TY - JOUR
T1 - Triple genetic variation in the HNF-4α gene is associated with early-onset type 2 diabetes mellitus in a Philippino family
AU - Gragnoli, Claudia
AU - Von Preussenthal, Guido Menzinger
AU - Habener, Joel F.
N1 - Funding Information:
Supported in part by PHS Grant No. DK-55365. J.F.H. is an Investigator with the Howard Hughes Medical Institute.
PY - 2004/8
Y1 - 2004/8
N2 - 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-4α gene. The HNF-4α 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-4α 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-1α, GCK, HNF-4α, IPF-1, HNF-6, and NGN3. We identified a new missense mutation in exon 5 (V199I) of the HNF-4α 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-4α contributes to type 2 diabetes in the Philippine-1 family. The intron variations may contribute susceptibility to diabetes.
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-4α gene. The HNF-4α 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-4α 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-1α, GCK, HNF-4α, IPF-1, HNF-6, and NGN3. We identified a new missense mutation in exon 5 (V199I) of the HNF-4α 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-4α contributes to type 2 diabetes in the Philippine-1 family. The intron variations may contribute susceptibility to diabetes.
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U2 - 10.1016/j.metabol.2004.03.003
DO - 10.1016/j.metabol.2004.03.003
M3 - Article
C2 - 15281001
AN - SCOPUS:3342887866
VL - 53
SP - 959
EP - 963
JO - Metabolism: Clinical and Experimental
JF - Metabolism: Clinical and Experimental
SN - 0026-0495
IS - 8
ER -