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- Title
Clinical and molecular characterization of a dominant form of congenital hyperinsulinism caused by a mutation in the high-affinity sulfonylurea receptor.
- Authors
Thornton, Paul S.; MacMullen, Courtney; Ganguly, Arupa; Ruchelli, Eduardo; Steinkrauss, Linda; Crane, Ana; Aguilar-Bryan, Lydia; Stanley, Charles A.
- Abstract
Recessive mutations of sulfonylurea receptor 1 (SUR1) and potassium inward rectifier 6.2 (Kir6.2), the two adjacent genes on chromosome lip that comprise the β-cell plasma membrane ATP-sensitive K[sup +] (K[sub ATP]) channels, are responsible for the most common form of congenital hyperinsulinism in children. The present study was undertaken to identify the genetic defect in a family with dominantly inherited hyperinsulinism affecting five individuals in three generations. Clinical tests were carried out in three of the patients using acute insulin responses (AIRs) to intravenous stimuli to localize the site of defect in insulin regulation. The affected individuals showed abnormal positive calcium AIR, normal negative leucine AIR, subnormal positive glucose AIR, and impaired tolbutamide AIR. This AIR pattern suggested a K[sub ATP] channel defect because it resembled that seen in children with recessive hyperinsulinism due to two common SUR1 mutations, g3992-9a and delPhe1388. Genetic linkage to the K[sub ATP] locus was established using intragenic polymorphisms. Mutation analysis identified a novel trinucleotide deletion in SUR1 exon 34 that results in the loss of serine 1387. Studies of delSer1387 in COSm6 cells confirmed that the expressed mutant protein assembles with Kir6.2 and trafficks to the plasma membrane, but it had no [sup 86]Rb effiux ion transport activity. These results indicate that hyperinsulinism in this family is caused by a SUR1 mutation that is expressed dominantly rather than recessively.
- Subjects
GENETIC mutation; PANCREATIC beta cells; POTASSIUM channels; INSULIN shock; DIABETES in children
- Publication
Diabetes, 2003, Vol 52, Issue 9, p2403
- ISSN
0012-1797
- Publication type
journal article
- DOI
10.2337/diabetes.52.9.2403