title: Activating mutations in the ABCC8 gene in neonatal diabetes mellitus.
abstract: BACKGROUND
  The ATP-sensitive potassium (K(ATP)) channel, composed of the beta-cell proteins sulfonylurea receptor (SUR1) and inward-rectifying potassium channel subunit Kir6.2, is a key regulator of insulin release. It is inhibited by the binding of adenine nucleotides to subunit Kir6.2, which closes the channel, and activated by nucleotide binding or hydrolysis on SUR1, which opens the channel. The balance of these opposing actions determines the low open-channel probability, P(O), which controls the excitability of pancreatic beta cells. We hypothesized that activating mutations in ABCC8, which encodes SUR1, cause neonatal diabetes.
  
  
  METHODS
  We screened the 39 exons of ABCC8 in 34 patients with permanent or transient neonatal diabetes of unknown origin. We assayed the electrophysiologic activity of mutant and wild-type K(ATP) channels.
  
  
  RESULTS
  We identified seven missense mutations in nine patients. Four mutations were familial and showed vertical transmission with neonatal and adult-onset diabetes; the remaining mutations were not transmitted and not found in more than 300 patients without diabetes or with early-onset diabetes of similar genetic background. Mutant channels in intact cells and in physiologic concentrations of magnesium ATP had a markedly higher P(O) than did wild-type channels. These overactive channels remained sensitive to sulfonylurea, and treatment with sulfonylureas resulted in euglycemia.
  
  
  CONCLUSIONS
  Dominant mutations in ABCC8 accounted for 12 percent of cases of neonatal diabetes in the study group. Diabetes results from a newly discovered mechanism whereby the basal magnesium-nucleotide-dependent stimulatory action of SUR1 on the Kir pore is elevated and blockade by sulfonylureas is preserved.
authors.affiliation: Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, USA.
authors.forename: Andrey P
authors.initials: AP
authors.lastname: Babenko
authors.forename: Michel
authors.initials: M
authors.lastname: Polak
authors.forename: Hélène
authors.initials: H
authors.lastname: Cavé
authors.forename: Kanetee
authors.initials: K
authors.lastname: Busiah
authors.forename: Paul
authors.initials: P
authors.lastname: Czernichow
authors.forename: Raphael
authors.initials: R
authors.lastname: Scharfmann
authors.forename: Joseph
authors.initials: J
authors.lastname: Bryan
authors.forename: Lydia
authors.initials: L
authors.lastname: Aguilar-Bryan
authors.forename: Martine
authors.initials: M
authors.lastname: Vaxillaire
authors.forename: Philippe
authors.initials: P
authors.lastname: Froguel
mesh_terms: D018528:ATP-Binding Cassette Transporters / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D001724:Birth Weight; D002658:Developmental Disabilities / Q000150:complications; D048909:Diabetes Complications; D003920:Diabetes Mellitus / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism; D005260:Female; D006579:Heterozygote; D006801:Humans; D007004:Hypoglycemic Agents / Q000627:therapeutic use; D007231:Infant, Newborn; D050417:Insulin-Secreting Cells / Q000187:drug effects / Q000378:metabolism; D008297:Male; D020125:Mutation, Missense; D010375:Pedigree; D015221:Potassium Channels / Q000235:genetics* / Q000378:metabolism; D024661:Potassium Channels, Inwardly Rectifying / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D011955:Receptors, Drug / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D013453:Sulfonylurea Compounds / Q000627:therapeutic use; D064233:Sulfonylurea Receptors; D014044:Tolbutamide / Q000494:pharmacology; D000099161:Kcnj11 Channel
chemical_list: D018528:ATP-Binding Cassette Transporters; D007004:Hypoglycemic Agents; D015221:Potassium Channels; D024661:Potassium Channels, Inwardly Rectifying; D011955:Receptors, Drug; D013453:Sulfonylurea Compounds; D064233:Sulfonylurea Receptors; D014044:Tolbutamide; D000099161:Kcnj11 Channel; C577507:ABCC8 protein, human