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Characterization of a naturally occurring mutation (L107I) in the HNF1 α (MODY3) gene


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 α . 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 α 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 α in HeLa cells lacking HNF1 α. The transcriptional activity was not suppressed when the mutant was co-expressed with wild type HNF1 α suggesting that the decreased activity was not mediated by a dominant negative mechanism. The L107I/HNF1α protein showed normal nuclear targeting but impaired binding to an HNF1 α 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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Cervin, .C., Orho-Melander, .M., Ridderstråle, .M. et al. Characterization of a naturally occurring mutation (L107I) in the HNF1 α (MODY3) gene. Diabetologia 45, 1703–1708 (2002).

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  • MODY Type II diabetes HNF1α gene expression DNA binding cell lines mutation metabolism insulin