SEQUENCE VARIANTS IN THE PANCREATIC-ISLET BETA-CELL INWARDLY RECTIFYING K- IDENTIFICATION AND LACK OF ROLE IN CAUCASIAN PATIENTS WITH NIDDM( CHANNEL KIR6.2 (BIR) GENE )

Signals derived from the metabolism of glucose in pancreatic beta-cell s lead to insulin secretion via the closure of ATP-sensitive K+ channe ls (K-ATP). The cloning of the gene encoding the beta-cell inward rect ifier Kir6.2 (Bir), a subunit of the beta-cell K-ATP channel, provided the opportunity to look for mutations in this gene that might contrib ute to the impaired insulin secretion of NIDDM. By single-strand confo rmational polymorphism (SSCP) analysis on 35 Northern-European Caucasi an patients with NIDDM, six sequence variants were detected: Glu(10gag -->)Lys(10agg) (E10K), Glu(23gag-->)Lys(23aag) (E23K), Leu(270ctg-->)V al(270gtg) (L270V), Ile(337atc-->)Val(337gtc) (I337V), and two silent mutations. Allelic frequencies for the missense variants were compared between the NIDDM group (n = 306) and nondiabetic control subjects (n = 175) and did not differ between the two groups. Pairwise allelic as sociations indicated significant linkage disequilibrium between the va riants in Kir6.2 and between them and a nearby pancreatic beta-cell su lfonylurea receptor (SUR1) missense variant (S1370A), but these linkag e disequilibria did not differ between the NIDDM and control groups. T he results of these studies thus revealed that mutations in the coding region of Kir6.2 1) were not responsible for the previously noted ass ociation of the SUR1 variants with NIDDM (Inoue H et al., Diabetes 45: 825-831, 1996) and 2) did not contribute to the impaired insulin secre tion characteristic of NIDDM in Caucasian patients.