title: Diazoxide-unresponsive congenital hyperinsulinism in children with dominant mutations of the β-cell sulfonylurea receptor SUR1.
abstract: OBJECTIVE
  Congenital hyperinsulinemic hypoglycemia is a group of genetic disorders of insulin secretion most commonly associated with inactivating mutations of the β-cell ATP-sensitive K(+) channel (K(ATP) channel) genes ABCC8 (SUR1) and KCNJ11 (Kir6.2). Recessive mutations of these genes cause hyperinsulinism that is unresponsive to treatment with diazoxide, a channel agonist. Dominant K(ATP) mutations have been associated with diazoxide-responsive disease. We hypothesized that some medically uncontrollable cases with only one K(ATP) mutation might have dominant, diazoxide-unresponsive disease.
  
  
  METHODS
  Mutations of the K(ATP) genes were identified by sequencing genomic DNA. Effects of mutations on K(ATP) channel function in vitro were studied by expression in COSm6 cells.
  
  
  RESULTS
  In 15 families with diazoxide-unresponsive diffuse hyperinsulism, we found 17 patients with a monoallelic missense mutation of SUR1. Nine probands had de novo mutations, two had an affected sibling or parent, and four had an asymptomatic carrier parent. Of the 13 different mutations, 12 were novel. Expression of mutations revealed normal trafficking of channels but severely impaired responses to diazoxide or MgADP. Responses were significantly lower compared with nine SUR1 mutations associated with dominant, diazoxide-responsive hyperinsulinism.
  
  
  CONCLUSIONS
  These results demonstrate that some dominant mutations of SUR1 can cause diazoxide-unresponsive hyperinsulinism. In vitro expression studies may be helpful in distinguishing such mutations from dominant mutations of SUR1 associated with diazoxide-responsive disease.
authors.affiliation: Division of Endocrinology/Diabetes, The Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania, USA.
authors.forename: Courtney M
authors.initials: CM
authors.lastname: Macmullen
authors.forename: Qing
authors.initials: Q
authors.lastname: Zhou
authors.forename: Kara E
authors.initials: KE
authors.lastname: Snider
authors.forename: Paul H
authors.initials: PH
authors.lastname: Tewson
authors.forename: Susan A
authors.initials: SA
authors.lastname: Becker
authors.forename: Ali Rahim
authors.initials: AR
authors.lastname: Aziz
authors.forename: Arupa
authors.initials: A
authors.lastname: Ganguly
authors.forename: Show-Ling
authors.initials: SL
authors.lastname: Shyng
authors.forename: Charles A
authors.initials: CA
authors.lastname: Stanley
mesh_terms: D018528:ATP-Binding Cassette Transporters / Q000235:genetics*; D000959:Antihypertensive Agents / Q000627:therapeutic use; D044903:Congenital Hyperinsulinism / Q000188:drug therapy* / Q000235:genetics*; D003981:Diazoxide / Q000627:therapeutic use*; D006801:Humans; D008954:Models, Biological; D009154:Mutation; D020125:Mutation, Missense / Q000235:genetics; D010375:Pedigree; D024661:Potassium Channels, Inwardly Rectifying / Q000235:genetics*; D011955:Receptors, Drug / Q000235:genetics*; D064233:Sulfonylurea Receptors
chemical_list: C577507:ABCC8 protein, human; D018528:ATP-Binding Cassette Transporters; D000959:Antihypertensive Agents; D024661:Potassium Channels, Inwardly Rectifying; D011955:Receptors, Drug; D064233:Sulfonylurea Receptors; D003981:Diazoxide