title: Genotype-phenotype correlations in children with congenital hyperinsulinism due to recessive mutations of the adenosine triphosphate-sensitive potassium channel genes.
abstract: Congenital hyperinsulinism (HI) is most commonly caused by recessive mutations of the pancreatic beta-cell ATP-sensitive potassium channel (K(ATP)), encoded by two genes on chromosome 11p, SUR1 and Kir6.2. The two mutations that have been best studied, SUR1 g3992-9a and SUR1 delF1388, are null mutations yielding nonfunctional channels and are characterized by nonresponsiveness to diazoxide, a channel agonist, and absence of acute insulin responses (AIRs) to tolbutamide, a channel antagonist, or leucine. To examine phenotypes of other K(ATP) mutations, we measured AIRs to calcium, leucine, glucose, and tolbutamide in infants with recessive SUR1 or Kir6.2 mutations expressed as diffuse HI (n = 8) or focal HI (n = 14). Of the 24 total mutations, at least seven showed evidence of residual K(ATP) channel function. This included positive AIR to both tolbutamide and leucine in diffuse HI cases or positive AIR to leucine in focal HI cases. One patient with partial K(ATP) function also responded to treatment with the channel agonist, diazoxide. Six of the seven patients with partial defects had amino acid substitutions or insertions; whereas, the other patient was compound heterozygous for two premature stop codons. These results indicate that some K(ATP) mutations can yield partially functioning channels, including cases of hyperinsulinism that are fully responsive to diazoxide therapy.
authors.affiliation: Division of Endocrinology/Diabetes, The Children's Hospital of Philadelphia, Pennsylvania 19104, USA.
authors.forename: Maria J
authors.initials: MJ
authors.lastname: Henwood
authors.forename: Andrea
authors.initials: A
authors.lastname: Kelly
authors.forename: Courtney
authors.initials: C
authors.lastname: Macmullen
authors.forename: Pooja
authors.initials: P
authors.lastname: Bhatia
authors.forename: Arupa
authors.initials: A
authors.lastname: Ganguly
authors.forename: Paul S
authors.initials: PS
authors.lastname: Thornton
authors.forename: Charles A
authors.initials: CA
authors.lastname: Stanley
mesh_terms: D018528:ATP-Binding Cassette Transporters; D019943:Amino Acid Substitution; D001483:Base Sequence; D002648:Child; D003981:Diazoxide / Q000627:therapeutic use; D005808:Genes, Recessive; D005838:Genotype; D006801:Humans; D006946:Hyperinsulinism / Q000151:congenital / Q000235:genetics* / Q000628:therapy; D007328:Insulin / Q000378:metabolism; D000078790:Insulin Secretion; D007515:Islets of Langerhans / Q000378:metabolism; D054086:KATP Channels; D008954:Models, Biological; D009154:Mutation; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D015221:Potassium Channels / Q000235:genetics*; D024661:Potassium Channels, Inwardly Rectifying; D011955:Receptors, Drug; D017384:Sequence Deletion; D064233:Sulfonylurea Receptors
chemical_list: C577507:ABCC8 protein, human; D018528:ATP-Binding Cassette Transporters; D007328:Insulin; D054086:KATP Channels; D015221:Potassium Channels; D024661:Potassium Channels, Inwardly Rectifying; D011955:Receptors, Drug; D064233:Sulfonylurea Receptors; C092520:uK-ATP-1 potassium channel; D003981:Diazoxide