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Characterization of...
Characterization of a naturally occurring mutation (L107I) in the HNF1 alpha (MODY3) gene.
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- Cervin, Camilla (author)
- Lund University,Lunds universitet,Diabetes - klinisk obesitasforskning,Forskargrupper vid Lunds universitet,Diabetes - Clinical Obesity,Lund University Research Groups
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- Orho-Melander, Marju (author)
- Lund University,Lunds universitet,Diabetes - kardiovaskulär sjukdom,Forskargrupper vid Lunds universitet,Diabetes - Cardiovascular Disease,Lund University Research Groups
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- Ridderstråle, Martin (author)
- Lund University,Lunds universitet,Diabetes - klinisk obesitasforskning,Forskargrupper vid Lunds universitet,Diabetes - Clinical Obesity,Lund University Research Groups
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Lehto, M (author)
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- Barg, Sebastian (author)
- Lund University,Lunds universitet,Islet cell physiology,Forskargrupper vid Lunds universitet,Lund University Research Groups
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- Groop, Leif (author)
- Lund University,Lunds universitet,Genomik, diabetes och endokrinologi,Forskargrupper vid Lunds universitet,Genomics, Diabetes and Endocrinology,Lund University Research Groups
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- Cilio, Corrado (author)
- Lund University,Lunds universitet,Diabetes - immunovirologi,Forskargrupper vid Lunds universitet,Diabetes - Immunovirology,Lund University Research Groups
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(creator_code:org_t)
- Springer Science and Business Media LLC, 2002
- 2002
- English.
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In: Diabetologia. - : Springer Science and Business Media LLC. - 1432-0428 .- 0012-186X. ; 45:12, s. 1703-1708
- Related links:
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http://www.ncbi.nlm....
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http://dx.doi.org/10...
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https://lup.lub.lu.s...
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https://doi.org/10.1...
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Abstract
Subject headings
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- 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.
Subject headings
- MEDICIN OCH HÄLSOVETENSKAP -- Klinisk medicin -- Endokrinologi och diabetes (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Clinical Medicine -- Endocrinology and Diabetes (hsv//eng)
Keyword
- MODY
- DNA binding
- HNF1 α
- Type II diabetes
- gene expression
- cell lines
- mutation
- metabolism
- insulin
Publication and Content Type
- art (subject category)
- ref (subject category)
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