Mutations in the Sulfonylurea Receptor Gene Are Associated with Familial Hyperinsulinism in Ashkenazi Jews

• Published in: Human molecular genetics Vol. 5; no. 11; pp. 1813 - 1822
• Main Authors: Nestorowicz, Ann, Wilson, Beth Anne, Schoor, Kathleen P., Inoue, Hiroshi, Glaser, Benjamin, Landau, Heddy, Stanley, Charles A., Thornton, Paul S., Clement, John P., Bryan, Joseph, Aguilar-Bryan, Lydia, Permutt, M. Alan
• Format: Journal Article
• Language: English
• Published: Oxford Oxford University Press 01.11.1996
• Subjects: Biological and medical sciences; Endocrine pancreas. Apud cells (diseases); Endocrinopathies; Medical sciences; Tumors. Hypoglycemia; Endocrinopathy; Human; Hyperinsulinemia; Metabolic diseases; Ionic channel; Founder effect; Hypoglycemia; Genetic disease; Gene; Sulfonylureas; Genetics; Mutation; Haplotype; Jew; Potassium; Biological receptor
• ISSN: 0964-6906; 1460-2083
• DOI: 10.1093/hmg/5.11.1813

Familial hyperinsulinism (HI) is a disorder of pancreatic β-cell function characterized by persistent hyperinsulinism despite severe hypoglycemia. To define the molecular genetic basis of HI in Ashkenazi Jews, 25 probands were screened for mutations in the sulfonylurea receptor (SUR1) gene by single-strand conformation polymorphism (SSCP) analysis of genomic DNA and subsequent nucleotide sequence analyses. Two common mutations were identified: (i) a novel in-frame deletion of three nucleotides (nt) in exon 34, resulting in deletion of the codon for F1388 (ΔF1388) and (ii) a previously described g→a transition at position −9 of the 3′ splice site of intron 32 (designated 3992-9g→a). Together, these mutations are associated with 88% of the HI chromosomes of the patients studied. 86Rb+ efflux measurements of COSm6 cells co-expressing Kir6.2 and either wild-type or ΔF1388 SUR1 revealed that the F1388 mutation abolished ATP-sensitive potassium channel (KATP) activity in intact cells. Extended haplotype analyses indicated that the ΔF1388 mutation was associated with a single specific haplotype whereas the 3992-9g→a mutation was primarily associated with a single haplotype but also occurred in the context of several other different haplotypes. These data suggest that HI in Ashkenazi Jews is predominantly associated with mutations in the SUR1 gene and provide evidence for the existence of at least two founder HI chromosomes in this population.