title: Hyperinsulinaemic hypoglycaemia and diabetes mellitus due to dominant ABCC8/KCNJ11 mutations.
abstract: OBJECTIVE
  Dominantly acting loss-of-function mutations in the ABCC8/KCNJ11 genes can cause mild medically responsive hyperinsulinaemic hypoglycaemia (HH). As controversy exists over whether these mutations predispose to diabetes in adulthood we investigated the prevalence of diabetes in families with dominantly inherited ATP-sensitive potassium (K(ATP)) channel mutations causing HH in the proband.
  
  
  METHODS
  We studied the phenotype of 30 mutation carriers (14 children and 16 adults) from nine families with dominant ABCC8/KCNJ11 mutations. Functional consequences of six novel missense mutations were examined by reconstituting the K(ATP) channel in human embryonic kidney 293 (HEK293) cells and evaluating the effect of drugs and metabolic poisoning on the channels using the (86)Rb flux assay.
  
  
  RESULTS
  The mutant channels all showed a lack of (86)Rb efflux on exposure to the channel agonist diazoxide or metabolic inhibition. In the families, dominant ABCC8/KCNJ11 mutations were associated with increased birthweight (median + 1.56 SD score [SDS]). Fourteen children had HH and five adults were reported with HH or hypoglycaemic episodes (63%). Progression from hypoglycaemia to diabetes mellitus occurred in two individuals. Eight adults had a history of gestational diabetes in multiple pregnancies or were diabetic (diagnosed at a median age of 31 years). Within these families, none of the 19 adults who were not carriers of the ABCC8/KCNJ11 mutation was known to be diabetic.
  
  
  CONCLUSIONS
  The phenotype associated with dominant ABCC8/KCNJ11 mutations ranges from asymptomatic macrosomia to persistent HH in childhood. In adults, it may also be an important cause of dominantly inherited early-onset diabetes mellitus.
authors.affiliation: Developmental Endocrinology Research Group, Clinical and Molecular Genetics Unit, Institute of Child Health, University College London, 30 Guilford Street, London, WC1N 1EH, UK.
authors.forename: R R
authors.initials: RR
authors.lastname: Kapoor
authors.forename: S E
authors.initials: SE
authors.lastname: Flanagan
authors.forename: C T
authors.initials: CT
authors.lastname: James
authors.forename: J
authors.initials: J
authors.lastname: McKiernan
authors.forename: A M
authors.initials: AM
authors.lastname: Thomas
authors.forename: S C
authors.initials: SC
authors.lastname: Harmer
authors.forename: J P
authors.initials: JP
authors.lastname: Shield
authors.forename: A
authors.initials: A
authors.lastname: Tinker
authors.forename: S
authors.initials: S
authors.lastname: Ellard
authors.forename: K
authors.initials: K
authors.lastname: Hussain
mesh_terms: D018528:ATP-Binding Cassette Transporters / Q000235:genetics*; D000328:Adult; D000368:Aged; D003920:Diabetes Mellitus / Q000209:etiology* / Q000235:genetics*; D005260:Female; D006801:Humans; D006946:Hyperinsulinism / Q000209:etiology* / Q000235:genetics*; D007003:Hypoglycemia / Q000209:etiology* / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D009154:Mutation; D024661:Potassium Channels, Inwardly Rectifying / Q000235:genetics*; D011955:Receptors, Drug / Q000235:genetics*; D064233:Sulfonylurea Receptors; D055815:Young Adult; D000099161:Kcnj11 Channel
chemical_list: D018528:ATP-Binding Cassette Transporters; D024661:Potassium Channels, Inwardly Rectifying; D011955:Receptors, Drug; D064233:Sulfonylurea Receptors; D000099161:Kcnj11 Channel