A missense mutation in hepatocyte nuclear factor-4α, resulting in a reduced transactivation activity, in human late-onset non-insulin-dependent diabetes mellitus

Non-insulin-dependent diabetes mellitus (NIDDM) is a heterogeneous disorder characterized by hyperglycemia resulting from defects in insulin secretion and action. Recent studies have found mutations in the hepatocyte nuclear factor-4 alpha gene (HNF-4 alpha) in families with maturity-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 susceptibility genes contributing to the more common late-onset NIDDM forms, 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 families with NIDDM diagnosed before 45 yr of age, Thus, we screened these families for mutations in the HNF-4 alpha gene, We found a missense mutation, resulting in a valine-to-isoleucine substitution at codon 393 in a single family, This mutation cosegregated with diabetes and impaired insulin secretion, and was not present in 119 control subjects. Expression studies showed that this conservative substitution is associated with a marked reduction of transactivation activity, a result consistent with this mutation contributing to the insulin secretory defect observed in this family.