PMID- 10545530
OWN - NLM
STAT- MEDLINE
DCOM- 19991207
LR  - 20181113
IS  - 0021-9738 (Print)
IS  - 0021-9738 (Linking)
VI  - 104
IP  - 9
DP  - 1999 Nov
TI  - Missense mutations in the insulin promoter factor-1 gene predispose to type 2
      diabetes.
PG  - R33-9
AB  - The transcription factor insulin promoter factor-1 (IPF-1) plays a central role
      in both the development of the pancreas and the regulation of insulin gene
      expression in the mature pancreatic beta cell. A dominant-negative frameshift
      mutation in the IPF-l gene was identified in a single family and shown to cause
      pancreatic agenesis when homozygous and maturity-onset diabetes of the young
      (MODY) when heterozygous. We studied the role of IPF-1 in Caucasian diabetic and 
      nondiabetic subjects from the United Kingdom. Three novel IPF-1 missense
      mutations (C18R, D76N, and R197H) were identified in patients with type 2
      diabetes. Functional analyses of these mutations demonstrated decreased binding
      activity to the human insulin gene promoter and reduced activation of the insulin
      gene in response to hyperglycemia in the human beta-cell line Nes2y. These
      mutations are present in 1% of the population and predisposed the subject to type
      2 diabetes with a relative risk of 3.0. They were not highly penetrant MODY
      mutations, as there were nondiabetic mutation carriers 25-53 years of age. We
      conclude that mutations in the IPF-1 gene may predispose to type 2 diabetes and
      are a rare cause of MODY and pancreatic agenesis, with the phenotype depending
      upon the severity of the mutation.
FAU - Macfarlane, W M
AU  - Macfarlane WM
AD  - Department of Molecular and Cell Biology, Institute of Medical Sciences,
      University of Aberdeen, Foresterhill, Aberdeen AB25 2ZD, United Kingdom.
FAU - Frayling, T M
AU  - Frayling TM
FAU - Ellard, S
AU  - Ellard S
FAU - Evans, J C
AU  - Evans JC
FAU - Allen, L I
AU  - Allen LI
FAU - Bulman, M P
AU  - Bulman MP
FAU - Ayres, S
AU  - Ayres S
FAU - Shepherd, M
AU  - Shepherd M
FAU - Clark, P
AU  - Clark P
FAU - Millward, A
AU  - Millward A
FAU - Demaine, A
AU  - Demaine A
FAU - Wilkin, T
AU  - Wilkin T
FAU - Docherty, K
AU  - Docherty K
FAU - Hattersley, A T
AU  - Hattersley AT
LA  - eng
GR  - Wellcome Trust/United Kingdom
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PL  - United States
TA  - J Clin Invest
JT  - The Journal of clinical investigation
JID - 7802877
RN  - 0 (Homeodomain Proteins)
RN  - 0 (Insulin)
RN  - 0 (Trans-Activators)
RN  - 0 (pancreatic and duodenal homeobox 1 protein)
RN  - IY9XDZ35W2 (Glucose)
SB  - IM
MH  - Adult
MH  - Aged
MH  - Blotting, Western
MH  - Cell Nucleus/metabolism
MH  - Cells, Cultured
MH  - Cytoplasm/metabolism
MH  - DNA Mutational Analysis
MH  - Diabetes Mellitus, Type 2/*genetics
MH  - Female
MH  - Genetic Predisposition to Disease
MH  - Glucose/metabolism
MH  - *Homeodomain Proteins
MH  - Humans
MH  - Insulin/genetics
MH  - Male
MH  - Middle Aged
MH  - Mutation, Missense
MH  - Pedigree
MH  - Phenotype
MH  - Phosphorylation
MH  - Trans-Activators/*genetics
MH  - Transcription, Genetic
PMC - PMC481047
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/JCI7449 [doi]
PST - ppublish
SO  - J Clin Invest. 1999 Nov;104(9):R33-9. doi: 10.1172/JCI7449.