title: Partially dominant mutant channel defect corresponding with intermediate LQT2 phenotype.
abstract: BACKGROUND
  The hereditary Long QT Syndrome is a common cardiac disorder where ventricular repolarization is delayed, abnormally prolonging the QTc interval on electrocardiograms. LQTS is linked to various genetic loci, including the KCNH2 (HERG) gene that encodes the α-subunit of the cardiac potassium channel that carries I(Kr). Here, we report and characterize a novel pathologic missense mutation, G816V HERG, in a patient with sudden cardiac death.
  
  
  METHODS
  Autopsy-derived tissue sample was used for DNA extraction and sequencing from an unexpected sudden death victim. The G816V HERG mutation was studied using heterologous expression in mammalian cell culture, whole cell patch clamp, confocal immunofluorescence, and immunochemical analyses.
  
  
  RESULTS
  The mutant G816V HERG channel has reduced protein expression and shows a trafficking defective phenotype that is incapable of carrying current when expressed at physiological temperatures. The mutant channel showed reduced cell surface localization compared to wild-type HERG (WT HERG) but the mutant and wild-type subunits are capable of interacting. Expression studies at reduced temperatures enabled partial rescue of the trafficking defect with appearance of potassium currents, albeit with reduced current density and altered voltage-dependent activation. Lastly, we examined a potential role for hypokalemia as a contributory factor to the patient's lethal arrhythmia by possible low-potassium-induced degradation of WT HERG and haplo-insufficiency of G816V HERG.
  
  
  CONCLUSIONS
  The G816V mutation in HERG causes a trafficking defect that acts in a partially dominant negative manner. This intermediate severity defect agrees with the mild clinical presentation in other family members harboring the same mutation. Possible hypokalemia in the proband induced WT HERG degradation combined with haplo-insufficiency may have further compromised repolarization reserve and contributed to the lethal arrhythmia.
authors.affiliation: Department of Molecular Pharmacology, Albert Einstein College of Medicine, Bronx, New York 10461, USA.
authors.forename: Yamini
authors.initials: Y
authors.lastname: Krishnan
authors.forename: Renjian
authors.initials: R
authors.lastname: Zheng
authors.forename: Christine
authors.initials: C
authors.lastname: Walsh
authors.forename: Yingying
authors.initials: Y
authors.lastname: Tang
authors.forename: Thomas V
authors.initials: TV
authors.lastname: McDonald
mesh_terms: D000328:Adult; D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels / Q000235:genetics*; D005260:Female; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D006801:Humans; D008133:Long QT Syndrome / Q000235:genetics*; D009154:Mutation / Q000235:genetics; D010641:Phenotype
chemical_list: D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels; C000606913:KCNH2 protein, human