Article

Diabetologia

, Volume 48, Issue 5, pp 878-885

Molecular genetics and phenotypic characteristics of MODY caused by hepatocyte nuclear factor 4α mutations in a large European collection

  • E. R. PearsonAffiliated withDiabetes and Vascular Medicine, Institute of Biomedical and Clinical Science, Peninsula Medical School
  • , S. PruhovaAffiliated withDepartment of Paediatrics, 3rd Faculty of Medicine, Charles University
  • , C. J. TackAffiliated withDivision of General Internal Medicine, 541, University Medical Centre Nijmegen
  • , A. JohansenAffiliated withSteno Diabetes Centre and Hagedorn Research Institute
  • , H. A. J. CastledenAffiliated withDiabetes and Vascular Medicine, Institute of Biomedical and Clinical Science, Peninsula Medical School
  • , P. J. LumbAffiliated withDepartment of Chemical Pathology, St Thomas’ Hospital
  • , A. S. WierzbickiAffiliated withDepartment of Chemical Pathology, St Thomas’ Hospital
  • , P. M. ClarkAffiliated withRegional Endocrine Laboratories, University Hospital Birmingham
  • , J. LeblAffiliated withDepartment of Paediatrics, 3rd Faculty of Medicine, Charles University
    • , O. PedersenAffiliated withSteno Diabetes Centre and Hagedorn Research Institute
    • , S. EllardAffiliated withDiabetes and Vascular Medicine, Institute of Biomedical and Clinical Science, Peninsula Medical School
    • , T. HansenAffiliated withSteno Diabetes Centre and Hagedorn Research Institute
    • , A. T. HattersleyAffiliated withDiabetes and Vascular Medicine, Institute of Biomedical and Clinical Science, Peninsula Medical School Email author 

Abstract

Aims/hypothesis

Heterozygous mutations in the gene of the transcription factor hepatocyte nuclear factor 4α (HNF-4α) 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-4α mutations in a large European Caucasian collection.

Methods

HNF-4α was sequenced in 48 MODY probands, selected for a phenotype of HNF-1α MODY but negative for HNF-1α mutations. Clinical characteristics and biochemistry were compared between 54 HNF-4α mutation carriers and 32 familial controls from ten newly detected or previously described families.

Results

Mutations in HNF-4α were found in 14/48 (29%) probands negative for HNF-1α 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-4α 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-4α 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/interpretation

HNF-4α mutations are common when no HNF-1α mutation is found in strictly defined MODY families. The HNF-4α clinical phenotype and beta cell dysfunction are similar to HNF-1α MODY and are associated with reduced apolipoprotein A2 levels. We suggest that sequencing of HNF-4α should be performed in patients with clinical characteristics of HNF-1α MODY in whom mutations in HNF-1α are not found.

Keywords

Apolipoprotein A1 Apolipoprotein A2 Diabetes Hepatocyte nuclear factor 4 α HNF-4α MODY P2 promoter Transcription factors