PMID- 15281001
OWN - NLM
STAT- MEDLINE
DCOM- 20040913
LR  - 20190725
IS  - 0026-0495 (Print)
IS  - 0026-0495 (Linking)
VI  - 53
IP  - 8
DP  - 2004 Aug
TI  - Triple genetic variation in the HNF-4alpha gene is associated with early-onset 
      type 2 diabetes mellitus in a philippino family.
PG  - 959-63
AB  - Maturity-onset diabetes of the young-type 1 (MODY1) is a form of monogenic type 2 
      diabetes mellitus (T2DM) with long-term complications due to mutations in the 
      HNF-4alpha gene. The HNF-4alpha gene is involved in hepatic differentiation and 
      expression of genes regulating glucose transport, glycolysis, and lipid 
      metabolism. The abnormal glucose-stimulated insulin secretion in MODY1 subjects 
      may be due to reduced glucose transport and glycolysis. To date, 14 mutations in 
      the HNF-4alpha gene have been identified as a cause of either MODY1 or late-onset 
      type 2 diabetes. So far, no screening has been performed in subjects from the 
      Philippines. We recruited a Philippino family with autosomal dominant early-onset 
      type 2 diabetes and screened the proband for mutations in the genes for 
      HNF-1alpha, GCK, HNF-4alpha, IPF-1, HNF-6, and NGN3. We identified a new missense 
      mutation in exon 5 (V199I) of the HNF-4alpha gene and 2 new single-nucleotide 
      substitutions in intron 4, IVS4-nt4 (G --> A) and IVS4-nt20 (C --> T), all 
      cosegregating with diabetes in the 3 affected available siblings. These 
      variations were not present in 100 normal healthy subjects. Bioinformatic 
      analysis suggests that these variations in the whole, and overall the IVS4-nt4 
      variation located at splicing site, may affect the splicing potential of intron 
      4. We have biochemically and clinically characterized the Philippine-1 family. We 
      suggest that the V199I missense mutation located in the ligand 
      binding/dimerization domain of HNF-4alpha contributes to type 2 diabetes in the 
      Philippine-1 family. The intron variations may contribute susceptibility to 
      diabetes.
CI  - Copyright 2004 Elsevier Inc.
FAU - Gragnoli, Claudia
AU  - Gragnoli C
AD  - Laboratory of Molecular Endocrinology, Massachusetts General Hospital, Harvard 
      Medical School, Boston 02114, USA.
FAU - Menzinger Von Preussenthal, Guido
AU  - Menzinger Von Preussenthal G
FAU - Habener, Joel F
AU  - Habener JF
LA  - eng
GR  - DK-55365/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  - Metabolism
JT  - Metabolism: clinical and experimental
JID - 0375267
RN  - 0 (DNA-Binding Proteins)
RN  - 0 (HNF4A protein, human)
RN  - 0 (Hepatocyte Nuclear Factor 4)
RN  - 0 (Phosphoproteins)
RN  - 0 (Transcription Factors)
RN  - 9007-49-2 (DNA)
SB  - IM
MH  - Adult
MH  - Age of Onset
MH  - Aged
MH  - DNA/genetics
MH  - DNA-Binding Proteins/*genetics
MH  - Diabetes Mellitus, Type 2/blood/*genetics
MH  - Exons/genetics
MH  - Female
MH  - Hepatocyte Nuclear Factor 4
MH  - Humans
MH  - Islets of Langerhans/metabolism
MH  - Male
MH  - Middle Aged
MH  - Mutation, Missense/genetics/physiology
MH  - Pedigree
MH  - Phenotype
MH  - Philippines
MH  - Phosphoproteins/*genetics
MH  - Transcription Factors/*genetics/metabolism
EDAT- 2004/07/29 05:00
MHDA- 2004/09/14 05:00
CRDT- 2004/07/29 05:00
PHST- 2004/07/29 05:00 [pubmed]
PHST- 2004/09/14 05:00 [medline]
PHST- 2004/07/29 05:00 [entrez]
AID - S002604950400160X [pii]
AID - 10.1016/j.metabol.2004.03.003 [doi]
PST - ppublish
SO  - Metabolism. 2004 Aug;53(8):959-63. doi: 10.1016/j.metabol.2004.03.003.