title: R127W-HNF-4alpha is a loss of function mutation but not a rare polymorphism and causes Type II diabetes in a Japanese family with MODY1.
abstract: OBJECTIVE
  Mutations in the hepatocyte nuclear factor (HNF)-4alpha gene cause the type 1 form of maturity-onset diabetes of the young (MODY1). The R127W mutation is a missense mutation located in the T-box region of HNF-4alpha that was first identified in a Japanese family with MODY. We have examined the functional properties of this mutation in order to clarify the molecular basis of MODY1.
  
  
  METHODS
  The intracellular localisation, DNA binding ability, transactivation activity and functional synergism with the coactivator CREB-binding protein (CBP) of R127W-HNF-4alpha were investigated.
  
  
  RESULTS
  The nuclear import and functional synergy with CBP of R127W-HNF-4alpha were normal. The DNA binding ability of the mutant was decreased as was its transcriptional activation of the HNF-1alpha and L-type pyruvate kinase (PKL) genes.
  
  
  CONCLUSIONS
  The R127W mutation seems to be a loss-of-function mutation.
authors.affiliation: The Department of Internal Medicine and Molecular Science, Graduate School of Medicine, Osaka University, Japan.
authors.forename: Q
authors.initials: Q
authors.lastname: Yang
authors.forename: K
authors.initials: K
authors.lastname: Yamagata
authors.forename: K
authors.initials: K
authors.lastname: Yamamoto
authors.forename: Y
authors.initials: Y
authors.lastname: Cao
authors.forename: J
authors.initials: J
authors.lastname: Miyagawa
authors.forename: A
authors.initials: A
authors.lastname: Fukamizu
authors.forename: T
authors.initials: T
authors.lastname: Hanafusa
authors.forename: Y
authors.initials: Y
authors.lastname: Matsuzawa
mesh_terms: D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; D002460:Cell Line; D002467:Cell Nucleus / Q000737:chemistry; D004247:DNA / Q000378:metabolism; D004268:DNA-Binding Proteins; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics*; D006367:HeLa Cells; D051557:Hepatocyte Nuclear Factor 4; D006801:Humans; D007564:Japan; D009154:Mutation; D020125:Mutation, Missense; D010375:Pedigree; D010750:Phosphoproteins / Q000032:analysis / Q000235:genetics* / Q000378:metabolism; D011770:Pyruvate Kinase / Q000235:genetics; D014157:Transcription Factors / Q000032:analysis / Q000235:genetics* / Q000378:metabolism; D014158:Transcription, Genetic; D015533:Transcriptional Activation; D014162:Transfection
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; D014157:Transcription Factors; D004247:DNA; D011770:Pyruvate Kinase