title: Clinical and molecular characterization of a dominant form of congenital hyperinsulinism caused by a mutation in the high-affinity sulfonylurea receptor.
abstract: Recessive mutations of sulfonylurea receptor 1 (SUR1) and potassium inward rectifier 6.2 (Kir6.2), the two adjacent genes on chromosome 11p that comprise the beta-cell plasma membrane ATP-sensitive K(+) (K(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(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(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 (86)Rb efflux ion transport activity. These results indicate that hyperinsulinism in this family is caused by a SUR1 mutation that is expressed dominantly rather than recessively.
authors.affiliation: Children's Hospital of Philadelphia, Philadelphia, Pennsylvania 19104, USA.
authors.forename: Paul S
authors.initials: PS
authors.lastname: Thornton
authors.forename: Courtney
authors.initials: C
authors.lastname: MacMullen
authors.forename: Arupa
authors.initials: A
authors.lastname: Ganguly
authors.forename: Eduardo
authors.initials: E
authors.lastname: Ruchelli
authors.forename: Linda
authors.initials: L
authors.lastname: Steinkrauss
authors.forename: Ana
authors.initials: A
authors.lastname: Crane
authors.forename: Lydia
authors.initials: L
authors.lastname: Aguilar-Bryan
authors.forename: Charles A
authors.initials: CA
authors.lastname: Stanley
mesh_terms: D018528:ATP-Binding Cassette Transporters; D000328:Adult; D005192:Family Health; D005260:Female; D015870:Gene Expression; D005799:Genes, Dominant; D006239:Haplotypes; D006801:Humans; D006946:Hyperinsulinism / Q000151:congenital / Q000235:genetics*; D007223:Infant; D007231:Infant, Newborn; D007328:Insulin / Q000378:metabolism; D000078790:Insulin Secretion; D007515:Islets of Langerhans / Q000378:metabolism; D008297:Male; D010375:Pedigree; D017354:Point Mutation; D011110:Polymorphism, Genetic; D015221:Potassium Channels / Q000235:genetics*; D024661:Potassium Channels, Inwardly Rectifying; D011955:Receptors, Drug / Q000235:genetics*; D064233:Sulfonylurea Receptors
chemical_list: C577507:ABCC8 protein, human; D018528:ATP-Binding Cassette Transporters; D007328:Insulin; D015221:Potassium Channels; D024661:Potassium Channels, Inwardly Rectifying; D011955:Receptors, Drug; D064233:Sulfonylurea Receptors