Mutations in the genes encoding the transcription factors hepatocyte nuclear factor 1 alpha (HNF1A) and 4 alpha (HNF4A) in maturity-onset diabetes of the young

Maturity-onset diabetes of the young (MODY) is a monogenic form of diabetes mellitus characterized by autosomal dominant inheritance, early age of onset (often < 25 years of age), and pancreatic beta-cell dysfunction. MODY is both clinically and genetically heterogeneous, with six different genes identified to date; glucokinase (GCK), hepatocyte nuclear factor-1 alpha (HNFIA, or TCF1), hepatocyte nuclear factor-4 alpha (HNF4A), insulin promoter factor-1 (IPF1 or PDX1), hepatocyte nuclear factor-1 beta (HNF1B or TCF2), and neurogenic differentiation 1 (NEUROD1). Mutations in the HNFIA gene are a common cause of MODY in the majority of populations studied. A total of 193 different mutations have been described in 373 families. The most common mutation is Pro291fs (P291fsinsC) in the polycytosine (poly C) tract of exon 4, which has been reported in 65 families. HNF4A mutations are rarer; 31 mutations reported in 40 families. Sensitivity to treatment with sulfonylurea tablets is a feature of both HNFIA and HNF4A mutations. The identification of an HNF1A or 4A gene mutation confirms a diagnosis of MODY and has important implications for clinical management.