title: Mutations in the hepatocyte nuclear factor-4alpha gene in Japanese with non-insulin-dependent diabetes: a nucleotide substitution in the polypyrimidine tract of intron 1b.
abstract: Mutations of the hepatocyte nuclear factor 4 alpha (HNF-4alpha) gene have been demonstrated in maturity-onset diabetes of the young (MODY) 1 families. To investigate the possibility that the HNF-4alpha gene contributes to the onset of non-insulin-dependent diabetes mellitus (NIDDM) in Japanese patients, we screened all exons and flanking introns of this gene for mutations in 100 patients with NIDDM diagnosed after 25 years of age. We identified two missense mutations: M49V in exon 1c and T1301 in exon 4; and two nucleotide substitutions in introns: cytosine to thymidine at -5 nt in intron 1b and adenine to thymidine at -21 nt in intron 5. We screened an additional 220 diabetic subjects for the polymorphism in intron 1b. The c/t substitution in intron 1b was associated with NIDDM. This substitution in the polypyrimidine tract, an important cis-acting element directing intron removal, is likely to influence pre-mRNA splicing of this gene. T1301 in exon 4 was observed in only two diabetic subjects. This mutation could influence the conformation of this peptide, resulting in changes in ligand binding domain function. M49V in exon 1c was found in both diabetic and non-diabetic subjects; isoforms HNF-4alpha 4, 5, and 6 with this mutation may impair glucose metabolism in tissue. In contrast to the primary cause of nonsense and missense mutations of the HNF-4alpha gene in MODY1, the nucleotide substitution in intron 1b may partially contribute to development of NIDDM in combination with other genetic and environmental factors.
authors.affiliation: Department of Internal Medicine II, Chiba University School of Medicine, Japan.
authors.forename: K
authors.initials: K
authors.lastname: Sakurai
authors.forename: N
authors.initials: N
authors.lastname: Seki
authors.forename: R
authors.initials: R
authors.lastname: Fujii
authors.forename: K
authors.initials: K
authors.lastname: Yagui
authors.forename: Y
authors.initials: Y
authors.lastname: Tokuyama
authors.forename: F
authors.initials: F
authors.lastname: Shimada
authors.forename: H
authors.initials: H
authors.lastname: Makino
authors.forename: Y
authors.initials: Y
authors.lastname: Suzuki
authors.forename: N
authors.initials: N
authors.lastname: Hashimoto
authors.forename: Y
authors.initials: Y
authors.lastname: Saito
authors.forename: T
authors.initials: T
authors.lastname: Egashira
authors.forename: K
authors.initials: K
authors.lastname: Matsui
authors.forename: A
authors.initials: A
authors.lastname: Kanatsuka
mesh_terms: D000368:Aged; D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; D004268:DNA-Binding Proteins; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics*; D005091:Exons; D005260:Female; D051557:Hepatocyte Nuclear Factor 4; D006801:Humans; D007438:Introns; D007564:Japan; D008297:Male; D008875:Middle Aged; D009154:Mutation; D020125:Mutation, Missense; D010750:Phosphoproteins / Q000235:genetics*; D016133:Polymerase Chain Reaction; D018807:Polymorphism, Single-Stranded Conformational; D011487:Protein Conformation; D014157:Transcription Factors / Q000235:genetics*
chemical_list: D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; D004268:DNA-Binding Proteins; C496592:HNF4A protein, human; D051557:Hepatocyte Nuclear Factor 4; C403128:MLX protein, human; D010750:Phosphoproteins; D014157:Transcription Factors