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

Cervin, Camilla LU ; Orho-Melander, Marju LU ; Ridderstråle, Martin LU ; Lehto, M; Barg, Sebastian LU ; Groop, Leif LU and Cilio, Corrado LU (2002) In Diabetologia 45(12). p.1703-1708
Abstract
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... (More)
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. (Less)
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author
organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
MODY, DNA binding, HNF1 α, Type II diabetes, gene expression, cell lines, mutation, metabolism, insulin
in
Diabetologia
volume
45
issue
12
pages
1703 - 1708
publisher
Springer Verlag
external identifiers
  • wos:000180041600011
  • pmid:12488960
  • scopus:0036460025
ISSN
1432-0428
DOI
10.1007/s00125-002-0977-4
language
English
LU publication?
yes
id
d8aecf81-875e-4183-a43d-e794ab13c9b2 (old id 114575)
alternative location
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12488960&dopt=Abstract
date added to LUP
2007-07-11 11:33:53
date last changed
2017-01-01 05:06:32
@article{d8aecf81-875e-4183-a43d-e794ab13c9b2,
  abstract     = {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.},
  author       = {Cervin, Camilla and Orho-Melander, Marju and Ridderstråle, Martin and Lehto, M and Barg, Sebastian and Groop, Leif and Cilio, Corrado},
  issn         = {1432-0428},
  keyword      = {MODY,DNA binding,HNF1 α,Type II diabetes,gene expression,cell lines,mutation,metabolism,insulin},
  language     = {eng},
  number       = {12},
  pages        = {1703--1708},
  publisher    = {Springer Verlag},
  series       = {Diabetologia},
  title        = {Characterization of a naturally occurring mutation (L107I) in the HNF1 alpha (MODY3) gene.},
  url          = {http://dx.doi.org/10.1007/s00125-002-0977-4},
  volume       = {45},
  year         = {2002},
}