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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
- 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]
- Subjects :
- Adult
Male
medicine.medical_specialty
Endocrinology, Diabetes and Metabolism
medicine.medical_treatment
Mutant
Biology
Arginine
medicine.disease_cause
Internal medicine
Diabetes mellitus
Insulin Secretion
Internal Medicine
medicine
Humans
Insulin
Hepatocyte Nuclear Factor 1-alpha
Nuclear protein
Promoter Regions, Genetic
Gene
Hepatocyte Nuclear Factor 1-beta
Mutation
C-Peptide
Nuclear Proteins
DNA
Glucose Tolerance Test
Middle Aged
Glucagon
medicine.disease
DNA-Binding Proteins
Hepatocyte nuclear factors
Diabetes Mellitus, Type 1
Endocrinology
Diabetes Mellitus, Type 2
Hepatocyte Nuclear Factor 1
Hepatocyte Nuclear Factor 1-Beta
Female
Transcription Factors
Subjects
Details
- ISSN :
- 14320428 and 0012186X
- Volume :
- 42
- Database :
- OpenAIRE
- Journal :
- Diabetologia
- Accession number :
- edsair.doi.dedup.....c0bde1e703a01bf15424f69771d77369