title: T130I mutation in HNF-4alpha gene is a loss-of-function mutation in hepatocytes and is associated with late-onset Type 2 diabetes mellitus in Japanese subjects.
abstract: OBJECTIVE
  Mutations in hepatocyte nuclear factor (HNF)-4alpha gene cause a form of maturity-onset diabetes of the young (MODY1). The T130I mutation is a rare missense mutation, which affects a conserved amino acid in a DNA binding domain. This mutation can be found in the general population, so this variant alone does not cause MODY. However, its significance in the development of late-onset Type 2 diabetes is not known.
  
  
  METHODS
  We screened 423 unrelated Japanese patients with late-onset Type 2 diabetes and 354 unrelated non-diabetic control subjects for the T130I mutation in the HNF-4alpha gene. The transactivation ability of T130I-HNF-4alpha was assessed using reporter gene assay.
  
  
  RESULTS
  The frequency of the T130I mutation was higher in Type 2 diabetic patients ( p=0.015, odds ratio 4.3, 95%CI 1.24-14.98) than control subjects. The serum HDL-cholesterol concentration was lower in Type 2 diabetic patients with the T130I mutation compared with those without this mutation ( p=0.006). Reporter gene analysis showed that T130I-HNF-4alpha transcriptional activity was not impaired compared with wild-type HNF-4alpha in Hela and MIN6 cells, but it was reduced in HepG2 and primary cultured mouse hepatocytes (27-78% of wild type, p<0.05).
  
  
  CONCLUSIONS
  Our findings suggest that T130I-HNF-4alpha is a loss-of-function mutation in hepatocytes and that this mutation is associated with late-onset Type 2 diabetes in Japanese subjects. The T130I mutation in the HNF-4alpha gene might be involved in the development of Type 2 diabetes in the Japanese population.
authors.affiliation: Department of Internal Medicine and Molecular Science, Graduate School of Medicine, B5, Osaka University, 2-2 Yamada-oka, Suita, Osaka 565-0871, Japan.
authors.forename: Q
authors.initials: Q
authors.lastname: Zhu
authors.forename: K
authors.initials: K
authors.lastname: Yamagata
authors.forename: A
authors.initials: A
authors.lastname: Miura
authors.forename: N
authors.initials: N
authors.lastname: Shihara
authors.forename: Y
authors.initials: Y
authors.lastname: Horikawa
authors.forename: J
authors.initials: J
authors.lastname: Takeda
authors.forename: J
authors.initials: J
authors.lastname: Miyagawa
authors.forename: Y
authors.initials: Y
authors.lastname: Matsuzawa
mesh_terms: D017668:Age of Onset; D000368:Aged; D044466:Asian People / Q000235:genetics*; D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; D004268:DNA-Binding Proteins; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics*; D005260:Female; D005820:Genetic Testing; D051557:Hepatocyte Nuclear Factor 4; D006801:Humans; D007564:Japan; D008297:Male; D020125:Mutation, Missense / Q000235:genetics / Q000502:physiology; D010750:Phosphoproteins / Q000235:genetics* / Q000502:physiology*; D014157:Transcription Factors / Q000235:genetics* / Q000502:physiology*
chemical_list: D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; D004268:DNA-Binding Proteins; C496592:HNF4A protein, human; D051557:Hepatocyte Nuclear Factor 4; C403128:MLX protein, human; D010750:Phosphoproteins; C501970:Tcfl4 protein, mouse; D014157:Transcription Factors