title: The diabetic phenotype in HNF4A mutation carriers is moderated by the expression of HNF4A isoforms from the P1 promoter during fetal development.
abstract: OBJECTIVE
  Mutations in the alternatively spliced HNF4A gene cause maturity-onset diabetes of the young (MODY). We characterized the spatial and developmental expression patterns of HNF4A transcripts in human tissues and investigated their role as potential moderators of the MODY phenotype.
  
  
  METHODS
  We measured the expression of HNF4A isoforms in human adult tissues and gestationally staged fetal pancreas by isoform-specific real-time PCR. The correlation between mutation position and age of diagnosis or age-related penetrance was assessed in a cohort of 190 patients with HNF4A mutations.
  
  
  RESULTS
  HNF4A was expressed exclusively from the P2 promoter in adult pancreas, but from 9 weeks until at least 26 weeks after conception, up to 23% of expression in fetal pancreas was of P1 origin. HNF4A4-6 transcripts were not detected in any tissue. In whole pancreas, HNF4A9 expression was greater than in islets isolated from the endocrine pancreas (relative level 22 vs. 7%). Patients with mutations in exons 9 and 10 (absent from HNF4A3, HNF4A6, and HNF4A9 isoforms) developed diabetes later than those with mutations in exons 2-8, where all isoforms were affected (40 vs. 24 years; P = 0.029). Exon 9/10 mutations were also associated with a reduced age-related penetrance (53 vs. 10% without diabetes at age 55 years; P < 0.00001).
  
  
  CONCLUSIONS
  We conclude that isoforms derived from the HNF4A P1 promoter are expressed in human fetal, but not adult, pancreas, and that their presence during pancreatic development may moderate the diabetic phenotype in individuals with mutations in the HNF4A gene.
authors: Institute of Biomedical and Clinical Sciences, Peninsula Medical School, Exeter, UK. l.w.harries@exeter.ac.uk
authors: Lorna W
authors: LW
authors: Harries
authors: Jonathan M
authors: JM
authors: Locke
authors: Beverley
authors: B
authors: Shields
authors: Neil A
authors: NA
authors: Hanley
authors: Karen Piper
authors: KP
authors: Hanley
authors: Anna
authors: A
authors: Steele
authors: Pål R
authors: PR
authors: Njølstad
authors: Sian
authors: S
authors: Ellard
authors: Andrew T
authors: AT
authors: Hattersley
mesh_terms: D000328:Adult; D000368:Aged; D017398:Alternative Splicing; D003920:Diabetes Mellitus / Q000235:genetics*; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics*; D005260:Female; D047109:Fetal Development / Q000235:genetics*; D020869:Gene Expression Profiling; D051557:Hepatocyte Nuclear Factor 4 / Q000235:genetics*; D006801:Humans; D007668:Kidney / Q000502:physiology / Q000503:physiopathology; D008297:Male; D008875:Middle Aged; D009154:Mutation; D010179:Pancreas / Q000502:physiology / Q000503:physiopathology; D016133:Polymerase Chain Reaction; D011401:Promoter Regions, Genetic; D020033:Protein Isoforms / Q000235:genetics; D044465:White People
chemical_list: C496592:HNF4A protein, human; D051557:Hepatocyte Nuclear Factor 4; D020033:Protein Isoforms