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

Aims/hypothesis: Heterozygous mutations in the gene of the transcription factor hepatocyte nuclear factor 4 proportional to (HNF-4 proportional to) 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-4 alpha mutations in a large European Caucasian collection. Methods: HNF-4 alpha was sequenced in 48 MODY probands, selected for a phenotype of HNF-1 alpha MODY but negative for HNF-1 alpha mutations. Clinical characteristics and biochemistry were compared between 54 HNF-4 alpha mutation carriers and 32 familial controls from ten newly detected or previously described families. Results: Mutations in HNF-4 alpha were found in 14/48 (29%) probands negative for HNF-1 alpha 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-4a 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-4 alpha 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-4 alpha mutations are common when no HNF-1 alpha mutation is found in strictly defined MODY families. The HNF-4 alpha clinical phenotype and beta cell dysfunction are similar to HNF-1 alpha MODY and are associated with reduced apolipoprotein A2 levels. We suggest that sequencing of HNF-4 alpha should be performed in patients with clinical characteristics of HNF-1 alpha MODY in whom mutations in HNF-1 alpha are not found.