renal (BOR) syndrome (OMIM 113650), in which phenotypic manifestations are restricted to the areas of branchial arch, ear, and kidney, with usually no anomalies in the eye. The EYA1 gene is expressed very early, between the 4th and 6th weeks of human development. Deafness relates to
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abnormalities in the three ossicles of the middle ear derived from the first and second branchial arches, whereas the branchial fistulae relates to abnormalities of the second, third, and fourth arches. In the embryonic human kidney, the EYA1 gene is expressed strongly; in the BOR syndrome, there is an inductive fault between the ureteric bud and the metanephric mesenchymal mass as the ureteric bud branches into the renal parenchyma (33). Mutations in human EYA1 gene are mapping on chromosome 8q13.3. The BOR syndrome is an autosomal dominant disease characterized by hearing loss of early onset, preauricular pits, branchial clefts, and early progressive chronic renal failure in up to 40% of family affected members (33). Azuma et al. (34) identified three novel missense mutations in patients who had congenital cataracts and ocular anterior segment anomalies. One of the patients had clinical features of BOR syndrome as well. The most important renal abnormalities that lead to end-stage renal disease include unilateral renal agenesis with controlateral hypodysplasia characterized by decreased renal volume and size, loss of ultrasound normal corticomedullary differenciation, and hyperechogenicity of the renal cortex. Histologically there is glomerular hyalinization, mesangial proliferation, and basement membrane splitting. Bilateral renal agenesis is the extreme, leading to miscarriage or immediate neonatal death. Other renal abnormalities include bifid kidneys with double ureters, cystic dysplasia, vesico-ureteric reflux, and pelviureteric stenoses (33). The BOR syndrome should be included in the differential diagnosis of deafness and chronic renal failure in childhood and adolescence.
BMP7 Mutation (OMIM 600779) The bone morphogenetic proteins are members of the TGF- superfamily purified by Ozkaynak et al. (35). Hahn et al. (36) mapped the BMP7 gene to human chromosome 20 by study of human-rodent somatic cell hybrid lines with cDNA probes. Marker et al. (37) suggested that the human BMP7 gene may be on 20q13.1– q13.3, extrapolating from the fact that the BMP7 gene in the mouse is between Ada (localized to 20q12– q13.11) and Pck1 (localized to 20q13.2– q13.31). BMP-7 and Kidney Development. During vertebrate development, the metanephric mesenchyme undergoes an epithelial transformation to form the glomerulus and the tubules of the nephrons. This nephrogenic process begins at 11.5 days post conception (dpc) with mesenchymal condensation and is initiated by signals coming from the ureteric bud such as growth factors. Observations reported suggest that BMP-7 is an early inducer of nephrogenesis. Moreover, deletion of BMP-7 in mice results in failure of the metanephric mesenchyme and leads to loss of mesenchymal cell condensation around the ureteric bud and eventually to glomerular and tubular agenesis and severely hypoplastic kidneys. In addition to its role as a renal morphogen, BMP-7 probably is a critical renal tubular differentiation factor determining epithelial cell phenotype. In the absence of BMP-7, only incomplete mesenchymal condensations are identified in the kidney at 12.5 dpc and the metanephric mesenchymal cells died before 14.5 dpc, a phenome-
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Table 1. Oculorenal syndromesa Genes, Genes Products, and Chromosomes
Before nephrogenesis
Lesions Clinical Syndrome Eye
Kidney
Pax2 10q24.3– q25.1
Orbital cysts, Renal agenesis, microphthalmia duplication, vesicocoloboma (optic nerve, ureteral reflux, retina) hydronephrosis Pax6, WT1 11p13 Aniridia, decreased Nephroblastoma, renal vision, cataract, failure glaucoma, Peter’s anomaly, corneal clouding Renal dysplasia, JAG⫺1 (NOTCH 1) Protenia embryotoxon, 20q121 keratoconus, mesangiolipidosis, strabismus, myopia, tubulointerstitial retinitis pigmentosa nephritis, tubuloacidosis, renal failure, medullary cystic disease
During nephrogenesis ureteric duct induction Pax2 10q24.3– q25.1
EYA1 8q13.3
WT1
Orbital cysts, Renal agenesis, microphthalmia duplication, vesicocoloboma (optic nerve, ureteral reflux, retina) hydronephrosis Renal dysplasia/ aplasia, renal collecting system anomalies, polycystic kidneys Aniridia Nephroblastoma, renal failure Renal hypo/dysplasia, reduction in nephron number
Renal-coloboma syndrome
WAGR contiguous deletion syndrome
Alagille syndrome
Renal-coloboma syndrome, morning glory syndrome BOR syndrome
WAGR syndrome
collecting system development
EGF, EYA1, Pax2
mesenchymalepithelial transition glomerulogenesis filtration barrier
BMP7 chr20 Intergrin ␣8
Absence of lens formation (in mice)
Renal hypo/dysplasia, tubular agenesis
LMX1b 9q34.1
Strabismus cataract, micro-cornea, microphthalmia, nystagmus, glaucoma, keratoconus, heterochromia
Normal renal architecture, proteinuria, microscopic hematuria, glomerulonephritis, nephrotic syndrome, renal failure Glomerulosclerosis
Nail-patella syndrome
ADPKD
mesangial
After nephrogenesis collecting system, mesenchyme-derived tubules
PDGF- and PDGF- receptors WT1
Oligomeganephronia, BOR syndrome, Renal-coloboma syndrome ?
Denys-Drash syndrome
PKD1/PKD2 (16p/4q)
Blepharochalasis
Cyst formation
vHL 3p26–p25
Retinal hemangioma, retinal detachment
Cyst formation, renal von Hippel Lindeau hemangioblastoma, disease renal cell carcinoma, renal cysts
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Table 1. Oculorenal syndromesa (cont’d) Genes, Genes Products, and Chromosomes
collecting system TSC1 (9q34) TSC2 (Tuberin) (16p13.3)
X-linked Xq22
glomerulus
a
Lesions Clinical Syndrome Eye
Retinal astrocystic hamartoma, microphthalmia, exophthalmos, optic nerve atrophy
Kidney
Cyst formation, angiomyolipoma, renal cell carcinoma
Cornea verticilata, Renal failure, isosthenuria, cataract, conjunctival tubular dysfunction, irefrinvaricosity, retinal vessel gent lipid globules in tortuosity, retinal artery urine, foum vacuole cells occlusion Nephrocystin 2q13 Retinitis pigmentosa, retinal Medullary cystic disease, aplasia/hypoplasia, retinal renal failure, isosthenuria, dystrophy hypokalemia, excess urinary sodium and potassium loss, interstitial fibrosis, tubular atrophy, relatively spared glomeruli PEX 7p11.23 Corneal dystrophy, Cyst formation, proteinuria, microphthalmia, retinal aminoaciduria, cortical degeneration, cataract dysplasia Hydronephrosis, absence renal peroxisomes Elastin 7q11.2 Stellate pattern of iris Small, or solitary kidney pelvic kidney, nephrocalcinosis, renal insufficiency, renal artery stenosis, vesicoureteral reflux P-type ATPase Kayser-Fleiscer corneal Proximal renal tubular 13q14.3 ring, cataract dysfunction, renal calculi Progressive anterior Microscopic hematuria, Col4A3A4 (2q35–q37) lenticonus, pigment nephritis, renal failure, Col4A5 (xq11–q22) epitheliopathy, cataract nephrotic syndrome fundus punctatus, optic nerve drusen Fibrillin 1 (FBN1) Lens ectopia retinal Focal segmental and/or 15q21.1 detachment, corneal mesangial flatness, hydromygia, glomerulonephritis, renal iris hypoplasia, early artery stenosis glaucoma Renal dysplasia, mesangioJAG⫺1 (NOTCH 1) Protenia embryotoxon, 20q12 keratoconus, strabismus, lipidosis, tubulointerstitial myopia, retinitis nephritis, tubuloacidosis, pigmentosa renal failure, medullary cystic disease LCAT 16q22.1 Corneal dystrophy, corneal Renal failure before 50 yr, lipid deposits, corneal Glomerular lacunes with opacities, vascular dense bodies retinopathy, arcus juvenitis, angoid streaks, papilledema, aniridia, megalocornea
TSC
Fabry disease
Nephronophthisis Senior-Loken syndrome
Zellweger syndrome
Williams-Beuren syndrome
Wilson disease Alport syndrome
Marfan syndrome
Alagille syndrome
LCAT deficiency (Norum syndrome)
EGF, epithelial growth factor; BMP7, bone morphogenetic protein7; PDGF, platelet degradation growth factor; ADPKD, autosomal dominant polycystic disease; vHL, von Hippel Lindau; TSC, tuberous sclerosis complex; PEX, peroxysome; LCAT, Lecithin:cholesterol acyltransferase.
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non that is also observed when the metanephric mesenchyme is cultured in the absence of proper inductive tissues (38). BMP-7 and Eye Development. Lens formation is the result of reciprocal inductive interaction between the optic vesicle and the surface ectoderm. Genetic evidence has demonstrated that the optic vesicle is required for lens formation in mice (39). This reciprocal interaction leads to the formation of the lens vesicle from the surface ectoderm at ~10.5 dpc (40). In about 35 % of BMP-7m1/BMP-7m1 embryos, interaction between the optic vesicle and the surface ectoderm did not occur properly, resulting in the unilateral or bilateral absence of lens formation in these animals. The expression of BMP-7 during eye development suggests that it is involved directly in lens formation. The importance of BMP-7 during eye development has also been suggested by in vitro culture experiments showing that anti-BMP-7 antibodies can block lens formation in cultured rat embryos. However, 86% of the BMP-7m1 embryos did develop lens (or lenses), indicating that genes segregating in the F2 animals can suppress this aspect of the BMP-7– deficient phenotype.
Renal Cyst and Ocular Abnormalities Alagille Syndrome (AGS; OMIM 118450). In addition to neonatal jaundice, features of this syndrome include posterior embryotoxon and retinal pigmentary changes and: • In the heart: pulmonic valvular stenosis as well as peripheral arterial stenosis • In the bones: abnormal vertebrae (butterfly vertebrae) and decrease in interpediculate distance in the lumbar spine • In the nervous system: absent deep tendon reflexes and poor school performance • In the facies: broad forehead, pointed mandible, and bulbous tip of the nose • In the fingers: varying degrees of foreshortening (41,42) • The syndrome has an autosomal dominant inheritance, and the gene is located at 20p12 (43). Most often, AGS leads to chronic liver disease in childhood with severe morbidity and a mortality of 10 to 20%. LaBrecque et al. (44) described 15 affected persons in four generations. They all presented with renal dyslasia and renal artery stenosis associated in some cases with hypertension. Simple ophthalmic examination of children with neonatal cholestatic jaundice and their parents should allow early diagnosis of AGS, eliminating the need for extensive and invasive investigations. The most common ocular abnormalities in patients were posterior embryotoxon (95%), iris abnormalities (45%), diffuse fundus hypopigmentation (57%), speckling of the retinal pigment epithelium (33%), and optic disc anomalies (76%). Microcornea was not associated with large refractive errors, and visual acuity was not significantly affected by these ocular changes. Martin et al. (45) described three children with Alagille syndrome, in two of whom a unilateral multicystic dysplastic kidney was detected by prenatal ultrasound. In the third child, a solitary cortical cyst was detected later in childhood. All had normal renal function, growth, and liver synthetic function but continued to have clinical and bio-
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chemical signs of cholestasis. Thus the authors concluded that AGS should be included in the differential diagnosis of cystic kidney disorders associated with cholestatic liver disease. A mesangiopathic glomerulopathy with fibrillary deposits and foam cells and medullar cysts have been described (46). Other renal lesions include membranous nephropathy and lamellated glomerular basement membrane (47). Cystic renal disease with or without renal dysplasia, tubulointerstitial nephritis, renal tubular acidosis, renal artery stenosis, renovascular hypertension, horseshoe kidney, and vesicoureteric reflux have also been reported in association with AGS. • Woolfenden et al. (48) described two children with sporadic AGS associated with moya-moya. They interpreted this finding as indicating that AGS is a vasculopathy. Li et al. (49) demonstrated that AGS is caused by mutations in the human homolog of Jagged-1 (Jag1), which encodes a ligand for Notch1. They concluded that AGS is caused by haploinsufficiency of Jag1. They mapped the human Jag1 gene (OMIM 601920) to the AGS critical region within 20p12. Giannakudis et al. (50) detected parental mosaicism for a Jag1 mutation in 4 of 51 families in which mutations had been identified in the AGS patients and where parental DNA was available. The co-localization and genetic interaction of Jag1 and Notch2 (OMIM 600275) imply that this ligand and this receptor physically interact, forming part of the signal transduction pathway required for glomerular differentiation and patterning. Notch2(del1)/Notch2(del1) homozygotes also display myocardial hypoplasia, edema, and hyperplasia of cells associated with the hyaloid vasculature of the eye. These data identify novel developmental roles for Notch2 in kidney, heart, and eye development (51). Zellweger Syndrome (OMIM 214100). Zellweger syndrome is a fatal recessively inherited disease with disturbed function of many organs. The disease is caused by a defect of peroxisomes, subcellular organelles, which are absent in these patients. Several genes are necessary for the formation and function of the peroxisomes. The clinical picture of Zellweger syndrome can be caused by defects in a number of genes. Ophthalmic manifestations include corneal opacification, cataract, glaucoma, pigmentary retinopathy, tapetoretinal degeneration, and optic atrophy (52). Polycystic kidneys with adequate functional renal parenchyma and cortical renal cysts were described. The Zellweger gene is on chromosome 7q11.13. Autosomal Dominant Polycystic Kidney Disease (OMIM 601313, 173910). Autosomal dominant polycystic kidney disease (ADPKD) is a frequent genetic disorder affecting 1 out of 1000 individuals. The predicted protein has been named polycystin. Cell-matrix interactions have been suggested to be important for kidney development (53), and there is some evidence that laminin-1 and its receptors could be involved (54). It has been determined that the embryogenetic stages of eye and kidney development occur rather simultaneously (55). From the 7th to the 10th week, the development of the ocular
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architecture progresses in parallel with the differenciation of the kidney tubules (56). It is conceivable that the unknown factor leading to the development of renal tubular cysts in utero might simultaneously affect the eye and the kidney. Meyrier et al. (57) reported a strongly association between ADPKD and blepharochalasis. Other ocular abnormalities including severe myopia, cataracts, papilledema, and peripheral retinal pigmentation have also been described in association with ADPKD (58). Mutant mice that develop severe kidney phenotypes as adults include the Bcl-2 mutant mice with polycystic kidneys (59), the s-liminin/laminin 2 mutant mice, which develop massive proteinuria (60), the epidermal growth factor receptor mutant mice with cystic dilations of the collectiong ducts (61), the tensin mutant mice, which develop progressive kidney degeneration (62), and the cyclooxygenase 2 mutant mice, which die from chronic renal failure most likely as a result of reduced nephron mass (63). Digenic inherantance have been reported for polycystic kidney disease, where it was hypothesized that cyst formation results from the inheritance of one germinal mutation in one of two PKD1 or PKD2 genes, and the occurrence of a second-hit, somatic mutation in the other interacting gene, thereby generating a trans-heterozygous situation in the affected cystic cell (64). von Hippel Lindau Disease (OMIM 193300). The von Hippel-Lindau (vHL) syndrome is transmitted as an autosomal dominant trait with variable penetrance. Its clinical manifestations include cerebellar and retinal hemangioblastomas, pancreatic cysts, carcinoma, renal cell carcinoma, and pheochromocytoma (65). The vHL gene is on chromosome 3 (3p25-26) (66) and functions normally as a tumor suppressor by inhibiting transcription elongation (67). The classic ophthalmologic finding is heamanglioblastoma, a round, red tumor of the retina with a pair of feeding vessels showing an increase in diameter and tortuosity. Angiomatosis retinae may cause severe impairment of vision as a result of retinal detachment. Blindness or near-blindness typically happens without preceding symptoms and without pain. Capillary hemangioma of the retina may occur as either an isolated retinal vascular abnormality or as one of the many systemic abnormalities of vHL disease. Progressive intraretinal and subretinal exudation occurs as the angioma develops. If it remains untreated, either exudative or tractional retinal detachment or retinoschisis may result (68). Retinal telangiectasis associated with facioscapulohumeral muscular dystrophy (69) and Alport syndrome may also cause massive outpouring of exudate into the outer retinal layers and may result in exudative retinal detachment. Kidney disorders have been found in up to 60% of vHL subjects at autopsy. The mean age at detection of renal lesions is approximately 35 yr (65). Loin pain or complaints of an abdominal mass and, infrequently, gross hematuria have been reported, mainly in patients with large tumors. Hypertension, renal function deterioration, and proteinuria have rarely been observed in vHL patients with renal lesions. Cysts as numerous as in polycystic kidney disease are very seldom too (65). Renal
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cysts and angiomas develop in approximately two thirds of cases (70) and include benign cysts and renal cell carcinoma. In addition, renal adenomas, hemangiomas, and adrenal cell carcinoma occur but are rare. Simple cysts are most frequent and are observed in about 75% of patients. Renal cell carcinoma tends to occur in younger patients, has an equal gender distribution, and is usually bilateral and multicentric. The clear cell type of renal cell carcinoma is the most common type of cancer in vHL. Carcinomas occur in about one fourth of cases, metastasize in about half of those, and cause death in about one third (71). It is estimated that renal carcinoma will develop in approximately 70% of patients who survive to age 60 yr (70). Computer tomography scanning, which is more sensitive, should be performed every 3 yr or more frequently in patients with multiple cysts (70). The renal lesions, depending or the sign and the number of the angiomata, could generate enlargement of the kidney and may cause renal failure. Pheochromocytoma, which is often asymptomatic, may occur with equal frequency. Pheochromocytoma occurs in 10 to 19% of vHL patients. There is usually bilateral involvement. The median age is 28 yr. Polycythemia, due to the ectopic production of erythropoietin by the hemangioblastoma or carcinoma, is occasionnally present and may disappear after the excision of the tumor (72). Sturge-Weber-Krabble Syndrome (Phacomatosis Pigmentovascularis; OMIM 185300). Sturge-Weber syndrome (SWS) or encephalotrigeminal syndrome is a dermato-oculoneural syndrome involving cutaneous facial nevus flammeus in the area of the first and/or second division of the trigeminal nerve, ipsilateral glaucoma, ipsilateral diffuse cavernous hemangioma of the choroid, and ipsilateral leptomeningeal hemangioma (73). The classical cutaneous feature of SWS is facial nevus flammeus, which is usually unilateral and may be associated with hypertrophy of the involved skin of the face. One of the ocular manifestations of SWS is diffuse choroidal hemangioma (74), usually on the same side as facial nevus flammeus. The ocular component manifests as glaucoma and vascular malformations of the conjunctiva, episclera, choroid, and retina. Glaucoma is present in approximately half of the cases on hemangioma’s facialis side. Patients in whom the lesion affects the upper eyelid are at increased risk of glaucoma (70). The Nevus of Ota is a melanocytic pigmentary disorder, most commonly involving the area innervated by the trigeminal nerve. Elevated intraocular pressure, with or without glaucomatous damage, is observed in 10% of the cases (75). Episcleral venous telangiectasia vessels were prominent features. Other ocular manifestations (retinal vascular tortuosity, iris heterochromia, choroidal hemangioma, buphthalmos, retinal detachment, and strabismus) also occurred (70 –76). Optic neuropathy has not been reported as a component of this syndrome (77). The involvement of the kidneys or urinary tract occurs usually by hemangiomas. Vascular manifestations occur within the renal pelvis, papilla, and urinary bladder. They are generally solitary, causing varying degrees of hematuria. Occasionally, the hemangioma may present as a mass with perirenal hematoma associated with other abnormalities, such as dupli-
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cation of the inferior vena cava or abnormalities of the renal venous system (78). Tuberous Sclerosis Complex (OMIM 191100). Tuberous sclerosis complex (TSC, synonym: Bourneville-Pringle disease) (79) an autosomal dominant disease with variable penetrance, is a multisytem disorder characterized by the formation of angiomyolipomas or tubers affecting predominantly the brain, the skin (called adenoma sebaceum), the kidneys, the eyes, and the heart (80). Two different genetic loci have been identified: one on chromosome 9 (TSC1) and one on chromosome 16p (TSC2) that is immediately adjacent to the gene for the most common form of autosomal dominant polycystic kidney disease (PKD1) (81). The most suggestive eye finding of TSC is the retinal astrocytic hamartoma found in 50 to 85% of patients (82). Other internal eye findings may include atypical colobomas, microphthalmia, exophtalmos, hypomelanotic maculs, and optic nerve atrophy. The main renal manifestations of TSC are angiomyolipomas, cysts, and renal cell carcinomas. Hematuria is not a common feature, possibly because of the expansive rather than infiltrative growth. On rare occasions, patients may have a catastrophic presentation of sudden flank pain associated with a palpable abdominal mass and symptoms of anemia. This complex syndrome is referred to as the Wunderlich triad and is caused by spontaneous rupture of the tumor into the retroperitoneal space (83). Less than 40% of the patients with renal angiomyolipoma have significant proteinuria. Massive proteinuria are rare. There is a high incidence of hypertension in TSC, even when the renal function is normal (84). Many patients with tuberous sclerosis have no symptoms referable to the kidney. Renin-dependent hypertension, due to focal areas or ischemia around the cyst, and chronic renal failure also can occur. Rarely, hypertension may result from renal artery aneurysm (85). The development of end-stage renal disease is unusual and appears to result primarily from the replacement and compression of the renal parenchyma by angiomyolipoma and cysts. The angiomyolipoma is found in 50 to 80% of the patientsand bilateral localisation has also been reported. The main manifestations of the renal angiomyolipomas relate to their potential for hemorrhage (hematuria, intratumoral, or retroperitoneal hemorrhage) and mass effects (abdominal or flank mass and tenderness, hypertension, renal insufficiency) (86). Angiomyolipomas can also cause fever of unknown origin (87). Cystic disease is the second most common renal manifestation of TSC (88). Renal cysts in TSC are predominately bilateral, multiple and vary in size from microscopic “hamartial germs” to that of a “grapefruit,” often similar to the adult type of polycystic kidney disease. The major clinical problem associated with severe cystic changes in TSC is the development of nephrolithiasis, hypertension, and renal failure. The majority of the patients with TSC that present with polycystic-like kidneys at an early age have a contiguous gene syndrome with deletions affecting both the TSC-2 and the PKD1 genes (89). Renal cell carcinoma in TSC has also been reported (90). Other associations rarely recognized include renal interstitial disease (91), focal segmental glomeruloscle-
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rosis, glomerular microharmartomas (92), renal artery stenosis (93), ureteropelvic junction stenosis, and horseshoe kidney. Bardet-Biedl Syndrome (OMIM 209900). Bardet-Biedl syndrome (BBS) is a genetically heterogeneous disorder with the primary features of obesity, pigmentary retinopathy, polydactyly, renal malformations, mental retardation, and hypogenitalism. BBS is considered an autosomal recessive disorder, with increased risk for diabetes mellitus, hypertension, and congenital heart disease. The incidence of BBS is approximately 1/100,000 with a predicted heterozygote frequency of 1/160, and it has been suggested that heterozygotes are at increased risk of obesity and hypertension. What was once thought to be a homogeneous autosomal recessive disorder is now known to map to at least six loci: 11q13 (BBS1), 16q21 (BBS2), 3p13 p12 (BBS3), 15q22.3 q23 (BBS4), 2q31 (BBS5), and 20p12 (BBS6). There has been considerable interest in identifying the genes that underlie BBS, because some components of the phenotype are common. Cases of BBS mapping to BBS6 are caused by mutations in MKKS; mutations in this gene also cause McKusick-Kaufman syndrome (hydrometrocolpos, post-axial polydactyly and congenital heart defects). The BBS6 protein has similarity to a Thermoplasma acidophilum chaperonin, whereas BBS2 and BBS4 have no significant similarity to chaperonins. It has recently been suggested that three mutated alleles (two at one locus, and a third at a second locus) may be required for manifestation of BBS (triallelic inheritance). The identification of the gene BBS1 is a frequent cause of BBS and is not involved in triallelic inheritance (94). Ocular abnormalities include rod-cone dystrophy, onset be end of second decade (major), retinitis pigmentosa, strabismus, and cataracts Renal abnormalities have been described in up to 100% of BBS patients, and renal failure occuring in 30 to 60% of patients is the major cause of morbidity and early mortality in BBS. Hypertension has been noted in 50 to 66% of cases. Dysplasia, chronic glomerulonephritis, cystic tubular disease, calyceal and lower urinary tract malformations, defects of tubular concentrating ability, nephrogenic diabetes insipidus, and microaneurysms and occlusions in renal arterioles have all been reported (95).
Glomerulopathies and Eye Abnormalities Alport Syndrome. The classic phenotype as described by Alport (96) is nephritis, often progressing to renal failure, and sensorineural hearing loss affecting both genders in successive generations. The renal disease becomes evident as recurrent microscopic or gross hematuria as early as childhood, earlier in males than in females. Progression to renal failure is gradual and usually occurs in males by the fifth decade. Nephrotic syndrome is unusual but has been reported. The renal histology is nonspecific; both glomerular and interstitial abnormalities, including foam cells, occur. Immunofluorescence studies have provided little evidence for an immunologic basis for renal damage. Hearing loss, which is sensorineural and primarily affects high tones, occurs in 30 to 50% of relatives with renal disease. In about 85% of AS pedigrees, the disease is X-linked (Xq22) (OMIM 301050), and mutations identified so far are in the ␣5 (IV) collagen chain gene (COL4A5) (97). In the vast
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majority of the remaining families, the transmission is autosomal recessive with mutations detected in the genes coding ␣3 (IV) and ␣4 (IV) collagen chains (chromosome 2) (98). The gene frequency of AS is about 1 in 5000, and the disease accounts for about 0.6% of all patients who start renal replacement therapy in Europe. Diffuse leiomyomatosis and megathrombocytopenia have also been described in AS. The ocular manifestations (15 to 30%) of AS mainly involve the lens. Bilateral anterior lenticonus is the most specific abnormality (97–99). When present, the lenticonus is bilateral in about 75% of patients. It is far more common in affected males but may occur in females. Lens opacities may be seen in conjunction with lenticonus, occasionally resulting from rupture of the anterior lens capsule. Anterior lenticonus has been confused with anterior pyramidal opacities, which may be associated with microcornea and anterior chamber cleavage anomalies. Macular flecks are a second characteristic feature of AS. Govan (100) concluded that the diagnosis of AS may be made on the presence of characteristic features. Nontraumatic recurrent corneal erosion (101) and an association with a macular lesion similar to the cone dystrophy have only infrequently been reported. Pigmentary changes in the perimacular region, consisting of whitish or yellowish granulations surrounding the foveal area and corneal endothelial vesicles, have also been reported. Cataract, spherophakia, and cone dystrophy were also described in AS. Persistent microscopic hematuria is a constant feature in male patients with AS. Many also have episodic gross hematuria, precipitated by upper respiratory infections, during the first two decades of life. Proteinuria is usually absent during the first few years of life but develops eventually in males with X-linked AS and proteinuria increases progressively with age and may culminate in the nephrotic syndrome. Hypertension also increases in incidence and severity with age. The rate of progression to renal failure is fairly constant among affected males within a particular family, although significant intrakindred variability in the rate of progression to renal failure has occasionally been reported. Anti-GBM disease appears in 5 to 10% of Alport patients who received a kidney transplant after the development of renal failure. These antisera do not bind to Alport glomerular basement membrane and were found to be reactive to the ␣3(IV) chain. Kalluri et al. (102) found that posttransplant anti-GBM alloantibodies harvested from an X-linked Alport patient with complete COL4A5 gene deletion that were specifically targeted to the ␣3(IV) chain. In further studies, Kalluri et al. demonstrated posttransplant anti-␣3(IV) collagen alloantibodies in a patient with autosomal recessive AS caused by deletion of the last 198 amino acids of the ␣3(IV) chain. Milliner et al. (103) estimated that approximately 1 to 5% of Alport patients who received renal transplants develop a specific anti-GBM nephritis, subsequently leading to loss of the renal graft. These data suggested that Alport syndrome patients with a type IV collagen mutation resulting in absence of the NC domain have an increased risk of developing anti-GBM nephritis after renal transplantation. In nephrology, the association of renal failure and deafness
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immediately brings to mind the AS with which every nephrologist is well acquainted; this is not always correct. Morever, there are various inherited conditions in which sensorineural deafness is associated with renal disease, including Alport’s variants, Muckle-Wells syndrome, Refsum disease, Cockayne syndrome, renal tubular acidosis, ichtyosis and prolinuria, Charcot-Marie-Thoot syndrome, Alstro¨ m’s syndrome, ataxia, hyperuricemia, photomyoclonus, familial spastic paraplegia with intellectual retardation, mitochondrial disorders, and hypo and hyperparathyroidism (104). Nail Patella Syndrome (NPS, Onychoosteodysplasia) (OMIM 161200). Hereditary osteo-onychodysplasia (HOOD) or nail-patella syndrome (NPS) is a rare, autosomal dominant disorder. Dysplasia of the nails and absent or hypoplastic patellae are the cardinal features but others are iliac horns, abnormality of the elbows interfering with pronation and supination, and in some cases nephropathy. Renal involvement is an inconstant finding as the presence of fibrillar collagen within the GBM. The gene is closely linked to those coding for ABO blood groups and for adenylate kinase. The three genes are located at the distal end of the long arm of chromosome 9 (9q34) (105). Ocular manifestations include a dark pigmentation at inner margin of iris. Strabismus, lens opacities, Lester sign, microcornea, microphthalmia, kerotoconus, cataracts, heterochromia, anisocoria, and nystagmus have also been reported (106). Anterior segment anomalies can lead to impaired vision and glaucoma (107). Clinical renal involvement seems to occur in about 30 to 40 % of cases (108). Proteinuria, sometimes associated with microscopic haematuria, is the most frequent presenting feature. Nephrotic syndrome was observed in 3 of 122 patients reviewed by Meyrier et al. (109). Progression to end-stage renal failure occurs in about 30% of patients with renal symptoms. Cases of rapid evolution to renal failure have been observed in the pediatric population. Various types of superimposed nephritis, Goodpasture syndrome (110), membranous nephropathy (111), necrotizing angiitis (112), and IgA nephropathy (109) have been observed in HOOD patients. As demonstrated by electron microscopy by Morita et al. (113) among others, many collagen fibrils are present in the thickened basement membranes and in mesangial matrix of otherwise normal glomeruli. Abnormalities of collagen at this site have also been demonstrated in AS. Both of these conditions may be special forms of heritable disorders of connective tissue. The Goodpasture antigen, an autoantibody, is directed against type IV collagen of basement membrane or some element closely associated with it. The occurrence of Goodpasture syndrome in a patient with NPS (110) may be more than a coincidence. Taguchi et al. (114) demonstrated that characteristic ultrastructural changes in the glomerulus can be present, even in patients without apparent clinical renal involvement. From study of a large family with 30 patients with NPS (which the authors referred to as HOOD), Looij et al. (115) concluded that a person with NPS has a risk of about 1 in 4 of having a child with NPS nephropathy and a risk of about 1 in 10 of having a child in whom renal failure will develop. The nail-patella locus and the ABO blood group locus are
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linked. The recombination fraction is about 10%, but it is higher in females than in males (116). The LIM-homeodomain protein Lmx1b plays a central role in dorsal/ventral patterning of the vertebrate limb. Targeted disruption of Lmx1b results in skeletal defects, including hypoplastic nails, absent patellae, and a unique form of renal dysplasia (117). Dreyer et al. (118) showed that the Lmx1B gene maps to 9q in the same region than the NPS locus by fluorescence in situ hybridization. Most NPS families only inquire about prenatal diagnosis in the hope that severity can be predicted. It is in this regard that ultrasound may be of use in detecting early signs of severe renal damage, because there is no correlation between the Lmx1b mutation and the presence of kidney disease or overall NPS severity. LCAT Deficiency (OMIM 245900). Familial lecithin: cholesterol acyltransferase (LCAT) deficiency syndrome is inherited as an autosomal recessive disorder and is characterized by disturbances in lipid metabolism. The gene for LCAT is found on the long arm of chromosome 16 in the region 16q22 (119) and appears to be linked to the serum ␣-haptoglobin locus (120). Clinically this enzymatic defect is characterized by diffuse corneal opacities: “arcus lipoides juvenits”, target cell hemolytic anemia, lipid accumulation, and “sea-blue” histiocytes on bone marrow, spleen, and arterial walls, and decreased cone plasma esterified cholesterol and kidney defects. Corneal opacities are found in all patients. They consist of numerous minute, grayish dots in the entire corneal stroma giving the cornea a cloudy to misty appearance. Arcus juvenilis may be seen in younger patients with blue sclera, megacornea, or aniridia. Fundus changes, as aneurysmatic vein dilatations angoid streaks, papilledema, retina arterial occlusion, and disc protrusion have been occasionally described. Renal impairment with proteinuria before the age of 50 yr is a common feature that is the major cause of morbidity and mortality. Typical histologic findings are lacunae containing characteristic dense bodies in the glomerular and tubule membranes and the interstitium. The gene encoding LCAT on chromosome 16 is the site of the mutation in both Norum disease and fish-eye disease. According to Norum et al. (121), there is apparently no increased risk of premature atherosclerotic cardiovascular disease in either form of LCAT deficiency.
Ocular Abnormalities Associated with Proximal Renal Tubular Acidosis
The human Na⫹-HCO3⫺-cotransporter (NBC1) gene encodes two electrogenic sodium-bicarbonate cotransport proteins, pancreatic type (pNBC1) and kidney type (kNBC1), which are candidate proteins for mediating electrogenic sodium-bicarbonate cotransport in ocular cells. Both kidney type (kNBC-1) and pancreatic type (pNBC-1) transporters are present in the corneal endothelium, trabecular meshwork, ciliary epithelium, and lens epithelium. In the human lens epithelial (HLE) cells, RT-PCR detected mRNAs of both kNBC-1 and pNBC-1. Although a Na⫹-HCO3⫺ cotransport activity has not been detected in mammalian lens epithelia, the normal transport activity of NBC-1 is indispensable not only for the maintenance of corneal and lenticular transparency but also for
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the regulation of aqueous humor outflow. Mutations in the coding region of the human NBC1 gene in exons common to both pNBC1 and kNBC1 result in a syndrome with a severe ocular and renal phenotype (blindness, band keratopathy, glaucoma, cataracts, and proximal renal tubular acidosis) (122).
References 1. Pohl M, Bhatnagar V, Mendoza SA, Nigam SK: Toward an etiological classification of developmental disorders of the kidney and upper urinary tract. Kidney Int 61: 10 –19, 2002 2. Dahl E, Koseki H, Balling R: Pax genes and organogenesis. Bioessays 19: 755–765, 1997 3. Mrowka C, Schedl A: Wilms’ tumor suppressor gene WT1: From structure to renal pathophysiologic features. J Am Soc Nephrol 11: S106-S115, 2000 4. Wagner N, Wagner KD, Schley G, Coupland SE, Heimann H, Grantyn R, Scholz H: The wilms’ tumor suppressor wt1 is associated with the differentiation of retinoblastoma cells. Cell Growth Differ 13: 297–305, 2002 5. Armstrong JF, Pritchard-Jones K, Bickmore WA, Hastie ND, Bard JB: The expression of the Wilms’ tumour gene, WT1, in the developing mammalian embryo. Mech Dev 40: 85–97, 1993 6. Wang SW, Gan L, Martin SE, Klein WH: Abnormal polarization and axon outgrowth in retinal ganglion cells lacking the POUdomain transcription factor Brn-3b. Mol Cell Neurosci 16: 141– 156, 2000 7. Schimmenti LA, Cunliffe HE, McNoe LA, Ward TA, French MC, Shim HH, Zhang Y-H, Proesmans W, Leys A, Byerly KA, Braddock SR, Masuno M, Imaizumi K, Devriendt K, Eccles MR: Further delineation of renal-coloboma syndrome in patients with extreme variability of phenotype and identical PAX2 mutations. Am J Hum Genet 60: 869 – 878, 1997 8. Devriendt K, Matthijs G, Van Damme B, Van Caesbroeck D, Eccles M, Vanrenterghem Y, Fryns J-P, Leys A: Missense mutation and hexanucleotide duplication in the PAX2 gene in two unrelated families with renal-coloboma syndrome (MIM 120330). Hum Genet 103: 149 –153, 1998 9. Pagon RA: Ocular coloboma. Surv Ophthalmol 25: 223–36, 1981 10. Karcher H: Zum ‘morning glory’ Syndrom. Klin Mbl Augenheilk 175: 835-840, 1979 11. Weaver RG, Cashwell LF, Lorentz W, Whiteman D, Geisinger KR, Ball M: Optic nerve coloboma associated with renal disease. Am J Med Genet 29: 597– 605, 1988 12. Eccles MR, Bailey RR, Abbott GD, Sullivan MJ: Unravelling the genetics of vesicoureteric reflux: A common familial disorder. Hum Mol Genet 5: 1425-1429, 1996 13. Cunliffe HE, McNoe LA, Ward TA, Devriendt K, Brunner HG, Eccles MR: The prevalence of PAX2 mutations in patients with isolated colobomas or colobomas associated with urogenital anomalies. J Med Genet 35: 806 – 812, 1998 14. Feather SA, Malcolm S, Woolf AS, Wright V, Blaydon D, Reid CJ, Flinter FA, Proesmans W, Devriendt K, Carter J, Warwicker P, Goodship TH, Goodship JA: Primary, nonsyndromic vesicoureteric reflux and its nephropathy is genetically heterogeneous, with a locus on chromosome 1. Am J Hum Genet 66: 1420 –1425, 2000 15. Narahara K, Baker E, Ito S, Yokoyama Y, Yu S, Hewitt D, Sutherland GR, Eccles MR, Richards RI: Localisation of a 10q breakpoint within the PAX2 gene in a patient with a de novo t(10;13) translocation and optic nerve coloboma-renal disease. J Med Genet 34: 213–216, 1997
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16. Dressler GR, Deutsch U, Chowdhury K, Nornes HO, Gruss P: Pax2, a new murine paired-box-containing gene and its expression in the developing excretory system. Development 109: 787– 795, 1990 17. Otteson DC, Shelden E, Jones JM, Kameoka J, Hitchcock PF: Pax2 expression and retinal morphogenesis in the normal and Krd mouse. Dev Biol 193: 209 –224, 1998 18. Hildebrandt F: Nephronophthisis, In: Pediatric Nephrology, edited by Barratt TM, Avner ED, Harmon WE, Philadelphia, Lippincott Williams & Wilkins 1999, pp 453– 458 19. Antignac C, Kleinknecht C, Habib R: Nephronophthisis In: Oxford Textbook of Clinical Nephrology, edited by Davison AM, Cameron JS, Gru¨ nfeld JP, Kerr DNS, Ritz E, Winearls CG, Oxford, Oxford University Press, 1998, pp 2417–2426 20. Omran H, Sasmaz G, Haffner K, Volz A, Olbrich H, Melkaoui R, Otto E, Wienker TF, Korinthenberg R, Brandis M, Antignac C, Hildebrandt F: Identification of a gene locus for Senior-Loken syndrome in the region of the nephronophthisis type 3 gene. J Am Soc Nephrol 13: 75–79, 2002 21. Schuermann MJ, Otto E, Becker A, Saar K, Ruschendorf F, Polak BC, Ala-Mello S, Hoefele J, Wiedensohler A, Haller M, Omran H, Nurnberg P, Hildebrandt F: Mapping of gene loci for nephronophthisis type 4 and Senior-Loken syndrome, to chromosome 1p36. Am J Hum Genet 70: 1240 –1246, 2002 22. Mollet G, Salomon R, Gribouval O, Silbermann F, Bacq D, Landthaler G, Milford D, Nayir A, Rizzoni G, Antignac C, Saunier S: The gene mutated in juvenile nephronophthisis type 4 encodes a novel protein that interacts with nephrocystin. Nat Genet 32: 300-305, 2002 23. Otto E, Hoefele J, Ruf R, Mueller AM, Hiller KS, Wolf MT, Schuermann MJ, Becker A, Birkenhager R, Sudbrak R, Hennies HC, Nurnberg P, Hildebrandt F: A gene mutated in nephronophthisis and retinitis pigmentosa encodes a novel protein, nephroretinin, conserved in evolution. Am J Hum Genet 71: 1161-1167, 2002 24. Tellier AL, Cormier-Daire V, Abadie V, Amiel J, Sigaudy S, Bonnet D, de Lonlay-Debeney P, Morrisseau-Durand MP, Hubert P, Michel JL, Jan D, Dollfus H, Baumann C, Labrune P, Lacombe D, Philip N, LeMerrer M, Briard ML, Munnich A, Lyonnet S: CHARGE syndrome: Report of 47 cases and review. Am J Med Genet 76: 402– 409, 1998 25. Russell-Eggitt IM, Blake KD, Taylor DS, Wyse RK: The eye in the CHARGE association. Br J Ophthalmol 74: 421-426, 1990 26. Ragan DC, Casale AJ, Rink RC, Cain MP, Weaver DD: Genitourinary anomalies in the CHARGE association. J Urol 161: 622– 625, 1999 27. Kumar S, Rankin R: Renal insufficiency is a component of COACH syndrome. Am J Med Genet 61: 122-126, 1996 28. Gronskov K, Olsen JH, Sand A, Pedersen W, Carlsen N, Bak Jylling AM, Lyngbye T, Brondum-Nielsen K, Rosenberg T: Population-based risk estimates of Wilms tumor in sporadic aniridia. A comprehensive mutation screening procedure of PAX6 identifies 80% of mutations in aniridia. Hum Genet 109: 11–18, 2001 29. Wagner KD, Wagner N, Vidal VP, Schley G, Wilhelm D, Schedl A, Englert C, Scholz H: The Wilms’ tumor gene WT1 is required for normal development of the retina. EMBO J 21: 1398 –1405, 2002 30. Coppes MJ, Egeler RM: Genetics of Wilms’ tumor. Semin Urol Oncol 17: 2–10, 1999 31. Little M, Wells C: A clinical overview of WT1 gene mutations. Hum Mutat 9: 209 –225, 1997
Eye and Kidney
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32. Schumacher V, Scharer K, Wuhl E, Altrogge H, Bonzel KE, Guschmann M, Neuhaus TJ, Pollastro RM, Kuwertz-Broking E, Bulla M, Tondera AM, Mundel P, Helmchen U, Waldherr R, Weirich A, Royer-Pokora B: Spectrum of early onset nephrotic syndrome associated with WT1 missense mutations. Kidney Int 53: 1594 –1600, 1998 33. Pierides AM, Athanasiou Y, Demetriou K, Koptides M, Deltas CC: A family with the branchio-oto-renal syndrome: Clinical and genetic correlations. Nephrol Dial Transplant 17: 1014 –1018, 2002 34. Azuma N, Hirakiyama A, Inoue T, Asaka A, Yamada M: Mutations of a human homologue of the Drosophila eyes absent gene (EYA1) detected in patients with congenital cataracts and ocular anterior segment anomalies. Hum Mol Genet 9: 363–366, 2000 35. Ozkaynak E, Rueger DC, Drier EA, Corbett C, Ridge RJ, Sampath TK, Oppermann H: OP-1 cDNA encodes an osteogenic protein in the TGF-beta family. EMBO J 9: 2085–2093, 1990. 36. Hahn GV, Cohen RB, Wozney JM, Levitz CL, Shore EM, Zasloff MA, Kaplan FS: A bone morphogenetic protein subfamily: chromosomal localization of human genes for BMP5, BMP6, and BMP7. Genomics 14: 759 –762, 1992 37. Marker PC, King JA, Copeland NG, Jenkins NA, Kingsley DM: Chromosomal localization, embryonic expression, and imprinting tests for Bmp7 on distal mouse chromosome 2. Genomics 28: 576 –580, 1995 38. Saxen L, Lehtonen E: Embryonic kidney in organ culture. Differentiation 36: 2–11, 1987 39. Webster EH Jr, Silver AF, Gonsalves NI: The extracellular matrix between the optic vesicle and presumptive lens during lens morphogenesis in an anophthalmic strain of mice. Dev Biol 103: 142–1250, 1984 40. Kaufman MH: Postcranial morphological features of homozygous tetraploid mouse embryos. J Anat 180: 521–534, 1992 41. Watson GH, Miller V: Arteriohepatic dysplasia: familial pulmonary arterial stenosis with neonatal liver disease. Arch Dis Child 48: 459 – 466, 1973 42. Alagille D, Odievre M, Gautier M, Dommergues JP: Hepatic ductular hypoplasia associated with characteristic facies, vertebral malformations, retarded physical, mental and sexual development, and cardiac murmur. J Pediat 86: 63–71, 1975 43. Spinner NB, Rand EB, Fortina P, Genin A, Taub R, Semeraro A, Piccoli DA: Cytologically balanced t(2;20) in a two-generation family with Alagille syndrome: Cytogenetic and molecular. Am J Hum Genet 55: 238 –243, 1994. 44. LaBrecque DR, Mitros FA, Nathan RJ, Romanchuk KG, Judisch GF, El-Khoury GH: Four generations of arteriohepatic dysplasia. Hepatology 2: 467– 474, 1982 45. Martin, SR, Garel L, Alvarez F, Alagille’s syndrome associated with cystic renal disease. Arch Dis Child 74: 232–235, 1996. 46. Habib R, Dommergues JP, Gubler MC, Hadchouel M, Gautier M, Odievre M, Alagille D: Glomerular mesangiolipidosis in Alagille syndrome (arteriohepatic dysplasia). Pediatr Nephrol 1: 455– 464, 1987 47. Russo PA, Ellis D, Hashida Y: Renal histopathology in Alagille’s syndrome. Pediatr Pathol 7: 557–568, 1987 48. Woolfenden AR, Albers GW, Steinberg GK, Hahn JS, Johnston DCC, Farrell K: Moyamoya syndrome in children with Alagille syndrome: Additional evidence of a vasculopathy. Pediatrics 103: 505–508, 1999 49. Li L, Krantz ID, Deng Y, Genin A, Banta AB, Collins CC, Qi M, Trask BJ, Kuo WL, Cochran J, Costa T, Pierpont MEM, Rand
528
Journal of the American Society of Nephrology
EB, Piccoli DA, Hood L, Spinner NB: Alagille syndrome is caused by mutations in human Jagged1, which encodes a ligand for Notch1. Nature Genet. 16: 243–251, 1997 50. Giannakudis J, Ropke A, Kujat A, Krajewska-Walasek M, Hughes H, Fryns J-P, Bankier A, Amor D, Schlicker M, Hansmann I.: Parental mosaicism of JAG1 mutations in families with Alagille syndrome. Eur J Hum Genet 9: 209 –216, 2001 51. McCright B, Gao X, Shen L, Lozier J, Lan Y, Maguire M, Herzlinger D, Weinmaster G, Jiang R, Gridley T: Defects in development of the kidney, heart and eye vasculature in mice homozygous for a hypomorphic Notch2 mutation. Development 128: 491–502, 2001 52. Folz SJ, Trobe JD: The peroxisome and the eye. Surv Ophthalmol 35: 353–368, 1991 53. Ekblom P: Genetics of kidney development. Curr Opin Nephrol Hypertens 5: 282–287, 1996 54. Klein G, Langegger M, Timpl R, Ekblom P: Role of laminin A chain in the development of epithelial cell polarity. Cell 55: 331–341, 1988 55. Regenbogen LS, Eliahou HE: Diseases Affecting the Eye and the Kidney, Basel, Karger, 1993 56. Warkany J: Congenital Malformations Notes and Comments, Chicago, Year Book Medical Publishers, 1975 57. Meyrier A, Simon P: Drooping upper eyelids and polycystic kidney disease. J Am Soc Nephrol 5: 1266 –1270, 1994 58. Sadler LS, Robinson LK: Chorioretinal dysplasia-microcephalymental retardation syndrome: Report of an American family. Am J Med Genet 47: 65– 68, 1993 59. Veis DJ, Sorenson CM, Shutter JR, Korsmeyer SJ: Bcl-2-deficient mice demonstrate fulminant lymphoid apoptosis, polycystic kidneys, and hypopigmented hair. Cell 75: 229 –240, 1993 60. Noakes PG, Miner JH, Gautam M, Cunningham JM, Sanes JR, Merlie JP: The renal glomerulus of mice lacking s-laminin/ laminin beta 2: Nephrosis despite molecular compensation by laminin beta 1. Nat Genet 10: 400 – 406, 1995 61. Threadgill DW, Dlugosz AA, Hansen LA, Tennenbaum T, Lichti U, Yee D, LaMantia C, Mourton T, Herrup K, Harris RC, et al: Targeted disruption of mouse EGF receptor: effect of genetic background on mutant phenotype. Science 269: 230-234, 1995 62. Lo SH, Yu QC, Degenstein L, Chen LB, Fuchs E: Progressive kidney degeneration in mice lacking tensin. J Cell Biol 136: 1349 –1361, 1997 63. Dinchuk JE, Car BD, Focht RJ, Johnston JJ, Jaffee BD, Covington MB, Contel NR, Eng VM, Collins RJ, Czerniak PM, et al: Renal abnormalities and an altered inflammatory response in mice lacking cyclooxygenase II. Nature 378: 406 – 409, 1995 64. Koptides M, Deltas CC. Autosomal dominant polycystic kidney disease: Molecular genetics and molecular pathogenesis. Hum Genet 107: 115–126, 2000 65. Chauveau D, Duvic C, Chretien Y, Paraf F, Droz D, Melki P, Helenon O, Richard S, Grunfeld JP: Renal involvement in von Hippel-Lindau disease. Kidney Int 50: 944 –951, 1996 66. Neumann HP, Wiestler OD: Clustering of features of von Hippel-Lindau syndrome: Evidence for a complex genetic locus. Lancet 337: 1052–1054, 1991 67. Duan DR, Pause A, Burgess WH, Aso T, Chen DY, Garrett KP, Conaway RC, Conaway JW, Linehan WM, Klausner RD: Inhibition of transcription elongation by the VHL tumor suppressor protein. Science 269: 1402–1406, 1995 68. Webster AR, Maher ER, Moore AT: Clinical characteristics of ocular angiomatosis in von Hippel-Lindau disease and correla-
J Am Soc Nephrol 14: 516–529, 2003
tion with germline mutation. Arch Ophthalmol 117: 371–378, 1999 69. Gurwin EB, Fitzsimons RB, Sehmi KS, Bird AC: Retinal telangiectasis in facioscapulohumeral muscular dystrophy with deafness. Arch Ophthalmol 103: 1695–1700, 1985 70. Maher ER, Yates JR, Harries R, Benjamin C, Harris R, Moore AT, Ferguson-Smith MA: Clinical features and natural history of von Hippel-Lindau disease. Q J Med 77: 1151–1163, 1990 71. Glassberg KI. Renal dysplasia and cystic disease of the kidney. In: Campbell’s Urology, 6th edition, edited by Walsh PC, Philadelphia, WB Saunders, 1992, 1461–1463 72. Solomon D, Schawartz A: Renal pathology in vHL disease. Hum Pathol 19: 1072–1079, 1988 73. Sullivan TJ, Clarke MP, Morin JD: The ocular manifestations of the Sturge-Weber syndrome. J Pediatr Ophthalmol Strabismus 29: 349 –56, 1992 74. Augsburger JJ, Anand R, Sanborn GE: Choroidal hemangiomas. In: Ophthalmology, edited by Yanoff M, Duker JS, London, Mosby, 1999, 1– 4 75. Lee H, Choi SS, Kim SS, Hong YJ: A case of glaucoma associated with Sturge-Weber syndrome and Nevus of Ota. Korean J Ophthalmol 15: 48 –53, 2001 76. Celebi S, Alagoz G, Aykan U: Ocular findings in Sturge-Weber syndrome. Eur J Ophthalmol 10: 239 –243, 2000 77. Sadda SR, Miller NR, Tamargo R, Wityk R: Bilateral optic neuropathy associated with diffuse cerebral angiomatosis in Sturge-Weber syndrome. J Neuroophthalmol 20: 28 –31, 2000 78. Schofield D, Zaatari GS, Gay BB: Klippel-Trenaunay and Sturge-Weber syndromes with renal hemangioma and double inferior vena cava. J Urol 136: 442– 445, 1986 79. Van der Hoeve J: Les phakomatoses de Bourneville de Recklinghausen et de von Hippel-Lindau. J Belg Neurol Psychiatr 33: 752–762, 1933 80. Hyman MH, Whittemore VH: National Institutes of Health consensus conference: Tuberous sclerosis complex. Arch Neurol 57: 662– 665, 2000 81. Nellist M, Brook-Carter PT, Connor JM, Kwiatkowski DJ, Johnson P, Sampson JR: Identification of markers flanking the tuberous sclerosis locus on chromosome 9 (TSC1). J Med Genet 30: 224 –227, 1993 82. Gold DH, Weingeist TA. The Eye in Systemic Disease, Philadelphia, Lippincott 1990, pp 447– 455 83. Rascher W: Other organ systems in relation to kidney disease. In: Oxford Textbook of Clinical Nephrology, 1st edition, edited by Cameron S, Davison AM, Gru¨ nfeld JP, Kerr D, Ritz E, New York, Oxford Univsersity Press, 1992, 2143–2144 84. Okada RD, Platt MA, Fleishman J. Chronic renal failure in patients with tuberous sclerosis association with renal cysts. Nephron 30: 85– 88, 1982 85. Opitz JM, Barnes EG. Neonatal, congenital, and heritable disorders. In: Pediatric Kidney Disease, 2nd edition, edited by Edelmann CM Jr, Boston, Little Brown, 1992, pp 1072–1076 86. Blute ML, Malek RS, Segura JW: Angiomyolipoma: Clinical metamorphosis and concepts for management. J Urol 139: 20 – 24, 1988 87. Vekemans K, Van Oyen P, Denys H, Vergison R: Renal angiomyolipoma as a cause of fever of unknown origin. Br J Urol 60: 271, 1987 88. Bernstein J, Robbins TO: Renal involvement in tuberous sclerosis. Ann NY Acad Sci 615: 36 – 49, 1991 89. Brook-Carter PT, Peral B, Ward CJ, Thompson P et al: Deltion of the TSC-2 and PKD1 genes associated with sever infantile
J Am Soc Nephrol 14: 516–529, 2003
polycystic kidney disease: A contiguous gene syndrome. Nat Genet 8: 328 –332, 1994 90. Washecka R, Hanna M: Malignant renal tumors in tuberous sclerosis. Urology 37: 340 –343, 1991 91. Schillinger F, Montagnac R, Grapin JL, Schillinger D, Bressieux JM: Le rein au cours de la scle´ rose tube´ reuse de Bourneville. Rev Med Interne 9: 61– 66, 1988 92. Nagashima Y, Ohaki Y, Tanaka Y, Misugi K, Horiuchi M: A case of renal angiomyolipomas associated with multiple and various hamartomatous microlesions. Virchows Arch A Pathol Anat Histopathol 413: 177–182, 1988 93. Rolfes DB, Towbin R, Bove KE: Vascular dysplasia in a child with tuberous sclerosis. Pediabic Pathol 3: 359 –373, 1985 94. Mykytyn K, Nishimura DY, Searby CC, Shastri M, Yen HJ, Beck JS, Braun T, Streb LM, Cornier AS, Cox GF, Fulton AB, Carmi R, Luleci G, Chandrasekharappa SC, Collins FS, Jacobson SG, Heckenlively JR, Weleber RG, Stone EM, Sheffield VC: Identification of the gene (BBS1) most commonly involved in Bardet-Biedl syndrome, a complex human obesity syndrome. Nat Genet 31: 435– 438, 2002 95. Beales PL, Reid HA, Griffiths MH, Maher ER, Flinter FA, Woolf AS: Renal cancer and malformations in relatives of patients with Bardet-Biedl syndrome. Nephrol Dial Transplant 15: 1977–1985, 2000 96. Alport, AC: Hereditary familial congenital haemorrhagic nephritis. Brit Med J 1: 504 –506, 1927 97. Kashtan CE, Michael AF: Alport syndrome. Kidney Int 50: 1445-1463, 1996 98. Mochizuki T, Lemmink HH, Mariyama M, Antignac C, Gubler MC, Pirson Y, Verellen-Dumoulin C, Chan B, Schroder CH, Smeets HJ, et al: Identification of mutations in the alpha 3(IV) and alpha 4(IV) collagen genes in autosomal recessive Alport syndrome. Nat Genet 8: 77– 81, 1994 99. Jacobs M, Jeffrey B, Kriss A, Taylor D, Sa G, Barratt TM. Ophthalmologic assessment of young patients with Alport syndrome. Ophthalmology 99: 1039 –1044, 1992 100. Govan JA: Ocular manifestations of Alport’s syndrome: a hereditary disorder of basement membranes? Br J Ophthalmol 67: 493–503, 1983 101. Burke JP, Clearkin LG, Talbot JF: Recurrent corneal epithelial erosions in Alport’s syndrome. Acta Ophthalmol (Copenh) 69: 555–557, 1991 102. Kalluri R, Weber M, Netzer K-O, Sun MJ, Neilson EG, Hudson BG: COL4A5 gene deletion and production of post-transplant anti-alpha-3(IV) collagen alloantibodies in Alport syndrome. Kidney Int 45: 721–726, 1994 103. Milliner DS, Pierides AM, Holley KE: Renal transplantation in Alport’s syndrome: Anti-glomerular basement membrane glomerulonephritis in the allograft. Mayo Clin Proc 57: 35– 43, 1982 104. Richardson D, Shires M, Davison AM: Renal diagnosis without renal biopsy. Nephritis and sensorineural deafness. Nephrol Dial Transplant 16: 1291–1294, 2001 105. Ferguson-Smith MA, Aitken DA, Turleau C, de Grouchy J: Localisation of the human ABO: Np-1:AK-1 linkage group by regional assignment of AK-1 to 9q34. Hum Genet 34: 35– 43, 1976
Eye and Kidney
529
106. Singh SD, Chhaparwal BC, Dhanda RP, Pohowalla JN: A syndrome of dwarfism, mental retardation, lens opacities, nystagmus, strabismus, and cryptorchidism and absent patellae. Report of 2 cases in siblings. Indian J Pediatr 37: 197–199, 1970 107. Craig JE, Mackey DA: Glaucoma genetics: where are we? Where will we go? Curr Opin Ophthalmol 10: 126 –134, 1999 108. Simila S, Vesa L, Wasz-Hockert O: Hereditary onycho-osteodysplasia (the nail-patella syndrome) with nephrosis-like renal disease in a newborn boy. Pediatrics 46: 61– 65, 1970 109. Meyrier A, Rizzo R, Gubler MC: The Nail-Patella syndrome. A review. J Nephrol 2: 133–140, 1990 110. Curtis JJ, Athena DB, Leach RP, Galla JH, Lucas BA, Luke RG: Goodpasture’s syndrome in a patient with the nail-patella syndrome. Am J Med 61: 401– 406, 1976 111. Mackay IG, Doig A, Thomson D: Membranous nephropathy in a patient with nail-patella syndrome nephropathy. Scottish Med J 30: 47– 49, 1985 112. Croodk AD, Bashar Kahaleh M, Powers JM: Vasculitis and renal disease in nail-patella syndrome: Case report and literature review. Ann Rheum Dis 46: 562–565, 1987 113. Morita T, Laughlin O, Kawano K, Kimmelstiel P: Nail-patella syndrome. Arch Intern Med 131: 271–277, 1973 114. Taguchi T, Takebayashi S, Nishimura M, Tsuru N: Nephropathy of nail-patella syndrome. Ultrastruct Path 12: 175–183, 1988 115. Looij BJ Jr, Te Slaa RL, Hogewind BL, van de Kamp JJP: Genetic counselling in hereditary osteo-onychodysplasia (HOOD, nail-patella syndrome) with nephropathy. J Med Genet 25: 682– 686, 1988 116. Renwick JH, Schulze J: Male and female recombination fractions for the nail patella: ABO linkage in man. Ann Hum Genet 28: 379 –392, 1965 117. Chen H, Lun Y, Ovchinnikov D, Kokubo H, Oberg KC, Pepicelli CV, Gan L, Lee B, Johnson RL: Limb and kidney defects in Lmx1b mutant mice suggest an involvement of LMX1B in human nail patella syndrome. Nature Genet 19: 51–55, 1998 118. Dreyer SD, Zhou G, Baldini A, Winterpacht A, Zabel B, Cole W, Johnson RL, Lee B: Mutations in LMX1B cause abnormal skeletal patterning and renal dysplasia in nail patella syndrome. Nat Genet 19: 47–50, 1998 119. Gjone E, Blomhoff JP, Holme R, Hovig T, Olaisen B, Skarbovik AJ, Teisberg P: Familial lecithin:cholesterol acyltransferase deficiency: report of a fourth family from Northwestern Norway. Acta Med Scand 210: 3– 6, 1981 120. McIntyre N: Familial LCAT deficiency and fish-eye disease. J Inher Metab Dis 11: 45–56, 1988 121. Norum KR, Gjone E, Glomset JA: Familial lecithin:cholesterol acyltransferase deficiency including fish eye disease. In: The Metabolic Basis of Inherited Disease, edited by Scriver CR, Beaudet AL, Sly WS, Valle D, New York McGraw-Hill, 1989, pp 1181–1194 122. Usui T, Hara M, Satoh H, Moriyama N, Kagaya H, Amano S, Oshika T, Ishii Y, Ibaraki N, Hara C, Kunimi M, Noiri E, Tsukamoto K, Inatomi J, Kawakami H, Endou H, Igarashi T, Goto A, Fujita T, Araie M, Seki G: Molecular basis of ocular abnormalities associated with proximal renal tubular acidosis. J Clin Invest 108: 107–115, 2001
