title: Gain-of-function mutation S422L in the KCNJ8-encoded cardiac K(ATP) channel Kir6.1 as a pathogenic substrate for J-wave syndromes.
abstract: BACKGROUND
  J-wave syndromes have emerged conceptually to encompass the pleiotropic expression of J-point abnormalities including Brugada syndrome (BrS) and early repolarization syndrome (ERS). KCNJ8, which encodes the cardiac K(ATP) Kir6.1 channel, recently has been implicated in ERS following identification of the functionally uncharacterized missense mutation S422L.
  
  
  OBJECTIVE
  The purpose of this study was to further explore KCNJ8 as a novel susceptibility gene for J-wave syndromes.
  
  
  METHODS
  Using polymerase chain reaction, denaturing high-performance liquid chromatography, and direct DNA sequencing, comprehensive open reading frame/splice site mutational analysis of KCNJ8 was performed in 101 unrelated patients with J-wave syndromes, including 87 with BrS and 14 with ERS. Six hundred healthy individuals were examined to assess the allelic frequency for all variants detected. KCNJ8 mutation(s) was engineered by site-directed mutagenesis and coexpressed heterologously with SUR2A in COS-1 cells. Ion currents were recorded using whole-cell configuration of the patch-clamp technique.
  
  
  RESULTS
  One BrS case and one ERS case hosted the identical missense mutation S422L, which was reported previously. KCNJ8-S422L involves a highly conserved residue and was absent in 1,200 reference alleles. Both cases were negative for mutations in all known BrS and ERS susceptibility genes. K(ATP) current of the Kir6.1-S422L mutation was increased significantly over the voltage range from 0 to 40 mV compared to Kir6.1-WT channels (n = 16-21; P <.05).
  
  
  CONCLUSIONS
  These findings further implicate KCNJ8 as a novel J-wave syndrome susceptibility gene and a marked gain of function in the cardiac K(ATP) Kir6.1 channel secondary to KCNJ8-S422L as a novel pathogenic mechanism for the phenotypic expression of both BrS and ERS.
authors.affiliation: Department of Medicine (Division of Cardiovascular Diseases), Windland Smith Rice Sudden Death Genomics Laboratory, Mayo Clinic, Rochester, Minnesota 55905, USA.
authors.forename: Argelia
authors.initials: A
authors.lastname: Medeiros-Domingo
authors.forename: Bi-Hua
authors.initials: BH
authors.lastname: Tan
authors.forename: Lia
authors.initials: L
authors.lastname: Crotti
authors.forename: David J
authors.initials: DJ
authors.lastname: Tester
authors.forename: Lee
authors.initials: L
authors.lastname: Eckhardt
authors.forename: Alessandra
authors.initials: A
authors.lastname: Cuoretti
authors.forename: Stacie L
authors.initials: SL
authors.lastname: Kroboth
authors.forename: Chunhua
authors.initials: C
authors.lastname: Song
authors.forename: Qing
authors.initials: Q
authors.lastname: Zhou
authors.forename: Doug
authors.initials: D
authors.lastname: Kopp
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Schwartz
authors.forename: Jonathan C
authors.initials: JC
authors.lastname: Makielski
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Ackerman
mesh_terms: D000328:Adult; D001145:Arrhythmias, Cardiac / Q000235:genetics* / Q000503:physiopathology; D053840:Brugada Syndrome / Q000235:genetics* / Q000503:physiopathology; D002478:Cells, Cultured; D002851:Chromatography, High Pressure Liquid; D034201:Computers, Handheld; D004252:DNA Mutational Analysis; D004562:Electrocardiography; D005260:Female; D020022:Genetic Predisposition to Disease / Q000235:genetics; D006801:Humans; D054086:KATP Channels / Q000378:metabolism; D008297:Male; D016297:Mutagenesis, Site-Directed; D020125:Mutation, Missense; D009206:Myocardium / Q000378:metabolism; D024661:Potassium Channels, Inwardly Rectifying / Q000235:genetics*; D017422:Sequence Analysis, DNA; D014162:Transfection
chemical_list: D054086:KATP Channels; D024661:Potassium Channels, Inwardly Rectifying; C092520:uK-ATP-1 potassium channel