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

M. Alan Permitt, Ann Neftorowicz, Kathleen Sohoor, Betb A. Wilson, Colin G. Nichols, Show-Ling Shyng, Benjamin Qlmer, Charles Stanley, S. Paul, Tbomton Joseph Biyan, Lydia Agullv-Biyan

Research output: Contribution to journalArticle

Abstract

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.

Original languageEnglish (US)
JournalJournal of Investigative Medicine
Volume44
Issue number3
StatePublished - 1996
Externally publishedYes

Fingerprint

Sulfonylurea Receptors
Hyperinsulinism
Genes
Mutation
Jews
Insulin
Chromosomes
Haplotypes
Inwardly Rectifying Potassium Channel
Glucose
Islets of Langerhans
Exons
Complementary DNA
Congenital Hyperinsulinism
Single-Stranded Conformational Polymorphism
Nonsense Codon
Sequence Deletion
DNA
Missense Mutation
African Americans

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

Cite this

Permitt, M. A., Neftorowicz, A., Sohoor, K., Wilson, B. A., Nichols, C. G., Shyng, S-L., ... Agullv-Biyan, L. (1996). Identification of mutations in the sulfonylurea receptor gene associated with fame.ial hyperinsulinism. Journal of Investigative Medicine, 44(3).

Identification of mutations in the sulfonylurea receptor gene associated with fame.ial hyperinsulinism. / Permitt, M. Alan; Neftorowicz, Ann; Sohoor, Kathleen; Wilson, Betb A.; Nichols, Colin G.; Shyng, Show-Ling; Qlmer, Benjamin; Stanley, Charles; Paul, S.; Biyan, Tbomton Joseph; Agullv-Biyan, Lydia.

In: Journal of Investigative Medicine, Vol. 44, No. 3, 1996.

Research output: Contribution to journalArticle

Permitt, MA, Neftorowicz, A, Sohoor, K, Wilson, BA, Nichols, CG, Shyng, S-L, Qlmer, B, Stanley, C, Paul, S, Biyan, TJ & Agullv-Biyan, L 1996, 'Identification of mutations in the sulfonylurea receptor gene associated with fame.ial hyperinsulinism', Journal of Investigative Medicine, vol. 44, no. 3.
Permitt, M. Alan ; Neftorowicz, Ann ; Sohoor, Kathleen ; Wilson, Betb A. ; Nichols, Colin G. ; Shyng, Show-Ling ; Qlmer, Benjamin ; Stanley, Charles ; Paul, S. ; Biyan, Tbomton Joseph ; Agullv-Biyan, Lydia. / Identification of mutations in the sulfonylurea receptor gene associated with fame.ial hyperinsulinism. In: Journal of Investigative Medicine. 1996 ; Vol. 44, No. 3.
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AU - Nichols, Colin G.

AU - Shyng, Show-Ling

AU - Qlmer, Benjamin

AU - Stanley, Charles

AU - Paul, S.

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AU - Agullv-Biyan, Lydia

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