Cloning of cDNA and the gene encoding human hepatocyte nuclear factor (HNF)-3β and mutation screening in Japanese subjects with maturity-onset diabetes of the young

• Published in: Diabetologia 2000-01, Vol.43 (1), p.121-124
• Main Authors: YAMADA, S, ZHU, Q, INOUE, I, MORIKAWA, A, YAMAGATA, K, HANAFUSA, T, MATSUZAWA, Y, TAKEDA, I, AIHARA, Y, ONDA, H, ZHANG, Z, YU, L, JIN, L, SI, Y.-J, NISHIGORI, H, TOMURA, H
• Format: Article
• Language: English
• Subjects: Amino Acid Sequence; Animals; Base Sequence; Biological and medical sciences; Chromosome Mapping; Chromosomes, Human, Pair 20; Cloning, Molecular; Diabetes Mellitus, Type 2 - genetics; Diabetes. Impaired glucose tolerance; DNA Mutational Analysis; DNA, Complementary; DNA-Binding Proteins - chemistry; DNA-Binding Proteins - genetics; Endocrine pancreas. Apud cells (diseases); Endocrinopathies; Etiopathogenesis. Screening. Investigations. Target tissue resistance; Exons; Gene Library; Genomic Library; Hepatocyte Nuclear Factor 3-beta; Humans; Introns; Japan; Liver - metabolism; Medical sciences; Mice; Molecular Sequence Data; Nuclear Proteins - chemistry; Nuclear Proteins - genetics; Rats; Recombinant Proteins - chemistry; Sequence Alignment; Sequence Homology, Amino Acid; Transcription Factors - genetics; Xenopus; Zebrafish
• ISSN: 0012-186X; 1432-0428
• DOI: 10.1007/s001250050016

Molecular defects of the genes for transcription factors, hepatocyte nuclear factor (HNF)-4 alpha, HNF-1 alpha, HNF-1 beta and insulin promoter factor-1 cause maturity-onset diabetes of the young (MODY1, 3, 5, and 4, respectively). This suggests the HNF-related transcription cascade is important in insulin secretion which is induced by glucose. These genes and the gene encoding glycolytic enzyme glucokinase (MODY2) are, however, responsible for only 15-20% of cases of MODY in the Japanese. Searching for a novel form of MODY in this population, we cloned a new candidate gene encoding human HNF-3 beta, a winged helix transcription factor, which also belongs to the same HNF-transcription cascade. The cDNA clone for human HNF-3 beta was isolated from a liver cDNA library. The gene was also cloned from a genomic library and its organization and chromosomal localization were determined. We screened 68 Japanese subjects with MODY/early-onset diabetes for mutations in this gene. Human HNF-3 beta is composed of 457 amino acids. The human gene, which was mapped to the segment 30 cR from SHGC-37039 on chromosome 20p by radiation hybrid mapping, spans approximately 4.5 kb and consists of three exons. Direct sequencing of the exons and flanking regions identified one missense mutation A328 V and seven polymorphisms, although the functional significance of the mutation in the pathogenesis of diabetes is not known. The characterization of the structure of the HNF-3 beta gene and its mapping in the framework of markers will be helpful in genetic studies of the various forms of diabetes mellitus.