title: Coronary spasm and acute myocardial infarction due to a mutation (V734I) in the nucleotide binding domain 1 of ABCC9.
abstract: BACKGROUND
  Alterations in coronary vasomotor tone may participate in the pathogenesis of acute myocardial infarction (AMI). Vascular ATP-sensitive K(+) (KATP) channels, formed by Kir6.x/SUR2B, are key regulators of coronary tone and mutations in cardiac (Kir6.2/SUR2A) KATP channels result in heart disease. Here we explore the pathophysiological mechanism of a rare mutation (V734I) found in exon 17 of the ABCC9 gene, estimated to cause a 6.4-fold higher risk of AMI before the age of 60.
  
  
  RESULTS
  Eleven patients carrying the mutation were identified; they presented AMI of vasospastic origin associated with increased plasma levels of endothelin-1 and increased leukocyte ROCK activity. The effects of the mutation on the functional properties of the two splice variants of ABCC9 (SUR2A and SUR2B) were studied using patch-clamp electrophysiology. The mutation reduced the sensitivity to MgATP inhibition of Kir6.2/SUR2B channels but not of Kir6.2/SUR2A and Kir6.1/SUR2B channels. Furthermore, the stimulatory effects of MgNDP (MgADP, MgGDP and MgUDP) were unaltered in mutant Kir6.2/SUR2A and Kir6.1/SUR2B channels. In contrast, mutant channels composed of Kir6.2 and SUR2B were less sensitive to MgNDP activation, assessed in the presence of MgATP. The antianginal drug nicorandil activated Kir6.2/SUR2B-V734I channels, thus substituting for the loss of MgNDP stimulation, suggesting that this drug could be of therapeutic use in the treatment of AMI associated with V734I.
  
  
  CONCLUSIONS
  The 734I allele in ABCC9 may influence susceptibility to AMI by impairing the response of vascular, but not cardiac, KATP channels to intracellular nucleotides. This is the first human mutation in an ion channel gene to be implicated in AMI.
authors.affiliation: Faculty of Life Sciences, The University of Manchester, 46 Grafton Street, Manchester M13 9NT, United Kingdom.
authors.forename: Keith J
authors.initials: KJ
authors.lastname: Smith
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Chadburn
authors.forename: Aiste
authors.initials: A
authors.lastname: Adomaviciene
authors.forename: Piercarlo
authors.initials: P
authors.lastname: Minoretti
authors.forename: Luigi
authors.initials: L
authors.lastname: Vignali
authors.forename: Enzo
authors.initials: E
authors.lastname: Emanuele
authors.forename: Paolo
authors.initials: P
authors.lastname: Tammaro
mesh_terms: D000328:Adult; D001665:Binding Sites / Q000235:genetics; D002352:Carrier Proteins / Q000235:genetics*; D003329:Coronary Vasospasm / Q000000981:diagnostic imaging / Q000235:genetics* / Q000378:metabolism; D005260:Female; D020022:Genetic Predisposition to Disease; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D008297:Male; D008875:Middle Aged; D009154:Mutation / Q000235:genetics*; D009203:Myocardial Infarction / Q000000981:diagnostic imaging* / Q000235:genetics* / Q000378:metabolism; D011859:Radiography; D064233:Sulfonylurea Receptors / Q000235:genetics*
chemical_list: C577510:ABCC9 protein, human; D002352:Carrier Proteins; D047908:Intracellular Signaling Peptides and Proteins; C089765:NUBP1 protein, human; D064233:Sulfonylurea Receptors
keywords: ATP-sensitive potassium channel; Coronary vasospasm; Kir6.x; Myocardial infarction; SUR2