Molecular genetic analysis of MODY candidate genes in Japanese patients with non-obese juvenile onset diabetes mellitus.
We analyzed 84 Japanese patients with juvenile-onset (before 18 years of age) non-obese diabetes mellitus (DM) for mutations in the genes for HNF-1alpha, HNF-4alpha and HNF-1beta. In HNF-1alpha, previously reported mutations (R271W and R272C) and one novel sequence variant (at nucleotide -129/-130 insTTGGGG of the promoter region) were identified in three different patients. In vitro functional study of the new promoter variant demonstrated that the transcriptional activity was 1.6-2.0 times higher than that of the wild-type. This may lead to overexpression of HNF-1alpha and subsequent negative regulation of the target genes of HNF-1alpha. No mutation was identified in the HNF-4alpha and HNF-1beta genes. In this study on a small series of non-obese Japanese patients with juvenile-onset DM, the prevalence of MODY3 was 3.5%. The significance of the new promoter variant in the development of DM is unclear; however, a promoter mutation in the HNF-1alpha gene could be diabetogenic.
Department of Endocrinology and Metabolism, National Research Institute for Child Health and Development, Tokyo, Japan.
Masayo
M
Kagami-Takasugi
Noriyuki
N
Katsumata
Toshiaki
T
Tanaka
Toshihiro
T
Tajima
Kenji
K
Fujieda
D000293:Adolescent; D000328:Adult; D002648:Child; D003922:Diabetes Mellitus, Type 1 / Q000235:genetics*; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics*; D005260:Female; D051538:Hepatocyte Nuclear Factor 1-alpha / Q000235:genetics*; D051539:Hepatocyte Nuclear Factor 1-beta / Q000235:genetics*; D051557:Hepatocyte Nuclear Factor 4 / Q000235:genetics*; D006801:Humans; D007564:Japan; D008297:Male; D009154:Mutation; D011401:Promoter Regions, Genetic / Q000235:genetics
C496592:HNF4A protein, human; D051538:Hepatocyte Nuclear Factor 1-alpha; D051557:Hepatocyte Nuclear Factor 4; D051539:Hepatocyte Nuclear Factor 1-beta