title: Mutations in the sulonylurea receptor gene are associated with familial hyperinsulinism in Ashkenazi Jews.
abstract: Familial hyperinsulinism (HI) is a disorder of pancreatic beta-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 (delta F1388) 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 delta F1388 SUR1 revealed that the F1388 mutation abolished ATP-sensitive potassium channel (KATP) activity in intact cells. Extended haplotype analyses indicated that the delta F1388 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.
authors.affiliation: Division of Endocrinology, Diabetes and Metabolism, Washington University School of Medicine, St Louis, MO 63110, USA.
authors.forename: A
authors.initials: A
authors.lastname: Nestorowicz
authors.forename: B A
authors.initials: BA
authors.lastname: Wilson
authors.forename: K P
authors.initials: KP
authors.lastname: Schoor
authors.forename: H
authors.initials: H
authors.lastname: Inoue
authors.forename: B
authors.initials: B
authors.lastname: Glaser
authors.forename: H
authors.initials: H
authors.lastname: Landau
authors.forename: C A
authors.initials: CA
authors.lastname: Stanley
authors.forename: P S
authors.initials: PS
authors.lastname: Thornton
authors.forename: J P
authors.initials: JP
authors.lastname: Clement
authors.forename: J
authors.initials: J
authors.lastname: Bryan
authors.forename: L
authors.initials: L
authors.lastname: Aguilar-Bryan
authors.forename: M A
authors.initials: MA
authors.lastname: Permutt
mesh_terms: D000818:Animals; D005260:Female; D008297:Male; D018528:ATP-Binding Cassette Transporters; D019556:COS Cells; D004252:DNA Mutational Analysis; D018703:Founder Effect; D005787:Gene Frequency; D006239:Haplotypes; D006946:Hyperinsulinism / Q000235:genetics; D007585:Jews / Q000235:genetics; D008969:Molecular Sequence Data; D009154:Mutation / Q000235:genetics; D017354:Point Mutation / Q000235:genetics; D012150:Polymorphism, Restriction Fragment Length; D018807:Polymorphism, Single-Stranded Conformational; D015221:Potassium Channels / Q000235:genetics; D024661:Potassium Channels, Inwardly Rectifying; D011955:Receptors, Drug / Q000235:genetics; D012413:Rubidium / Q000378:metabolism; D017384:Sequence Deletion / Q000235:genetics; D064233:Sulfonylurea Receptors; D014162:Transfection; D006801:Humans
chemical_list: D018528:ATP-Binding Cassette Transporters; D015221:Potassium Channels; D024661:Potassium Channels, Inwardly Rectifying; D011955:Receptors, Drug; D012413:Rubidium; D064233:Sulfonylurea Receptors