title: A missense mutation in the hepatocyte nuclear factor 4 alpha gene in a UK pedigree with maturity-onset diabetes of the young.
abstract: Maturity-onset diabetes of the young (MODY) is a monogenic subgroup of non-insulin dependent diabetes mellitus (NIDDM) characterised bylan early age of onset (< 25 years) and an autosomal dominant mode of inheritance. MODY is genetically heterogeneous with three different genes identified to date; hepatocyte nuclear factor 4 alpha (HNF-4 alpha) [MODY1], glucokinase [MODY2] and hepatocyte nuclear factor 1 alpha (HNF-1 alpha) [MODY3]. A nonsense mutation in the HNF-4 alpha gene has recently been shown to cause MODY in a single large North American pedigree (RW). We screened a large UK Caucasian MODY family which showed weak evidence of linkage to the MODY1 locus on chromosome 20q (lod score for ADA 0.68 at theta = 0) for mutations in the coding region of the HNF-4 alpha gene by direct sequencing. A missense mutation resulting in the substitution of glutamine for glutamic acid was identified in exon 7 (E276Q). The mutation was present in all of the diabetic members of the pedigree plus two unaffected subjects and was not detected in 75 normal control subjects or 95 UK Caucasian subjects with late-onset NIDDM. This is the first missense mutation to be described in the HNF-4 alpha gene.
authors.affiliation: Division of Molecular Genetics, University of Exeter, UK.
authors.forename: M P
authors.initials: MP
authors.lastname: Bulman
authors.forename: M J
authors.initials: MJ
authors.lastname: Dronsfield
authors.forename: T
authors.initials: T
authors.lastname: Frayling
authors.forename: M
authors.initials: M
authors.lastname: Appleton
authors.forename: S C
authors.initials: SC
authors.lastname: Bain
authors.forename: S
authors.initials: S
authors.lastname: Ellard
authors.forename: A T
authors.initials: AT
authors.lastname: Hattersley
mesh_terms: D001483:Base Sequence; D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; D002874:Chromosome Mapping; D002890:Chromosomes, Human, Pair 20; D004268:DNA-Binding Proteins; D003922:Diabetes Mellitus, Type 1 / Q000235:genetics*; D005091:Exons; D005260:Female; D051557:Hepatocyte Nuclear Factor 4; D006801:Humans; D008126:Lod Score; D008297:Male; D010375:Pedigree; D010750:Phosphoproteins / Q000235:genetics*; D017354:Point Mutation; D014157:Transcription Factors / Q000235:genetics*; D006113:United Kingdom; D044465:White People
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