title: Analysis of a non-functional HNF-1alpha (TCF1) mutation in Japanese subjects with familial type 1 diabetes.
abstract: Mutations in the transcription factor hepatocyte nuclear factor-1alpha (HNF-1alpha; gene symbol TCF1) cause maturity-onset diabetes of the young type 3 (MODY3), a form of diabetes mellitus characterized by autosomal dominant inheritance, early onset, and pancreatic beta-cell dysfunction. Recent genetic studies, however, also found mutations in patients diagnosed with idiopathic (non-autoimmune based) type 1 diabetes. We identified a novel frameshift mutation (142delG) in the TCF1 gene in a family with a strong family history of type 1 diabetes and examined the functional properties of the mutant HNF 1alpha. The expression of the mutant protein was not detected in COS-7 cells by Western blot analysis after transfection of the mutant cDNA. This is the first case of an unstable mutant HNF-1alpha protein. Reporter gene analysis indicated that the mutant HNF-1alpha had no transactivation activity in HeLa and MIN6 cells. Haploinsufficiency for HNF-1alpha may lead to severe forms of diabetes like type 1 diabetes.
authors.affiliation: Department of Internal Medicine and Molecular Science, Graduate School of Medicine, Osaka University, Osaka, Japan.
authors.forename: I
authors.initials: I
authors.lastname: Yoshiuchi
authors.forename: K
authors.initials: K
authors.lastname: Yamagata
authors.forename: M
authors.initials: M
authors.lastname: Yoshimoto
authors.forename: Q
authors.initials: Q
authors.lastname: Zhu
authors.forename: Q
authors.initials: Q
authors.lastname: Yang
authors.forename: T
authors.initials: T
authors.lastname: Nammo
authors.forename: R
authors.initials: R
authors.lastname: Uenaka
authors.forename: E
authors.initials: E
authors.lastname: Kinoshita
authors.forename: T
authors.initials: T
authors.lastname: Hanafusa
authors.lastname: Miyagawa Ji
authors.forename: Y
authors.initials: Y
authors.lastname: Matsuzawa
mesh_terms: D000293:Adolescent; D000328:Adult; D000818:Animals; D019556:COS Cells; D004268:DNA-Binding Proteins; D003922:Diabetes Mellitus, Type 1 / Q000235:genetics* / Q000378:metabolism; D005091:Exons / Q000235:genetics; D005260:Female; D016368:Frameshift Mutation / Q000235:genetics; D020690:GTPase-Activating Proteins / Q000235:genetics; D017930:Genes, Reporter / Q000235:genetics; D051273:Glucose Transporter Type 2; D006367:HeLa Cells; D051537:Hepatocyte Nuclear Factor 1; D051538:Hepatocyte Nuclear Factor 1-alpha; D051539:Hepatocyte Nuclear Factor 1-beta; D006801:Humans; D007564:Japan; D008297:Male; D008875:Middle Aged; D009004:Monosaccharide Transport Proteins / Q000235:genetics; D009154:Mutation / Q000235:genetics*; D009687:Nuclear Proteins; D010375:Pedigree; D010641:Phenotype; D014157:Transcription Factors / Q000096:biosynthesis / Q000235:genetics* / Q000378:metabolism*; D015533:Transcriptional Activation; D014162:Transfection
chemical_list: D004268:DNA-Binding Proteins; C430213:GIT2 protein, human; D020690:GTPase-Activating Proteins; D051273:Glucose Transporter Type 2; C496487:HNF1A protein, human; C496495:HNF1B protein, human; D051538:Hepatocyte Nuclear Factor 1-alpha; D009004:Monosaccharide Transport Proteins; D009687:Nuclear Proteins; D014157:Transcription Factors; D051537:Hepatocyte Nuclear Factor 1; D051539:Hepatocyte Nuclear Factor 1-beta