PMID- 10545531
OWN - NLM
STAT- MEDLINE
DCOM- 19991207
LR  - 20181113
IS  - 0021-9738 (Print)
IS  - 0021-9738 (Linking)
VI  - 104
IP  - 9
DP  - 1999 Nov
TI  - Defective mutations in the insulin promoter factor-1 (IPF-1) gene in late-onset
      type 2 diabetes mellitus.
PG  - R41-8
AB  - Type 2 diabetes mellitus is a common disabling disease with onset in middle-aged 
      individuals, caused by an imbalance between insulin production and action.
      Genetic studies point to major genetic components, but, with the exception of
      maturity-onset diabetes of the young (MODY), specific diabetes susceptibility
      genes remain to be identified. Recent studies showed that a dominant negative
      mutation in the insulin promoter factor-1 (IPF-1), a pancreatic beta-cell
      specific transcription factor, causes pancreatic agenesis and MODY. Thus, we
      investigated 192 French, non-MODY type 2 diabetic families for mutations in
      IPF-1. We identified 3 novel IPF-1 mutations, including 2 substitutions (Q59L and
      D76N) and an in-frame proline insertion (InsCCG243). Functional transactivation
      assays of these IPF-1 mutant isoforms in a beta-pancreatic tumor cell line
      transfected with a transcriptional reporter and IPF-1 expression plasmids
      demonstrate a significant inhibition of basal insulin promoter activity (stronger
      with the InsCCG243 mutant). We find that the InsCCG243 mutation is linked, in 2
      families, to an autosomal dominant-like late-onset form of type 2 diabetes, in
      which insulin secretion becomes progressively impaired. The lower penetrance D76N
      and Q59L mutations were more prevalent and were associated with a relative risk
      of 12.6 for diabetes and with decreased glucose-stimulated insulin-secretion in
      nondiabetic subjects. We propose that IPF-1 mutations can cause MODY or
      apparently monogenic late-onset diabetes and that they represent a significant
      risk factor for type 2 diabetes in humans.
FAU - Hani, E H
AU  - Hani EH
AD  - Institute of Biology of Lille-CNRS UPRES A8090, Pasteur Institute, 59000 Lille,
      France.
FAU - Stoffers, D A
AU  - Stoffers DA
FAU - Chevre, J C
AU  - Chevre JC
FAU - Durand, E
AU  - Durand E
FAU - Stanojevic, V
AU  - Stanojevic V
FAU - Dina, C
AU  - Dina C
FAU - Habener, J F
AU  - Habener JF
FAU - Froguel, P
AU  - Froguel P
LA  - eng
GR  - P01 DK002456/DK/NIDDK NIH HHS/United States
GR  - DK 02456/DK/NIDDK NIH HHS/United States
GR  - DK 30457/DK/NIDDK NIH HHS/United States
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PT  - Research Support, U.S. Gov't, P.H.S.
PL  - United States
TA  - J Clin Invest
JT  - The Journal of clinical investigation
JID - 7802877
RN  - 0 (Blood Glucose)
RN  - 0 (Homeodomain Proteins)
RN  - 0 (Insulin)
RN  - 0 (Trans-Activators)
RN  - 0 (pancreatic and duodenal homeobox 1 protein)
RN  - EC 2.3.1.28 (Chloramphenicol O-Acetyltransferase)
SB  - IM
MH  - Blood Glucose/analysis
MH  - Blotting, Western
MH  - Chloramphenicol O-Acetyltransferase/metabolism
MH  - DNA Mutational Analysis
MH  - Diabetes Mellitus, Type 2/*genetics
MH  - Female
MH  - France
MH  - Genetic Predisposition to Disease
MH  - Genotype
MH  - *Homeodomain Proteins
MH  - Humans
MH  - Insulin/blood
MH  - Male
MH  - Mutation
MH  - Pedigree
MH  - Phenotype
MH  - Time Factors
MH  - Trans-Activators/*genetics
PMC - PMC409821
EDAT- 1999/11/05 00:00
MHDA- 1999/11/05 00:01
CRDT- 1999/11/05 00:00
PHST- 1999/11/05 00:00 [pubmed]
PHST- 1999/11/05 00:01 [medline]
PHST- 1999/11/05 00:00 [entrez]
AID - 10.1172/JCI7469 [doi]
PST - ppublish
SO  - J Clin Invest. 1999 Nov;104(9):R41-8. doi: 10.1172/JCI7469.