title: Molecular genetics and phenotypic characteristics of MODY caused by hepatocyte nuclear factor 4alpha mutations in a large European collection.
abstract: OBJECTIVE
  Heterozygous mutations in the gene of the transcription factor hepatocyte nuclear factor 4alpha (HNF-4alpha) are considered a rare cause of MODY with only 14 mutations reported to date. The description of the phenotype is limited to single families. We investigated the genetics and phenotype of HNF-4alpha mutations in a large European Caucasian collection.
  
  
  METHODS
  HNF-4alpha was sequenced in 48 MODY probands, selected for a phenotype of HNF-1alpha MODY but negative for HNF-1alpha mutations. Clinical characteristics and biochemistry were compared between 54 HNF-4alpha mutation carriers and 32 familial controls from ten newly detected or previously described families.
  
  
  RESULTS
  Mutations in HNF-4alpha were found in 14/48 (29%) probands negative for HNF-1alpha mutations. The mutations found included seven novel mutations: S34X, D206Y, E276D, L332P, I314F, L332insCTG and IVS5nt+1G>A. I314F is the first reported de novo HNF-4alpha mutation. The average age of diagnosis was 22.9 years with frequent clinical evidence of sensitivity to sulphonylureas. Beta cell function, but not insulin sensitivity, was reduced in diabetic mutation carriers compared to control subjects (homeostasis model assessment of beta cell function 29% p<0.001 vs controls). HNF-4alpha mutations were associated with lower apolipoprotein A2 (p=0.001), A1 (p=0.04) and total HDL-cholesterol (p=0.02) than in control subjects. However, in contrast to some previous reports, levels of triglycerides and apolipoprotein C3 were normal.
  
  
  CONCLUSIONS
  HNF-4alpha mutations are common when no HNF-1alpha mutation is found in strictly defined MODY families. The HNF-4alpha clinical phenotype and beta cell dysfunction are similar to HNF-1alpha MODY and are associated with reduced apolipoprotein A2 levels. We suggest that sequencing of HNF-4alpha should be performed in patients with clinical characteristics of HNF-1alpha MODY in whom mutations in HNF-1alpha are not found.
authors.affiliation: Diabetes and Vascular Medicine, Institute of Biomedical and Clinical Science, Peninsula Medical School, Barrack Road, Exeter EX2 5AX, UK. a.t.hattersley@exeter.ac.uk
authors.forename: E R
authors.initials: ER
authors.lastname: Pearson
authors.forename: S
authors.initials: S
authors.lastname: Pruhova
authors.forename: C J
authors.initials: CJ
authors.lastname: Tack
authors.forename: A
authors.initials: A
authors.lastname: Johansen
authors.forename: H A J
authors.initials: HA
authors.lastname: Castleden
authors.forename: P J
authors.initials: PJ
authors.lastname: Lumb
authors.forename: A S
authors.initials: AS
authors.lastname: Wierzbicki
authors.forename: P M
authors.initials: PM
authors.lastname: Clark
authors.forename: J
authors.initials: J
authors.lastname: Lebl
authors.forename: O
authors.initials: O
authors.lastname: Pedersen
authors.forename: S
authors.initials: S
authors.lastname: Ellard
authors.forename: T
authors.initials: T
authors.lastname: Hansen
authors.forename: A T
authors.initials: AT
authors.lastname: Hattersley
mesh_terms: D000293:Adolescent; D000328:Adult; D019943:Amino Acid Substitution; D015992:Body Mass Index; D049628:Body Size; D002648:Child; D004247:DNA / Q000235:genetics / Q000302:isolation & purification; D004268:DNA-Binding Proteins / Q000235:genetics*; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics*; D005060:Europe; D005260:Female; D020022:Genetic Predisposition to Disease; D051557:Hepatocyte Nuclear Factor 4; D006801:Humans; D008297:Male; D008967:Molecular Biology; D020125:Mutation, Missense; D010375:Pedigree; D010641:Phenotype; D010750:Phosphoproteins / Q000235:genetics*; D014157:Transcription Factors / Q000235:genetics*
chemical_list: D004268:DNA-Binding Proteins; C496592:HNF4A protein, human; D051557:Hepatocyte Nuclear Factor 4; D010750:Phosphoproteins; D014157:Transcription Factors; D004247:DNA