Genetic heterogeneity in familial hyperinsulinism [published erratum appears in Hum Mol Genet 1998 Sep;7(9):1527] |
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Authors: | Nestorowicz A; Glaser B; Wilson BA; Shyng SL; Nichols CG; Stanley CA; Thornton PS; Permutt MA |
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Institution: | Division of Endocrinology, Diabetes and Metabolism, Washington University School of Medicine, St Louis, MO 63110, USA. |
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Abstract: | Familial hyperinsulinism (HI) is a disorder characterized by dysregulation
of insulin secretion and profound hypoglycemia. Mutations in both the
Kir6.2 and sulfonylurea receptor (SUR1) genes have been associated with the
autosomal recessive form of this disorder. In this study, the spectrum and
frequency of SUR1 mutations in HI and their significance to clinical
manifestations of the disease were investigated by screening 45 HI probands
of various ethnic origins for mutations in the SUR1 gene. Single-strand
conformation polymorphism (SSCP) and nucleotide sequence analyses of
genomic DNA revealed a total of 17 novel and three previously described
mutations in SUR1 . The novel mutations comprised one nonsense and 10
missense mutations, two deletions, three mutations in consensus splice-site
sequences and an in- frame insertion of six nucleotides. One mutation
occurred in the first nucleotide binding domain (NBF-1) of the SUR1
molecule and another eight mutations were located in the second nucleotide
binding domain (NBF-2), including two at highly conserved amino acid
residues within the Walker A sequence motif. The majority of the remaining
mutations was distributed throughout the three putative transmembrane
domains of the SUR1 protein. With the exception of the 3993-9G-->A
mutation, which was detected on 4.5% (4/88) disease chromosomes, allelic
frequencies for the identified mutations varied between 1.1 and 2.3% for HI
chromosomes, indicating that each mutation was rare within the patient
cohort. The clinical manifestations of HI in those patients homozygous for
mutations in the SUR1 gene are described. In contrast with the allelic
homogeneity of HI previously described in Ashkenazi Jewish patients, these
findings suggest that a large degree of allelic heterogeneity at the SUR1
locus exists in non-Ashkenazi HI patients. These data have important
implications for genetic counseling and prenatal diagnosis of HI, and also
provide a basis to further elucidate the molecular mechanisms underlying
the pathophysiology of this disease.
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