A NONSENSE MUTATION IN THE INWARD RECTIFIER POTASSIUM CHANNEL GENE, KIR6.2, IS ASSOCIATED WITH FAMILIAL HYPERINSULINISM

ATP-sensitive potassium (K-ATP) channels are an essential component of glucose-dependent insulin secretion in pancreatic islet beta-cells, T hese channels comprise the sulfonylurea receptor (SUR1) and Kir6.2, a member of the inward rectifier K+ channel family, Mutations in the SUR 1 subunit are associated with familial hyperinsulinism (HI) (MIM:25645 0), an inherited disorder characterized by hyperinsulinism in the neon ate, Since the Kir6.2 gene maps to human chromosome 11p15.1 (1,2), whi ch also encompasses a locus for HI, we screened the Kir6.2 gene for th e presence of mutations in 78 HI probands by single-strand conformatio n polymorphism (SSCP) and nucleotide sequence analyses. A nonsense mut ation, Tyr-->Stop at codon 12 (designated Y12X) was observed in the ho mozygous state in a single proband, Rb-86(+) efflux measurements and s ingle-channel recordings of COS-1 cells co-expressing SUR1 and either wild-type or Y12X mutant Kir6.2 proteins confirmed that K-ATP channel activity was abolished by this nonsense mutation, The identification o f an HI patient homozygous for the Kir6.2/Y12X allele affords an oppor tunity to observe clinical features associated with mutations resultin g in an absence of Kir6.2. These data provide evidence that mutations in the Kir6.2 subunit of the islet beta-cell K-ATP channel are associa ted with the HI phenotype and also suggest that the majority of HI cas es are not attributable to mutations in the coding region of the Kir6. 2 gene.