Genetic variation in the hepatocyte nuclear factor (HNF)-3 alpha gene doesnot contribute to maturity-onset diabetes of the young in Japanese

Heterozygous mutations in the genes encoding transcription factors in the h epatocyte nuclear factor (HNF) cascade are associated with maturity-onset d iabetes of the young (MODY), a monogenic form of diabetes mellitus. However , these genes are responsible for only similar to 20 % of the cases of MODY in Japanese patients. Searching for a novel MODY gene in this population, we investigated a candidate for encoding the forkhead transcription factor HNF-3 alpha, which also belongs to the HNF-transcription cascade. The human HNF-3 alpha gene, which was assigned to the segment near microsatellites D 14S75 and AFM200ZH4 on chromosome 14 by radiation hybrid mapping, spans sim ilar to 5 kb and consists of two exons. Ninety-five Japanese subjects with MODY/early-onset non-ketotic diabetes were screened for mutations in this g ene. Direct sequencing of the exons and flanking regions identified one mis sense mutation (Ala-83-Thr) in exon 2 and three nucleotide alterations in t he non-coding regions. However, their frequencies were not significantly di fferent between MODY and control subjects, indicating that mutations in the HNF-3 alpha gene are not a major cause of MODY in Japanese patients.