title: Novel monogenic diabetes mutations in the P2 promoter of the HNF4A gene are associated with impaired function in vitro.
abstract: OBJECTIVE
  Mutations in HNF4A cause a form of monogenic beta-cell diabetes. We aimed to identify mutations in the pancreas-specific P2 promoter of HNF4A in families with suspected HNF4A diabetes and to show that they impaired the function of the promoter in vitro.
  
  
  METHODS
  We screened families with a clinical suspicion of HNF4A monogenic beta-cell diabetes for mutations in the HNF4A P2 promoter. We investigated the function of the previously reported HNF4A P2 promoter mutation -192C>G linked to late-onset diabetes in several families, along with two new segregating mutations, in vitro using a modified luciferase reporter assay system with enhanced sensitivity.
  
  
  RESULTS
  We identified two novel HNF4A P2 promoter mutations that co-segregate with diabetes in two families, -136A>G and -169C>T. Both families displayed phenotypes typical of HNF4A monogenic beta-cell diabetes, including at least two affected generations, good response to sulphonylurea treatment and increased birthweight and/or neonatal hypoglycaemia. We show that both of these novel mutations and -192C>G impair the function of the promoter in transient transfection assays.
  
  
  CONCLUSIONS
  Two novel mutations identified here and the previously identified late-onset diabetes mutation, -192C>G, impair the function of the HNF4A P2 promoter in vitro.
authors.affiliation: Institut für Zellbiologie (Tumorforschung), Universitätsklinikum Essen, Universität Duisburg-Essen, Germany.
authors.forename: A
authors.initials: A
authors.lastname: Wirsing
authors.forename: K A
authors.initials: KA
authors.lastname: Johnstone
authors.forename: L W
authors.initials: LW
authors.lastname: Harries
authors.forename: S
authors.initials: S
authors.lastname: Ellard
authors.forename: G U
authors.initials: GU
authors.lastname: Ryffel
authors.forename: J
authors.initials: J
authors.lastname: Stanik
authors.forename: D
authors.initials: D
authors.lastname: Gasperikova
authors.forename: I
authors.initials: I
authors.lastname: Klimes
authors.forename: R
authors.initials: R
authors.lastname: Murphy
mesh_terms: D017668:Age of Onset; D003920:Diabetes Mellitus / Q000235:genetics*; D005260:Female; D051557:Hepatocyte Nuclear Factor 4 / Q000235:genetics*; D006801:Humans; D008297:Male; D009154:Mutation; D010375:Pedigree; D011401:Promoter Regions, Genetic / Q000235:genetics*; D014162:Transfection; D044465:White People / Q000235:genetics
chemical_list: D051557:Hepatocyte Nuclear Factor 4