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Functional consequences of mutations in the MODY4 gene (IPF1) and coexistence with MODY3 mutations

Weng, J.; Macfarlane, W.M.; Lehto, M.; Gu, H.F.; Shepherd, L.M.; Ivarsson, Sten LU ; Wibell, L.; Smith, T. and Groop, Leif LU (2001) In Diabetologia 44(2). p.249-258
Abstract
Aims/hypothesis. The aim of this study was to examine the putative role of mutations in the insulin promoter 1 (IPF1) gene in early-onset diabetes. Methods. We carried out mutation screening of the IPF1 gene in 115 Scandinavian families with at least two members with onset of diabetes younger than 40 years. The allele frequencies were also tested in 183 unrelated patients with late-onset Type II (noninsulin-dependent) diabetes mellitus and in 92 nondiabetic control subjects. Results. Two novel IPF1 variants (G212R and P239Q) and one previously reported (D76N) IPF1 variant were identified in the 115 families (3.5%). The D76N variant was found in one MODY3 family (S315fsinsA of HNF1 alpha) and also in two families with late-onset Type II... (More)
Aims/hypothesis. The aim of this study was to examine the putative role of mutations in the insulin promoter 1 (IPF1) gene in early-onset diabetes. Methods. We carried out mutation screening of the IPF1 gene in 115 Scandinavian families with at least two members with onset of diabetes younger than 40 years. The allele frequencies were also tested in 183 unrelated patients with late-onset Type II (noninsulin-dependent) diabetes mellitus and in 92 nondiabetic control subjects. Results. Two novel IPF1 variants (G212R and P239Q) and one previously reported (D76N) IPF1 variant were identified in the 115 families (3.5%). The D76N variant was found in one MODY3 family (S315fsinsA of HNF1 alpha) and also in two families with late-onset Type II diabetes. The P239Q variant was identified in two families with early-onset diabetes including one with MODY3 (R272C of HNF1 alpha) and in three families with late-onset Type II diabetes. Despite the fact that the variants did not segregate completely with diabetes, the non-diabetic carriers of the IPF1 variants had increased blood glucose concentrations (p < 0.05) and reduced insulin:glucose ratios (p < 0.05) during an oral glucose tolerance test compared with non-diabetic family members without these variants. In addition, when the G212R and P239Q variants were expressed in cells without IPF1 i.e.. Nes2y cells, both variants showed about a 50% reduction in their ability to activate insulin gene transcription compared to wild-type IPF1, as measured by reporter gene assay. Conclusion/interpretation. Although mutations in the IPF-1 gene are rare in early- (3.5%) and late-onset (2.7%) Type II diabetes, they are functionally important and occur also in families with other MODY mutations. (Less)
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author
organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
Insulin promoter factor 1, Type II diabetes, maturity-onset diabetes of the young (MODY, gene expression, insulin gene
in
Diabetologia
volume
44
issue
2
pages
249 - 258
publisher
Springer Verlag
external identifiers
  • wos:000167005200018
  • scopus:0035137251
ISSN
1432-0428
DOI
10.1007/s001250051608
language
English
LU publication?
yes
id
432bde2c-b9a4-4f75-bee6-b6e3f3a31fad (old id 1119576)
date added to LUP
2008-07-17 11:25:12
date last changed
2018-01-07 05:46:16
@article{432bde2c-b9a4-4f75-bee6-b6e3f3a31fad,
  abstract     = {Aims/hypothesis. The aim of this study was to examine the putative role of mutations in the insulin promoter 1 (IPF1) gene in early-onset diabetes. Methods. We carried out mutation screening of the IPF1 gene in 115 Scandinavian families with at least two members with onset of diabetes younger than 40 years. The allele frequencies were also tested in 183 unrelated patients with late-onset Type II (noninsulin-dependent) diabetes mellitus and in 92 nondiabetic control subjects. Results. Two novel IPF1 variants (G212R and P239Q) and one previously reported (D76N) IPF1 variant were identified in the 115 families (3.5%). The D76N variant was found in one MODY3 family (S315fsinsA of HNF1 alpha) and also in two families with late-onset Type II diabetes. The P239Q variant was identified in two families with early-onset diabetes including one with MODY3 (R272C of HNF1 alpha) and in three families with late-onset Type II diabetes. Despite the fact that the variants did not segregate completely with diabetes, the non-diabetic carriers of the IPF1 variants had increased blood glucose concentrations (p &lt; 0.05) and reduced insulin:glucose ratios (p &lt; 0.05) during an oral glucose tolerance test compared with non-diabetic family members without these variants. In addition, when the G212R and P239Q variants were expressed in cells without IPF1 i.e.. Nes2y cells, both variants showed about a 50% reduction in their ability to activate insulin gene transcription compared to wild-type IPF1, as measured by reporter gene assay. Conclusion/interpretation. Although mutations in the IPF-1 gene are rare in early- (3.5%) and late-onset (2.7%) Type II diabetes, they are functionally important and occur also in families with other MODY mutations.},
  author       = {Weng, J. and Macfarlane, W.M. and Lehto, M. and Gu, H.F. and Shepherd, L.M. and Ivarsson, Sten and Wibell, L. and Smith, T. and Groop, Leif},
  issn         = {1432-0428},
  keyword      = {Insulin promoter factor 1,Type II diabetes,maturity-onset diabetes of the young (MODY,gene expression,insulin gene},
  language     = {eng},
  number       = {2},
  pages        = {249--258},
  publisher    = {Springer Verlag},
  series       = {Diabetologia},
  title        = {Functional consequences of mutations in the MODY4 gene (IPF1) and coexistence with MODY3 mutations},
  url          = {http://dx.doi.org/10.1007/s001250051608},
  volume       = {44},
  year         = {2001},
}