title: Rare variants identified in the HNF- 4 alpha beta-cell-specific promoter and alternative exon 1 lack biological significance in maturity onset diabetes of the young and young onset Type II diabetes.
abstract: OBJECTIVE
  The recently identified alternative promoter (P2) of HNF-4 alpha is the major HNF-4 alpha transcription start site in pancreatic beta cells. The significance of the P2 promoter was shown by the identification of a mutation in the IPF-1 binding site of the alternative promoter which cosegregated with diabetes in a large MODY family. The role of the P2 promoter and the associated alternative exon 1 in both MODY and polygenic Type II (non-insulin-dependent) diabetes mellitus is not known. Linkage to this region in studies of Type II diabetes makes the P2 region a strong candidate for a role in Type II diabetes susceptibility.
  
  
  METHODS
  To assess the role of the P2 region we screened MODY, young-onset Type II diabetic subjects, and probands from Type II diabetes families linked to chromosome 20 for variants of the P2 promoter and associated exon of HNF-4 alpha.
  
  
  RESULTS
  Two variants were found that were not present in the control subjects. The -79 C/T substitution was present in a MODY family but did not perfectly cosegregate with diabetes. A -276 G/T substitution was identified in two UK young-onset diabetes probands but did not co-segregate with diabetes. Reporter gene studies did not indicate changes in transcriptional activity caused by either the -79 C/T or -276 G/T single nucleotide substitutions.
  
  
  CONCLUSIONS
  We found no evidence to suggest that variation in the P2 proximal promoter region and associated alternative exon 1 of HNF-4 alpha contribute to young onset Type II diabetes susceptibility in Northern Europeans.
authors.affiliation: Department of Diabetes and Vascular Medicine, University of Exeter, Exeter, UK.
authors.forename: S M S
authors.initials: SM
authors.lastname: Mitchell
authors.forename: M
authors.initials: M
authors.lastname: Vaxillaire
authors.forename: H
authors.initials: H
authors.lastname: Thomas
authors.forename: M
authors.initials: M
authors.lastname: Parrizas
authors.forename: Y
authors.initials: Y
authors.lastname: Benmezroua
authors.forename: A
authors.initials: A
authors.lastname: Costa
authors.forename: T
authors.initials: T
authors.lastname: Hansen
authors.forename: K R
authors.initials: KR
authors.lastname: Owen
authors.forename: T
authors.initials: T
authors.lastname: Tuomi
authors.forename: F
authors.initials: F
authors.lastname: Pirie
authors.forename: G U
authors.initials: GU
authors.lastname: Ryffel
authors.forename: J
authors.initials: J
authors.lastname: Ferrer
authors.forename: P
authors.initials: P
authors.lastname: Froguel
authors.forename: A T
authors.initials: AT
authors.lastname: Hattersley
authors.forename: T M
authors.initials: TM
authors.lastname: Frayling
mesh_terms: D000293:Adolescent; D000328:Adult; D017668:Age of Onset; D000368:Aged; D017398:Alternative Splicing; D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; D002648:Child; D004268:DNA-Binding Proteins; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics*; D005091:Exons; D005260:Female; D005787:Gene Frequency; D014644:Genetic Variation; D051557:Hepatocyte Nuclear Factor 4; D006801:Humans; D007515:Islets of Langerhans / Q000502:physiology*; D008297:Male; D008875:Middle Aged; D010750:Phosphoproteins / Q000235:genetics*; D011401:Promoter Regions, Genetic; D014157:Transcription Factors / Q000235:genetics*
chemical_list: D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; D004268:DNA-Binding Proteins; D051557:Hepatocyte Nuclear Factor 4; C403128:MLX protein, human; D010750:Phosphoproteins; D014157:Transcription Factors