A MISSENSE MUTATION IN HEPATOCYTE NUCLEAR FACTOR-4-ALPHA, RESULTING IN A REDUCED TRANSACTIVATION ACTIVITY, IN HUMAN LATE-ONSET NON-INSULIN-DEPENDENT DIABETES-MELLITUS

Non-insulin-dependent diabetes mellitus (NIDDM) is a heterogeneous dis order characterized by hyperglycemia resulting from defects in insulin secretion and action. Recent studies have found mutations in the hepa tocyte nuclear factor-4 alpha gene (HNF-4 alpha) in families with matu rity-onset diabetes of the young (MODY), an autosomal dominant form of diabetes characterized by early age at onset and a defect in glucose- stimulated insulin secretion, During the course of our search for susc eptibility genes contributing to the more common late-onset NIDDM form s, we observed nominal evidence for linkage between NIDDM and markers in the region of the HNF-4 alpha/MODY1 locus in a subset of French fam ilies with NIDDM diagnosed before 45 yr of age, Thus, we screened thes e families for mutations in the HNF-4 alpha gene, We found a missense mutation, resulting in a valine-to-isoleucine substitution at codon 39 3 in a single family, This mutation cosegregated with diabetes and imp aired insulin secretion, and was not present in 119 control subjects. Expression studies showed that this conservative substitution is assoc iated with a marked reduction of transactivation activity, a result co nsistent with this mutation contributing to the insulin secretory defe ct observed in this family.