title: Congenital hyperinsulinism and glucose hypersensitivity in homozygous and heterozygous carriers of Kir6.2 (KCNJ11) mutation V290M mutation: K(ATP) channel inactivation mechanism and clinical management.
abstract: OBJECTIVE
  The ATP-sensitive K(+) channel (K(ATP)) controls insulin secretion from the islet. Gain- or loss-of-function mutations in channel subunits underlie human neonatal diabetes and congenital hyperinsulinism (HI), respectively. In this study, we sought to identify the mechanistic basis of K(ATP)-induced HI in two probands and to characterize the clinical course.
  
  
  METHODS
  We analyzed HI in two probands and characterized the course of clinical treatment in each, as well as properties of mutant K(ATP) channels expressed in COSm6 cells using Rb efflux and patch-clamp methods.
  
  
  RESULTS
  We identified mutation V290M in the pore-forming Kir6.2 subunit in each proband. In vitro expression in COSm6 cells supports the mutation resulting in an inactivating phenotype, which leads to significantly reduced activity in intact cells when expressed homomerically, and to a lesser extent when expressed heteromerically with wild-type subunits. In one heterozygous proband, a fluoro-DOPA scan revealed a causal focal lesion, indicating uniparental disomy with loss of heterozygosity. In a second family, the proband, homozygous for the mutation, was diagnosed with severe diazoxide-unresponsive hypersinsulinism at 2 weeks of age. The patient continues to be treated successfully with octreotide and amlodipine. The parents and a male sibling are heterozygous carriers without overt clinical HI. Interestingly, both the mother and the sibling exhibit evidence of abnormally enhanced glucose tolerance.
  
  
  CONCLUSIONS
  V290M results in inactivating K(ATP) channels that underlie HI. Homozygous individuals may be managed medically, without pancreatectomy. Heterozygous carriers also show evidence of enhanced glucose sensitivity, consistent with incomplete loss of K(ATP) channel activity.
authors.affiliation: Department of Pediatrics, University of North Carolina School of Medicine, Chapel Hill, USA.
authors.forename: Karen J
authors.initials: KJ
authors.lastname: Loechner
authors.forename: Alejandro
authors.initials: A
authors.lastname: Akrouh
authors.forename: Harley T
authors.initials: HT
authors.lastname: Kurata
authors.forename: Carlo
authors.initials: C
authors.lastname: Dionisi-Vici
authors.forename: Arianna
authors.initials: A
authors.lastname: Maiorana
authors.forename: Milena
authors.initials: M
authors.lastname: Pizzoferro
authors.forename: Vittoria
authors.initials: V
authors.lastname: Rufini
authors.forename: Jean
authors.initials: J
authors.lastname: de Ville de Goyet
authors.forename: Carlo
authors.initials: C
authors.lastname: Colombo
authors.forename: Fabrizio
authors.initials: F
authors.lastname: Barbetti
authors.forename: Joseph C
authors.initials: JC
authors.lastname: Koster
authors.forename: Colin G
authors.initials: CG
authors.lastname: Nichols
mesh_terms: D000255:Adenosine Triphosphate / Q000037:antagonists & inhibitors; D002353:Carrier State; D002648:Child; D004247:DNA / Q000097:blood / Q000235:genetics / Q000302:isolation & purification; D008401:Gas Chromatography-Mass Spectrometry; D005784:Gene Amplification; D020868:Gene Silencing; D005951:Glucose Tolerance Test; D006579:Heterozygote; D006720:Homozygote; D006801:Humans; D006946:Hyperinsulinism / Q000151:congenital* / Q000628:therapy; D015151:Immunoblotting; D007328:Insulin / Q000378:metabolism; D000078790:Insulin Secretion; D015640:Ion Channel Gating / Q000235:genetics; D007515:Islets of Langerhans / Q000378:metabolism; D008297:Male; D009154:Mutation; D010641:Phenotype; D016133:Polymerase Chain Reaction; D020641:Polymorphism, Single Nucleotide; D015221:Potassium Channels / Q000235:genetics* / Q000502:physiology; D024661:Potassium Channels, Inwardly Rectifying / Q000235:genetics*; D012413:Rubidium / Q000378:metabolism; D000099161:Kcnj11 Channel
chemical_list: D000255:Adenosine Triphosphate; D004247:DNA; D007328:Insulin; D015221:Potassium Channels; D024661:Potassium Channels, Inwardly Rectifying; D012413:Rubidium; D000099161:Kcnj11 Channel; C117780:mitochondrial K(ATP) channel