title: Identification of mutations in the hepatocyte nuclear factor (HNF)-1 alpha gene in Japanese subjects with IDDM.
abstract: One form of maturity-onset diabetes of the young, MODY3, is characterized by a severe insulin secretory defect, compared with MODY2, a glucokinase-deficient diabetes. It has recently been shown that mutations of the gene encoding the transcription factor hepatocyte nuclear factor (HNF)-1 alpha cause MODY3. Because of the rapid progress to overt diabetes and the high prevalence of required insulin treatment in patients with MODY3, we screened the HNF-1 alpha gene for mutations in Japanese subjects with IDDM. Ten exons and flanking introns of the HNF-1 alpha gene in these subjects were amplified by polymerase chain reaction and direct sequencing of the products. Mutations were identified in three (5.5%) of the 55 unrelated subjects with IDDM. A missense mutation of R272H (replacement of Arg by His in codon 272) in the DNA binding domain of HNF-1 alpha was found in a subject who developed IDDM 1 year after diagnosis of NIDDM at 8 years of age. A frameshift mutation of P291 fsinsC (insertion of a C in a polyC tract around codon 291 for Pro), which would generate a mutant truncated protein of 340 amino acids, was found in a subject who started insulin treatment when hyperglycemia and ketonuria were noticed at 13 years of age. A missense mutation of R583G (replacement of Arg by Gly in codon 583) in the transactivation domain of HNF-1 alpha was found in a subject with sudden-onset IDDM at 20 years of age. None of these mutations were present in 100 nondiabetic subjects (200 normal chromosomes). These results indicate that the HNF-1 alpha gene defects could lead to the development of not only early-onset NIDDM but also IDDM, implicating the importance of subclassification of HNF-1 alpha-deficient IDDM from a classical type of autoimmune-based IDDM in Japanese.
authors.affiliation: Department of Molecular Genetics, School of Medicine, Gunma University, Maebashi, Japan.
authors.forename: S
authors.initials: S
authors.lastname: Yamada
authors.forename: H
authors.initials: H
authors.lastname: Nishigori
authors.forename: H
authors.initials: H
authors.lastname: Onda
authors.forename: T
authors.initials: T
authors.lastname: Utsugi
authors.forename: T
authors.initials: T
authors.lastname: Yanagawa
authors.forename: T
authors.initials: T
authors.lastname: Maruyama
authors.forename: K
authors.initials: K
authors.lastname: Onigata
authors.forename: K
authors.initials: K
authors.lastname: Nagashima
authors.forename: R
authors.initials: R
authors.lastname: Nagai
authors.forename: A
authors.initials: A
authors.lastname: Morikawa
authors.forename: T
authors.initials: T
authors.lastname: Takeuchi
authors.forename: J
authors.initials: J
authors.lastname: Takeda
mesh_terms: D000293:Adolescent; D000328:Adult; D000818:Animals; D001323:Autoantibodies / Q000097:blood; D001665:Binding Sites; D002648:Child; D002675:Child, Preschool; D004247:DNA / Q000378:metabolism; D004268:DNA-Binding Proteins; D003922:Diabetes Mellitus, Type 1 / Q000235:genetics* / Q000276:immunology; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics; D016368:Frameshift Mutation; D051537:Hepatocyte Nuclear Factor 1; D051538:Hepatocyte Nuclear Factor 1-alpha; D051539:Hepatocyte Nuclear Factor 1-beta; D006801:Humans; D007223:Infant; D007564:Japan; D051379:Mice; D009154:Mutation; D009687:Nuclear Proteins / Q000235:genetics*; D010375:Pedigree; D016133:Polymerase Chain Reaction; D014157:Transcription Factors / Q000172:deficiency / Q000235:genetics*
chemical_list: D001323:Autoantibodies; D004268:DNA-Binding Proteins; C496487:HNF1A protein, human; C496495:HNF1B protein, human; D051538:Hepatocyte Nuclear Factor 1-alpha; C496488:Hnf1a protein, mouse; C496496:Hnf1b protein, mouse; D009687:Nuclear Proteins; D014157:Transcription Factors; D051537:Hepatocyte Nuclear Factor 1; D051539:Hepatocyte Nuclear Factor 1-beta; D004247:DNA