Hepatocyte nuclear factor-4α (HNF-4α) is a member of the nuclear receptor superfamily, a class of ligand-activated transcription factors. A nonsense mutation in the gene encoding this transcription factor was recently found in a white family with one form of maturity-onset diabetes of the young, MODY1. Here, we report the exonintron organization and partial sequence of the human HNF-4α gene. In addition, we have screened the 12 exons, flanking introns and minimal promoter region for mutations in a group of 57 unrelated Japanese subjects with early-onset NIDDM/MODY of unknown cause. Eight nucleotide substitutions were noted, of which one resulted in the mutation of a conserved arginine residue, Argl27 (CGG)→Trp (TGG) (designated R127W), located in the T-box, a region of the protein that may play a role in HNF-4α dimerization and DNA binding. This mutation was not found in 214 unrelated nondiabetic subjects (53 Japanese, 53 Chinese, 51 white, and 57 African-American). The R127W mutation was only present in three of five diabetic members in this family, indicating that it is not the only cause of diabetes in this family. The remaining seven nucleotide substitutions were located in the proximal promoter region and introns. They are not predicted to affect the transcription of the gene or mRNA processing and represent polymorphisms and rare variants. The results suggest that mutations in the HNF-4α gene may cause early-onset NIDDM/MODY in Japanese but they are less common than mutations in the HNF-1α/MODY3 gene. The information on the sequence of the HNF-4α gene and its promoter region will facilitate the search for mutations in other populations and studies of the role of this gene in determining normal pancreatic β-cell function.
Organization and Partial Sequence of the Hepatocyte Nuclear Factor-4α/MODY1 Gene and Identification of a Missense Mutation, R127W, in a Japanese Family With MODY
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Hiroto Furuta, Naoko Iwasaki, Naohisa Oda, Yoshinori Hinokio, Yukio Horikawa, Kazuya Yamagata, Nobuki Yano, Jun Sugahiro, Makiko Ogata, Hisako Ohgawara, Yasue Omori, Yasuhiko Iwamoto, Graeme I Bell; Organization and Partial Sequence of the Hepatocyte Nuclear Factor-4α/MODY1 Gene and Identification of a Missense Mutation, R127W, in a Japanese Family With MODY. Diabetes 1 October 1997; 46 (10): 1652–1657. https://doi.org/10.2337/diacare.46.10.1652
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