DIABETICMedicine DOI: 10.1111/dme.12758
Short Report: Genetics Abnormalities in chromosome 6q24 as a cause of early-onset, non-obese, non-autoimmune diabetes mellitus without history of neonatal diabetes T. Yorifuji1,2,3, K. Matsubara4, A. Sakakibara1, Y. Hashimoto1, R. Kawakita1, Y. Hosokawa1, R. Fujimaru1, A. Murakami2, N. Tamagawa2, K. Hatake3, H. Nagasaka5, J. Suzuki6, T. Urakami6, M. Izawa7 and M. Kagami4 1 Department of Pediatric Endocrinology and Metabolism, Children’s Medical Center, Osaka City General Hospital, 2Department of Genetic Medicine, Osaka City General Hospital, 3Clinical Research Center, Osaka City General Hospital, Osaka, 4Department of Molecular Endocrinology, National Research Institute for Child Health and Development, Tokyo, 5Department of Pediatrics, Takarazuka City Hospital, 6Department of Pediatrics, Nihon University School of Medicine and 7 Department of Endocrinology and Metabolism, Aichi Children’s Health and Medical Center, Japan
Accepted 20 March 2015
Abstract Aims Abnormalities in the imprinted locus on chromosome 6q24 are the most common causes of transient neonatal diabetes mellitus (6q24-related transient neonatal diabetes). 6q24-Related transient neonatal diabetes is characterized by the patient being small-for-gestational age, diabetes mellitus at birth, spontaneous remission within the first few months and frequent recurrence of diabetes after childhood. However, it is not clear whether individuals with 6q24 abnormalities invariably develop transient neonatal diabetes. This study explored the possibility that 6q24 abnormalities might cause early-onset, non-autoimmune diabetes without transient neonatal diabetes. Methods The 6q24 imprinted locus was screened for abnormalities in 113 Japanese patients with early-onset, nonobese, non-autoimmune diabetes mellitus who tested negative for mutations in the common maturation-onset diabetes of the young (MODY) genes and without a history of transient neonatal diabetes. Positive patients were further analysed by combined loss of heterozygosity / comparative genomic hybridization analysis and by microsatellite analysis. Detailed clinical data were collected through the medical records of the treating hospitals.
Three patients with paternal uniparental isodisomy of chromosome 6q24 were identified. None presented with hyperglycaemia in the neonatal period. Characteristically, these patients were born small-for-gestational age, representing 27.2% of the 11 patients whose birth weight standard deviation score (SDS) for gestational age was below 2.0.
Results
Conclusions Abnormalities in the imprinted locus on chromosome 6q24 do not necessarily cause transient neonatal diabetes. Non-penetrant 6q24-related diabetes could be an underestimated cause of early-onset, non-autoimmune diabetes in patients who are not obese and born small-for-gestational age.
Diabet. Med. 32, 963–967 (2015)
Introduction Abnormalities in the imprinted locus on chromosome 6q24 are the most common causes of transient neonatal diabetes mellitus, accounting for 70–80% of all cases of 6q24-related transient neonatal diabetes [1]. However, the incidence is extremely low, estimated at 1 in 300 000 term newborns [1]. The critical region for 6q24-related transient neonatal diabetes has been narrowed down to a 160–173-kb segment Correspondence to: Tohru Yorifuji. E-mail:
[email protected]
ª 2015 The Authors. Diabetic Medicine ª 2015 Diabetes UK
at 6q24 [2], which harbours only two genes, PLAGL1 and HYMAI. In the fetal pancreas, both of these genes are expressed only from the paternal allele, and the imprinting is supported by a 1-kb differentially methylated region (DMR) that overlaps with the shared promoter of these genes [3]. 6q24-related transient neonatal diabetes is believed to be caused by an overexpression of PLAGL1 via one of three mechanisms: (1) paternal uniparental disomy of chromosome 6 (pUPD, 41%), (2) duplication of the paternal allele (33%), or (3) epimutation causing hypomethylation of the maternal allele (26%) [3,4].
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DIABETICMedicine
Chromosome 6q24-related diabetes without transient neonatal diabetes mellitus T. Yorifuji et al.
What’s new? • This study clearly showed, for the first time, that abnormalities in the imprinted locus on chromosome 6q24 that are usually associated with transient neonatal diabetes, do not necessarily cause transient neonatal diabetes. • The results showed that those non-penetrant 6q24 abnormalities might be an underestimated cause of early-onset, non-autoimmune diabetes mellitus in nonobese patients born small-for-gestational age. Clinically, 6q24-related transient neonatal diabetes is characterized by the patients being small-for-gestational age and by the development of diabetes mellitus during the first day of life, although hyperglycaemia may not be recognized until later (median age of 4 days) [3,4]. The patients usually have little or no endogenous insulin and require insulin therapy [3]. Gradual improvement of hyperglycaemia follows, and spontaneous remission can be reached at the modal age of 2 months (median age of 3 months) [4]. However, in approximately half of these patients, diabetes recurs after childhood [3]. The specificity of the DNA methylation tests to detect 6q24 abnormalities is assumed to be nearly 100% [1]. However, few exceptional cases with 6q24 abnormalities, but without known history of transient neonatal diabetes, have been reported in all three subtypes: pUPD [5], paternal duplication [6], and maternal hypomethylation caused by mutations in ZFP57 [7]. Because these reports only refer to the absence of a history of transient neonatal diabetes, it remains possible that hyperglycaemia was actually present but was simply unrecognized in these cases. Therefore, it is not entirely clear whether individuals with these abnormalities invariably develop transient neonatal diabetes. In this study, we explored the possibility that abnormalities in chromosome 6q24 might be causes of early-onset, non-obese, non-autoimmune diabetes without a history of transient neonatal diabetes. Using a methylation-specific polymerase chain reaction (PCR), we systematically screened for the presence of 6q24 abnormalities in 113 such patients who tested negative for mutations in the common causative genes for maturation-onset diabetes of the young (MODY).
Methods Patients
The study subjects consisted of 113 consecutive Japanese patients who were referred to Osaka City General Hospital during 2004–2014 seeking molecular testing for MODY gene mutations and tested negative for mutations in the genes HNF1A, HNF1B, HNF4A and GCK. These patients were characterized by an early onset of diabetes mellitus with or
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without a family history of diabetes, absence of obesity or signs of insulin resistance, and they tested negative for autoantibodies, including anti-GAD or anti-IA2. None of the patients had a known history of neonatal diabetes mellitus. The clinical features of the subjects are listed in Table 1. The study protocol was approved by the Institutional Review Board at Osaka City General Hospital (No. 742), and written informed consent was obtained from the patients or their guardians.
Clinical data collection
Clinical data after development of diabetes were collected from treating physicians. Those during the neonatal period were collected from the medical records at each neonatal intensive care unit where the patients were treated.
Analytical Methods
Blood glucose was measured by the glucose oxidase/hydrogen peroxide electrode method using the ADAMS glucose GA-1171 system (Arkray, Kyoto, Japan). Insulin and Cpeptide were measured by the electrochemiluminescence/ magnetic particle method using the cobas 8000 modular analyzer (Roche, Indianapolis, IN, USA).
Mutational analysis of known MODY genes
Mutational analysis of the HNF1A, HNF1B, HNF4A, and GCK genes was performed as described previously [8].
Table 1 Clinical features of the study subjects Gender Gestational age (weeks)* Birth weight (g)† Birth weight SDS for GA‡ < 3 SDS 3 to 2 SDS 2 to 1 SDS 1 to 0 SDS 0–1 SDS 1–2 SDS 2–3 SDS