Intragenic single nucleotide polymorphism haplotype analysis of SUR1 mutations in familial hyperinsulinism

Familial hyperinsulinism (HI; MIM# 256450) is an autosomal recessive disord er of pancreatic beta-cell function, characterized by inadequate suppressio n of insulin secretion despite severe recurrent fasting hypoglycemia, Subto tal pancreatectomy is frequently required to prevent permanent neurologic s equelae, The incidence of HI in the Caucasian population is estimated at 1: 50,000, however an apparent increased incidence among Ashkenazi Jews and Sa udi Arabian Arabs has been reported. A locus for HI was assigned by linkage analyses to human chromosome 11p15.1. The sulfonylurea receptor (MIM# 6005 09, SUR1) and the potassium channel, inwardly rectifying, subfamily J membe r 11 (MIM# 600937, KIR6.2) genes, 2 components of the beta-cell K-ATP chann el, are clustered in this chromosomal region, and mutations in these genes have been implicated in HI. We previously demonstrated that two mutations i n the SUR1 gene are present on approximately 88% of HI-associated chromosom es in Ashkenazi Jewish patients. Haplotype analysis with microsatellite mar kers flanking the gene revealed that one mutation (delF1388), reported only in Ashkenazi probands, occurred on two related extended haplotypes. By con trast, the second, more common mutation (3992-9g-->a) was associated with n ine different intergenic haplotypes and has been reported in non-Jewish HI patients as well, In this study, we evaluated disease-associated chromosome s from 41 Ashkenazi Jewish and 2 non-Jewish HI patients carrying the 3992-9 g-->a mutation by assessing haplotypes defined by nine common single nucleo tide polymorphisms (SNPs), six in the SUR1 gene, and three in the KIR6.2 ge ne. Our results indicate that all 54 chromosomes carrying the 3992-9g-->a m utation in the Jewish patients appear to have originated from one founder m utation, whereas the same mutation on chromosomes from non-Jewish patients originated independently. Furthermore, our findings have implications conce rning the HI-associated chromosomes on which no mutation has been identifie d. Hum Mutat 14:23-29, 1999. (C) 1999 Wiley-Liss, Inc.