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Search for MODY and Type 2 diabetes genes

Lehto, Markku LU (1999)
Abstract
Diabetes is a heterogeneous disease influenced by both environmental and genetic factors. Maturity-onset diabetes of the young (MODY) is considered as a subform of Type 2 diabetes, which is inherited in an autosomal dominant fashion and expressed at childhood or early adult life. The aims of the study was to a) search for susceptibility loci for Type 2 diabetes in 26 Finnish families with late-onset diabetes by using a genome scan approach, b) clone and search for mutations in the genes causing maturity-onset diabetes of the young (MODY) in Scandinavian families with early-onset diabetes, and c) perform phenotypic characterization of MODY families.



As a result of the genome wide scan, a subset of Type 2 diabetic... (More)
Diabetes is a heterogeneous disease influenced by both environmental and genetic factors. Maturity-onset diabetes of the young (MODY) is considered as a subform of Type 2 diabetes, which is inherited in an autosomal dominant fashion and expressed at childhood or early adult life. The aims of the study was to a) search for susceptibility loci for Type 2 diabetes in 26 Finnish families with late-onset diabetes by using a genome scan approach, b) clone and search for mutations in the genes causing maturity-onset diabetes of the young (MODY) in Scandinavian families with early-onset diabetes, and c) perform phenotypic characterization of MODY families.



As a result of the genome wide scan, a subset of Type 2 diabetic families, presenting with an insulin secretory defect, were positively linked to the MODY3 region on chromosome 12, which was named NIDDM2. In the search for MODY-mutations in Scandinavian families with early-onset diabetes, we identified 2 families with mutations in the hepatocyte nuclear factor (HNF) -4a (MODY1) gene, 4 families with mutations in the glucokinase (MODY2) gene and 12 families with a mutations in the HNF-1a (MODY3) gene. Notable, a mutational hot spot was identified in exon 4 of the HNF-1a gene. In addition, three families with early-onset diabetes were found to carry a specific mutation (A3243G) in the mitochondrial tRNALeu(UUR) gene. Both MODY1 and MODY3 mutation carriers had impaired insulin secretion suggesting defects in pancreatic b-cell function. Distinct from common Type 2 diabetes, MODY mutation carriers had no signs of dyslipidemia or insulin resistance. Of note, patients with MODY1 exhibit also low triglyceride and apoCIII concentrations even after long duration of diabetes. Therefore, mutations in the HNF-4a gene could also affect lipid metabolism. Absence of antibodies against glutamic acid decarboxylase (GAD) suggests that autoimmunity does not play a major role in the development of MODY diabetes.



Conclusions: In Scandinavian populations, the MODY3 locus on chromosome 12 is associated with both early- and late-onset forms of diabetes. The underlying genetic defect in NIDDM2 remains to be determined. Among the Scandinavian families with early-onset diabetes, mutations in the HNF-1a (MODY3) gene were the most common cause of MODY. (Less)
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author
opponent
  • Prof Pedersen, Oluf, University of Copenhagen
organization
publishing date
type
Thesis
publication status
published
subject
keywords
Type 2 diabetes, mutation, MODY, mitochondrial DNA, MIDD, insulin deficiency, hepatocyte nuclear factor, Gestational diabetes, glucokinase, Endocrinology, secreting systems, diabetology, Endokrinologi, sekretion, diabetologi
pages
136 pages
defense location
Medical Research Centre (Jubileumsaulan), Universityhospital MAS, Malmö
defense date
1999-09-02 10:15
external identifiers
  • Other:ISRN: LUMED/MEEK-1009-SE
ISBN
91-628-3662-5
language
English
LU publication?
yes
id
a0546994-5430-499b-a102-a1a03a3a510a (old id 39792)
date added to LUP
2007-06-21 13:02:04
date last changed
2016-09-19 08:45:18
@misc{a0546994-5430-499b-a102-a1a03a3a510a,
  abstract     = {Diabetes is a heterogeneous disease influenced by both environmental and genetic factors. Maturity-onset diabetes of the young (MODY) is considered as a subform of Type 2 diabetes, which is inherited in an autosomal dominant fashion and expressed at childhood or early adult life. The aims of the study was to a) search for susceptibility loci for Type 2 diabetes in 26 Finnish families with late-onset diabetes by using a genome scan approach, b) clone and search for mutations in the genes causing maturity-onset diabetes of the young (MODY) in Scandinavian families with early-onset diabetes, and c) perform phenotypic characterization of MODY families.<br/><br>
<br/><br>
As a result of the genome wide scan, a subset of Type 2 diabetic families, presenting with an insulin secretory defect, were positively linked to the MODY3 region on chromosome 12, which was named NIDDM2. In the search for MODY-mutations in Scandinavian families with early-onset diabetes, we identified 2 families with mutations in the hepatocyte nuclear factor (HNF) -4a (MODY1) gene, 4 families with mutations in the glucokinase (MODY2) gene and 12 families with a mutations in the HNF-1a (MODY3) gene. Notable, a mutational hot spot was identified in exon 4 of the HNF-1a gene. In addition, three families with early-onset diabetes were found to carry a specific mutation (A3243G) in the mitochondrial tRNALeu(UUR) gene. Both MODY1 and MODY3 mutation carriers had impaired insulin secretion suggesting defects in pancreatic b-cell function. Distinct from common Type 2 diabetes, MODY mutation carriers had no signs of dyslipidemia or insulin resistance. Of note, patients with MODY1 exhibit also low triglyceride and apoCIII concentrations even after long duration of diabetes. Therefore, mutations in the HNF-4a gene could also affect lipid metabolism. Absence of antibodies against glutamic acid decarboxylase (GAD) suggests that autoimmunity does not play a major role in the development of MODY diabetes.<br/><br>
<br/><br>
Conclusions: In Scandinavian populations, the MODY3 locus on chromosome 12 is associated with both early- and late-onset forms of diabetes. The underlying genetic defect in NIDDM2 remains to be determined. Among the Scandinavian families with early-onset diabetes, mutations in the HNF-1a (MODY3) gene were the most common cause of MODY.},
  author       = {Lehto, Markku},
  isbn         = {91-628-3662-5},
  keyword      = {Type 2 diabetes,mutation,MODY,mitochondrial DNA,MIDD,insulin deficiency,hepatocyte nuclear factor,Gestational diabetes,glucokinase,Endocrinology,secreting systems,diabetology,Endokrinologi,sekretion,diabetologi},
  language     = {eng},
  pages        = {136},
  title        = {Search for MODY and Type 2 diabetes genes},
  year         = {1999},
}