MUTATIONS IN THE SULFONYLUREA RECEPTOR GENE ARE ASSOCIATED WITH FAMILIAL HYPERINSULINISM IN ASHKENAZI JEWS

Familial hyperinsulinism (HI) is a disorder of pancreatic beta-cell fu nction characterized by persistent hyperinsulinism despite severe hypo glycemia. To define the molecular genetic basis of HI in Ashkenazi Jew s, 25 probands were screened for mutations in the sulfonylurea recepto r (SUR1) gene by single-strand conformation polymorphism (SSCP) analys is of genomic DNA and subsequent nucleotide sequence analyses. Two com mon mutations were identified: (i) a novel in-frame deletion of three nucleotides (nt) in exon 34, resulting in deletion of the codon for F1 388 (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 chromos omes of the patients studied. Rb-86(+) efflux measurements of COSm6 ce lls co-expressing Kir6.2 and either wild-type or Delta F1388 SUR1 reve aled that the F1388 mutation abolished ATP-sensitive potassium channel (K-ATP) activity in intact cells. Extended haplotype analyses indicat ed that the Delta F1388 mutation was associated with a single specific haplotype whereas the 3992-9g-->a mutation was primarily associated w ith a single haplotype but also occurred in the context of several oth er different haplotypes. These data suggest that HI in Ashkenazi Jews is predominantly associated with mutations in the SUR1 gene and provid e evidence for the existence of at least two founder HI chromosomes in this population.