title: The G53D mutation in Kir6.2 (KCNJ11) is associated with neonatal diabetes and motor dysfunction in adulthood that is improved with sulfonylurea therapy.
abstract: BACKGROUND
  Mutations in the Kir6.2 subunit (KCNJ11) of the ATP-sensitive potassium channel (KATP) underlie neonatal diabetes mellitus. In severe cases, Kir6.2 mutations underlie developmental delay, epilepsy, and neonatal diabetes (DEND). All Kir6.2 mutations examined decrease the ATP inhibition of KATP, which is predicted to suppress electrical activity in neurons (peripheral and central), muscle, and pancreas. Inhibitory sulfonylureas (SUs) have been used successfully to treat diabetes in patients with activating Kir6.2 mutations. There are two reports of improved neurological features in SU-treated DEND patients but no report of such improvement in adulthood.
  
  
  OBJECTIVE
  The objective of the study was to determine the molecular basis of intermediate DEND in a 27-yr-old patient with a KCNJ11 mutation (G53D) and the patient's response to SU therapy.
  
  
  METHODS
  The G53D patient was transferred from insulin to gliclazide and then to glibenclamide over a 160-d period. Motor function was assessed throughout. Electrophysiology assessed the effect of the G53D mutation on KATP activity.
  
  
  RESULTS
  The G53D patient demonstrated improved glycemic control and motor coordination with SU treatment, although glibenclamide was more effective than gliclazide. Reconstituted G53D channels exhibit reduced ATP sensitivity, which is predicted to suppress electrical activity in vivo. G53D channels coexpressed with SUR1 (the pancreatic and neuronal isoform) exhibit high-affinity block by gliclazide but are insensitive to block when coexpressed with SUR2A (the skeletal muscle isoform). High-affinity block by glibenclamide is present in G53D channels coexpressed with either SUR1 or SUR2A.
  
  
  CONCLUSIONS
  The results demonstrate that SUs can resolve motor dysfunction in an adult with intermediate DEND and that this improvement is due to inhibition of the neuronal but not skeletal muscle KATP.
authors: Washington University School of Medicine, Department of Cell Biology and Physiology, Box 8228, St. Louis, MO 63110, USA. jkoster@cellbiology.wustl.edu
authors: Joseph C
authors: JC
authors: Koster
authors: Francesco
authors: F
authors: Cadario
authors: Cinzia
authors: C
authors: Peruzzi
authors: Carlo
authors: C
authors: Colombo
authors: Colin G
authors: CG
authors: Nichols
authors: Fabrizio
authors: F
authors: Barbetti
mesh_terms: D000255:Adenosine Triphosphate / Q000494:pharmacology; D000328:Adult; D003920:Diabetes Mellitus / Q000188:drug therapy / Q000235:genetics* / Q000503:physiopathology; D005838:Genotype; D006801:Humans; D007231:Infant, Newborn; D009043:Motor Activity; D009154:Mutation; D024661:Potassium Channels, Inwardly Rectifying / Q000235:genetics* / Q000502:physiology; D013453:Sulfonylurea Compounds / Q000627:therapeutic use*; D000099161:Kcnj11 Channel
chemical_list: D000255:Adenosine Triphosphate; D024661:Potassium Channels, Inwardly Rectifying; D013453:Sulfonylurea Compounds; D000099161:Kcnj11 Channel