Mutations in the hepatocyte nuclear factor-4 alpha gene in Japanese with non-insulin-dependent diabetes: A nucleotide substitution in the polypyrimidine tract of intron 1b

Mutations of the hepatocyte nuclear factor 4 alpha (HNF-40 alpha) gene have been demonstrated in maturity-onset diabetes of the young (MODY) 1 familie s. To investigate the possibility that the HNF-4 alpha gene contributes to the onset of non-insulin-dependent diabetes mellitus (NIDDM) in Japanese pa tients, we screened all exons and flanking introns of this gene for mutatio ns in 100 patients with NIDDM diagnosed after 25 years of age. We identifie d two missense mutations: M49V in exon 1c and T130l in exon 4: and two nucl eotide substitutions in introns: cytosine to thymidine at -5 nt in intron 1 b 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 substitut ion in intron 1b was associated with NIDDM. This substitution in the polypy rimidine tract, an important cis-acting element directing intron removal, i s likely to influence pre-mRNA splicing of this gene. T130l in exon 4 was o bserved in only two diabetic subjects. This mutation could influence the co nformation of this peptide, resulting in changes in ligand binding domain f unction. M49V in exon 1c was found in both diabetic and non-diabetic subjec ts; isoforms HNF-4 alpha 4, 5, and 6 with this mutation may impair glucose metabolism in tissue. In contrast to the primary cause of nonsense and miss ense mutations of the HNF-4 alpha gene in MODY1, the nucleotide substitutio n in intron 1b may partially contribute to development of NIDDM in combinat ion with other genetic and environmental factors.