Characterisation of a naturally occurring mutation (L107I) in the HNF1α (MODY3) gene

被引:12
作者
Cervin, C
Orho-Melander, M
Ridderstråle, M
Lehto, M
Barg, S
Groop, L [1 ]
Cilio, CM
机构
[1] Malmo Univ Hosp, Dept Endocrinol, Wallenberg Lab, S-20502 Malmo, Sweden
[2] Natl Publ Hlth Inst, Dept Mol Med, Helsinki, Finland
[3] Lund Univ, Dept Physiol Sci, Lund, Sweden
基金
英国医学研究理事会;
关键词
MODY; Type II diabetes; HNF1; alpha; gene expression; DNA binding; cell lines; mutation; metabolism; insulin;
D O I
10.1007/s00125-002-0977-4
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
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, HNF1alpha. In this study we have examined the in vivo and in vitro effects of a mutation (L 1071) outside the DNA binding and dimerization domains in the N terminal part of the HNF1alpha 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 HNF1alpha in HeLa cells lacking HNF1alpha. The transcriptional activity was not suppressed when the mutant was co-expressed with wild type HNF1alpha 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 HNF1alpha 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.
引用
收藏
页码:1703 / 1708
页数:6
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