Identification of mutations in the sulfonylurea receptor gene associated with fame.ial hyperinsulinism

Familial Hyperinsulinism (HI) is an autosomal recessive disorder characterized by loss of regulation of insulin secretion. We have analyzed a total of 78 HI affected probands for the presence of mutations in the sulfonylurea receptor (SUR) gene, a newly described member of the ABC protein super-family. The SUR gene has been shown to be a component of the islet K-4Tp channel, and essential for normal glucose regulated insulin secretion. These probands included 25 Ashkenazi Jews, 5 Arabs, 5 African-Americans, 5 Danes, and other European Caucasians. All probands were screened for the presence of mutations in 27 exons of SUR by SSCP analysis of genomic DNA. A total of nine mutations were identified, including splice-site, nonsense, deletion, and missense mutations. Comparison of the HI allete frequencies between probands of known ethnic origin revealed that two mutations accounted for 42/48 (88%) of HI chromosomes in Ashkenazi Jews but the same mutations were not detected in non-Ashkenazi HI chromosomes. The remaining 7 mutations were observed only in non-Ashkenazi Jews. Extended haplotype analyses of Ashkenazi families revealed that one of the two common mutations in this population is associated with a single haplotype, whereas the second predominant mutation is associated with several different haplotypes, suggesting the existence of at least one founder mutation for HI in Ashkenazi Jews. The functional consequences of several SUR mutations upon pancreatic islet βcell K A TP channel activity were examined by electrophysiological studies of cells co-transfected with cDNAs encoding mutant SUR alleles and the β-cell K⁺ channel inward rectifier subunit (BIR). The results of these studies provide new insights into the etiology of HI and elucidate normal mechanisms of glucose-regulated insulin secretion.