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Three new mutations in the hepatocyte nuclear factor-1α gene in Japanese subjects with diabetes mellitus: clinical features and functional characterization

Authors :
Issei Yoshiuchi
Jun-ichiro Miyagawa
Kohei Okita
Takanori Oue
Akihisa Imagawa
T. Satoh
Yuji Matsuzawa
Y. Horikawa
H. Nakajima
Jun-ichi Miyazaki
Kazuya Yamagata
Shigeki Higashiyama
T. Hanafusa
Mitsuyoshi Namba
Qin Yang
Tomoya Hamaguchi
Hiromi Iwahashi
K. Yamamoto
Tomoyuki Yamasaki
Source :
Diabetologia. 42:621-626
Publication Year :
1999
Publisher :
Springer Science and Business Media LLC, 1999.

Abstract

Aims/hypothesis. Mutations in the hepatocyte nuclear factor-1α gene are a common cause of the type 3 form of maturity-onset diabetes of the young. We examined the clinical features and molecular basis of hepatocyte nuclear factor-1α (HNF-1α) diabetes. Methods. Thirty-seven Japanese subjects with early onset Type II (non-insulin-dependent) diabetes mellitus and 45 with Type I (insulin-dependent) diabetes mellitus were screened for mutations in this gene. Functional properties of mutant HNF-1α were also investigated. Results. Three new mutations [G415R, R272C and A site of the promoter ( + 102G-to-C)] were found. Insulin secretion was impaired in the three subjects. Insulin and glucagon secretory responses to arginine in the subject with the R272C mutation were also diminished. Molecular biological studies indicated that the G415R mutation generated a protein with about 50 % of the activity of wild-type HNF-1α. The R272C mutation had no transactivating or DNA binding activity and acted in a dominant negative manner. The + 102 G-to-C mutation in the A site of the promoter activity was associated with an increase in promoter activity and it had 42–75 % more activity than the wild-type sequence. Conclusion/interpretation. Mutations in the HNF-1α gene may affect the normal islet function by different molecular mechanisms. [Diabetologia (1999) 42: 621–626]

Details

ISSN :
14320428 and 0012186X
Volume :
42
Database :
OpenAIRE
Journal :
Diabetologia
Accession number :
edsair.doi.dedup.....c0bde1e703a01bf15424f69771d77369