Aims/hypothesis. Hepatocyte nuclear factor (HNF)3 beta, a transcription fac
tor expressed in pancreatic beta cells, is an upstream regulator of HNF-1 a
lpha/ MODY3, NNF-4 alpha/MODY1 and IPF1/MODY5 genes. Our previous screening
of MODY subjects showed that mutations in the HNF-3 beta gene are not a co
mmon cause of this form of diabetes in the Japanese, We tested the hypothes
is that mutations in the HNF-3 beta gene cause late-onset Type II (non-insu
lin-dependent) diabetes mellitus in this population.
Methods. Genotyping of the polymorphic TCC repeat in the HNF-3 beta gene wa
s done in 112 Japanese subjects with Type II diabetes (age at diagnosis > 3
5 and family history of Type II diabetes among their second-degree relative
s) and 96 Japanese control subjects. Furthermore, we screened 57 Type II di
abetic patients for mutations of the HNF-3 beta gene. Transactivation activ
ity of variant HNF-3 beta was investigated by transfection assay.
Results. The distribution of alleles of the TCC repeat was similar between
diabetic and control groups. Mutation screening identified two missense mut
ations, A86T and G114E, Neither mutation was observed in 225 control subjec
ts. The transactivation activity of G114E-HNF-3 beta was similar to that of
wild type-HNF3 beta. In contrast, the activity of A86T-HNF-3 beta was stat
istically significantly reduced to 83-86% of that of wild type.
Conclusions/Interpretation. The A86T mutation in the HNF-3 beta gene might
be involved in the development of late-onset Type II diabetes in a small gr
oup of Japanese people.