Abstract | AIMS/HYPOTHESIS: METHODS: Beta-cell function of the affected family members was assessed by an oral glucose tolerance test. Functional tests were carried out to explain the role of the mutation in vitro by transcriptional activity assay, Western blotting, DNA-binding assays and subcellular localization experiments. RESULTS: Affected family members showed an 86% decreased insulin response to glucose when compared to age-matched healthy control subjects. In vitro the mutation showed a 79% decrease in transcriptional activity as compared to wild type HNF1 alpha in HeLa cells lacking HNF1 alpha. The transcriptional activity was not suppressed when the mutant was co-expressed with wild type HNF1 alpha suggesting that the decreased activity was not mediated by a dominant negative mechanism. The L107I/HNF1alpha protein showed normal nuclear targeting but impaired binding to an HNF1 alpha consensus sequence. CONCLUSION/INTERPRETATION: Our results suggest that the L107I substitution represents a MODY3 mutation which impairs beta-cell function by a loss-of-function mechanism.
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Authors | C Cervin, M Orho-Melander, M Ridderstråle, M Lehto, S Barg, L Groop, C M Cilio |
Journal | Diabetologia
(Diabetologia)
Vol. 45
Issue 12
Pg. 1703-8
(Dec 2002)
ISSN: 0012-186X [Print] Germany |
PMID | 12488960
(Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
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Chemical References |
- Blood Glucose
- DNA-Binding Proteins
- HNF1A protein, human
- HNF1B protein, human
- Hepatocyte Nuclear Factor 1-alpha
- Insulin
- Nuclear Proteins
- Transcription Factors
- Isoleucine
- Hepatocyte Nuclear Factor 1
- Hepatocyte Nuclear Factor 1-beta
- DNA
- Leucine
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Topics |
- Adult
- Amino Acid Substitution
- Biological Transport
(genetics)
- Blood Glucose
(analysis)
- Cell Nucleus
(metabolism)
- DNA
(metabolism)
- DNA-Binding Proteins
- Dimerization
- Female
- Hepatocyte Nuclear Factor 1
- Hepatocyte Nuclear Factor 1-alpha
- Hepatocyte Nuclear Factor 1-beta
- Heterozygote
- Humans
- Insulin
(blood)
- Isoleucine
- Leucine
- Male
- Mutation
(genetics)
- Nuclear Proteins
- Pedigree
- Protein Structure, Tertiary
(physiology)
- Transcription Factors
(genetics, metabolism)
- Transcription, Genetic
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