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Cosegregation of MIDD and MODY in a Pedigree: Functional and Clinical Consequences.

Cervin, Camilla LU ; Liljeström, Brita; Tuomi, Tiinamaija; Heikkinen, Seija; Tapanainen, Juha S; Groop, Leif LU and Cilio, Corrado LU (2004) In Diabetes 53(7). p.1894-1899
Abstract
The aim of this study was characterization of a family carrying two mutations known to cause monogenic forms of diabetes, the M626K mutation in the HNF1α gene (MODY3) and the A3243G in mtDNA. β-Cell function and insulin sensitivity were assessed with the Botnia clamp. Heteroplasmy of the A3243G mutation and variants in type 2 diabetes susceptibility genes were determined, and transcriptional activity, DNA binding, and subcellular localization of mutated HNF1α were studied. Thirteen family members carried the mutation in mtDNA; 6 of them also had the M626K mutation, whereas none had only the M626K mutation. The protective Ala12 allele in peroxisome proliferator–activated receptor (PPAR)γ was present in two nondiabetic individuals. Carriers... (More)
The aim of this study was characterization of a family carrying two mutations known to cause monogenic forms of diabetes, the M626K mutation in the HNF1α gene (MODY3) and the A3243G in mtDNA. β-Cell function and insulin sensitivity were assessed with the Botnia clamp. Heteroplasmy of the A3243G mutation and variants in type 2 diabetes susceptibility genes were determined, and transcriptional activity, DNA binding, and subcellular localization of mutated HNF1α were studied. Thirteen family members carried the mutation in mtDNA; 6 of them also had the M626K mutation, whereas none had only the M626K mutation. The protective Ala12 allele in peroxisome proliferator–activated receptor (PPAR)γ was present in two nondiabetic individuals. Carriers of both mtDNA and HNF1α mutations showed an earlier age at onset of diabetes than carriers of only the mtDNA mutation (median 22 vs. 45 years) but no clear difference in β-cell function or insulin sensitivity. In vitro, the M626K mutation caused a 53% decrease in transcriptional activity in HeLa cells. The mutated protein showed normal nuclear targeting but increased DNA binding. These data demonstrate that several genetic factors might contribute to diabetes risk, even in families with mtDNA and HNF1α mutations. (Less)
Please use this url to cite or link to this publication:
author
organization
publishing date
type
Contribution to journal
publication status
published
subject
in
Diabetes
volume
53
issue
7
pages
1894 - 1899
publisher
American Diabetes Association Inc.
external identifiers
  • pmid:15220216
  • wos:000222397000033
  • scopus:3042779894
ISSN
1939-327X
DOI
10.2337/diabetes.53.7.1894
language
English
LU publication?
yes
id
35f7b5b3-a807-458a-a5dd-19d01f91aeff (old id 123897)
alternative location
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=15220216&dopt=Abstract
date added to LUP
2007-07-17 10:55:00
date last changed
2017-07-23 04:39:35
@article{35f7b5b3-a807-458a-a5dd-19d01f91aeff,
  abstract     = {The aim of this study was characterization of a family carrying two mutations known to cause monogenic forms of diabetes, the M626K mutation in the HNF1α gene (MODY3) and the A3243G in mtDNA. β-Cell function and insulin sensitivity were assessed with the Botnia clamp. Heteroplasmy of the A3243G mutation and variants in type 2 diabetes susceptibility genes were determined, and transcriptional activity, DNA binding, and subcellular localization of mutated HNF1α were studied. Thirteen family members carried the mutation in mtDNA; 6 of them also had the M626K mutation, whereas none had only the M626K mutation. The protective Ala12 allele in peroxisome proliferator–activated receptor (PPAR)γ was present in two nondiabetic individuals. Carriers of both mtDNA and HNF1α mutations showed an earlier age at onset of diabetes than carriers of only the mtDNA mutation (median 22 vs. 45 years) but no clear difference in β-cell function or insulin sensitivity. In vitro, the M626K mutation caused a 53% decrease in transcriptional activity in HeLa cells. The mutated protein showed normal nuclear targeting but increased DNA binding. These data demonstrate that several genetic factors might contribute to diabetes risk, even in families with mtDNA and HNF1α mutations.},
  author       = {Cervin, Camilla and Liljeström, Brita and Tuomi, Tiinamaija and Heikkinen, Seija and Tapanainen, Juha S and Groop, Leif and Cilio, Corrado},
  issn         = {1939-327X},
  language     = {eng},
  number       = {7},
  pages        = {1894--1899},
  publisher    = {American Diabetes Association Inc.},
  series       = {Diabetes},
  title        = {Cosegregation of MIDD and MODY in a Pedigree: Functional and Clinical Consequences.},
  url          = {http://dx.doi.org/10.2337/diabetes.53.7.1894},
  volume       = {53},
  year         = {2004},
}