Genetic heterogeneity in familial hyperinsulinism [published erratum appears in Hum Mol Genet 1998 Sep;7(9):1527]

Familial hyperinsulinism (HI) is a disorder characterized by dysregulationof insulin secretion and profound hypoglycemia. Mutations in both theKir6.2 and sulfonylurea receptor (SUR1) genes have been associated with theautosomal recessive form of this disorder. In this study, the spectrum andfrequency of SUR1 mutations in HI and their significance to clinicalmanifestations of the disease were investigated by screening 45 HI probandsof various ethnic origins for mutations in the SUR1 gene. Single-strandconformation polymorphism (SSCP) and nucleotide sequence analyses ofgenomic DNA revealed a total of 17 novel and three previously describedmutations in SUR1 . The novel mutations comprised one nonsense and 10missense mutations, two deletions, three mutations in consensus splice-sitesequences and an in- frame insertion of six nucleotides. One mutationoccurred in the first nucleotide binding domain (NBF-1) of the SUR1molecule and another eight mutations were located in the second nucleotidebinding domain (NBF-2), including two at highly conserved amino acidresidues within the Walker A sequence motif. The majority of the remainingmutations was distributed throughout the three putative transmembranedomains of the SUR1 protein. With the exception of the 3993-9G-->Amutation, which was detected on 4.5% (4/88) disease chromosomes, allelicfrequencies for the identified mutations varied between 1.1 and 2.3% for HIchromosomes, indicating that each mutation was rare within the patientcohort. The clinical manifestations of HI in those patients homozygous formutations in the SUR1 gene are described. In contrast with the allelichomogeneity of HI previously described in Ashkenazi Jewish patients, thesefindings suggest that a large degree of allelic heterogeneity at the SUR1locus exists in non-Ashkenazi HI patients. These data have importantimplications for genetic counseling and prenatal diagnosis of HI, and alsoprovide a basis to further elucidate the molecular mechanisms underlyingthe pathophysiology of this disease.