title: The first clinical case of a mutation at residue K185 of Kir6.2 (KCNJ11): a major ATP-binding residue.
abstract: BACKGROUND
  Closure of the adenosine triphosphate (ATP)-sensitive potassium (K(ATP)) channel plays a key role in insulin secretion from the pancreatic beta-cells. Many mutations in KCNJ11 and ABCC8, which respectively encode the pore-forming (Kir6.2) and regulatory (SUR1) subunits of the K(ATP) channel, cause neonatal diabetes. All such mutations impair the ability of metabolically generated ATP to close the channel. Although lysine 185 is predicted to be a major contributor to the ATP-binding site of Kir6.2, no mutations at this residue have been found to cause neonatal diabetes to date.
  
  
  METHODS
  We report a 3-year-old girl with permanent neonatal diabetes (PNDM) caused by a novel heterozygous mutation (K185Q) at residue K185 of KCNJ11. The patient presented with marked hyperglycaemia and ketoacidosis at 70 days after birth, and insulin therapy was commenced.
  
  
  RESULTS
  Wild-type and mutant K(ATP) channels were expressed in Xenopus oocytes and the effects of intracellular ATP on macroscopic K(ATP) currents in inside-out membrane patches were measured. In the simulated heterozygous state, the K185Q mutation caused a substantial reduction in the ability of MgATP to inhibit the channel. Heterozygous K185Q channels were still blocked effectively by the sulphonylurea tolbutamide.
  
  
  CONCLUSIONS
  We report the first clinical case of a PNDM caused by a mutation at K185. Functional studies indicate that the K185Q mutation causes PNDM by reducing the ATP sensitivity of the K(ATP) channel, probably via a reduction in ATP binding to Kir6.2. Based on the experimental data, the patient was successfully transferred to sulphonylurea therapy.
authors.affiliation: Henry Wellcome Centre for Gene Function, Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford, UK.
authors.forename: K
authors.initials: K
authors.lastname: Shimomura
authors.forename: G P
authors.initials: GP
authors.lastname: de Nanclares
authors.forename: C
authors.initials: C
authors.lastname: Foutinou
authors.forename: M
authors.initials: M
authors.lastname: Caimari
authors.forename: L
authors.initials: L
authors.lastname: Castaño
authors.forename: F M
authors.initials: FM
authors.lastname: Ashcroft
mesh_terms: D018528:ATP-Binding Cassette Transporters / Q000235:genetics / Q000502:physiology; D000255:Adenosine Triphosphate / Q000502:physiology; D002675:Child, Preschool; D048909:Diabetes Complications / Q000235:genetics; D003920:Diabetes Mellitus / Q000235:genetics* / Q000378:metabolism; D016883:Diabetic Ketoacidosis / Q000175:diagnosis; D005260:Female; D006801:Humans; D006943:Hyperglycemia / Q000175:diagnosis; D007231:Infant, Newborn; D009154:Mutation / Q000235:genetics*; D024661:Potassium Channels, Inwardly Rectifying / Q000235:genetics*; D017422:Sequence Analysis, DNA; D000099161:Kcnj11 Channel
chemical_list: D018528:ATP-Binding Cassette Transporters; D000255:Adenosine Triphosphate; D024661:Potassium Channels, Inwardly Rectifying; D000099161:Kcnj11 Channel