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Characterization of a naturally occurring mutation (L107I) in the HNF1 alpha (MODY3) gene.
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2002 (English)In: Diabetologia, ISSN 0012-186X, E-ISSN 1432-0428, Vol. 45, no 12, 1703-8 p.Article in journal (Refereed) Published
Abstract [en]

AIMS/HYPOTHESIS: Maturity onset diabetes of the young type 3 (MODY3) is a monogenic form of diabetes mellitus caused by mutations in the gene encoding for hepatocyte nuclear factor 1 alpha, HNF1 alpha. In this study we have examined the in vivo and in vitro effects of a mutation (L107I) outside the DNA binding and dimerization domains in the N terminal part of the HNF1 alpha gene.

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.

Place, publisher, year, edition, pages
2002. Vol. 45, no 12, 1703-8 p.
National Category
Medical and Health Sciences
URN: urn:nbn:se:uu:diva-161868DOI: 10.1007/s00125-002-0977-4PubMedID: 12488960OAI: oai:DiVA.org:uu-161868DiVA: diva2:457787
Available from: 2011-11-19 Created: 2011-11-19 Last updated: 2011-11-19

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