title: A KCNE2 mutation in a patient with cardiac arrhythmia induced by auditory stimuli and serum electrolyte imbalance.
abstract: OBJECTIVE
  Auditory stimulus-induced long QT syndrome (LQTS) is almost exclusively linked to mutations in the hERG potassium channel, which generates the I Kr ventricular repolarization current. Here, a young woman with prior episodes of auditory stimulus-induced syncope presented with LQTS and ventricular fibrillation (VF) with hypomagnesaemia and hypocalcaemia after completing a marathon, followed by subsequent VF with hypokalaemia. The patient was found to harbour a KCNE2 gene mutation encoding a T10M amino acid substitution in MiRP1, an ancillary subunit that co-assembles with and functionally modulates hERG. Other family members with the mutation were asymptomatic, and the proband had no mutations in hERG or other LQTS-linked cardiac ion channel genes. The T10M mutation was absent from 578 unrelated, ethnically matched control chromosomes analysed here and was previously described only once-in an LQTS patient-but not functionally characterized.
  
  
  RESULTS
  T10M-MiRP1-hERG currents were assessed using whole-cell voltage clamp of transfected Chinese Hamster ovary cells. T10M-MiRP1-hERG channels showed <or=80% reduced tail current, left-shifted steady-state inactivation, and 50% slower recovery from inactivation when compared with wild-type channels, with mixed wild-type/T10M channels displaying an intermediate phenotype. Lowering bath K+ concentration reduced wild-type and T10M currents equivalently.
  
  
  CONCLUSIONS
  Data suggest a mechanism for reduced penetrance, inherited arrhythmia in which baseline I Kr current reduction by the T10M mutation is exacerbated by superimposition of arrhythmogenic substrates such as auditory stimuli, or electrolyte disturbances that reduce I Kr (hypokalaemia) or otherwise lower the ventricular threshold for fibrillation (hypomagnesaemia and hypocalcaemia). This first example of a MiRP1 mutation associated with auditory stimulus-induced arrhythmia is supportive of the hypothesis that MiRP1 regulates hERG in the human heart.
authors.affiliation: Greenberg Division of Cardiology, Department of Medicine, Weill Medical College, Cornell University, 520 East 70th Street, New York, NY 10021, USA.
authors.forename: Earl
authors.initials: E
authors.lastname: Gordon
authors.forename: Gianina
authors.initials: G
authors.lastname: Panaghie
authors.forename: Liyong
authors.initials: L
authors.lastname: Deng
authors.forename: Katharine J
authors.initials: KJ
authors.lastname: Bee
authors.forename: Torsten K
authors.initials: TK
authors.lastname: Roepke
authors.forename: Trine
authors.initials: T
authors.lastname: Krogh-Madsen
authors.forename: David J
authors.initials: DJ
authors.lastname: Christini
authors.forename: Harry
authors.initials: H
authors.lastname: Ostrer
authors.forename: Craig T
authors.initials: CT
authors.lastname: Basson
authors.forename: Wendy
authors.initials: W
authors.lastname: Chung
authors.forename: Geoffrey W
authors.initials: GW
authors.lastname: Abbott
mesh_terms: D000161:Acoustic Stimulation; D000328:Adult; D000818:Animals; D016466:CHO Cells; D002118:Calcium / Q000097:blood; D006224:Cricetinae; D003412:Cricetulus; D051638:Ether-A-Go-Go Potassium Channels / Q000502:physiology; D005260:Female; D006801:Humans; D051657:KCNQ1 Potassium Channel / Q000502:physiology; D009154:Mutation; D024642:Potassium Channels, Voltage-Gated / Q000235:genetics* / Q000502:physiology; D014693:Ventricular Fibrillation / Q000209:etiology / Q000235:genetics*; D014883:Water-Electrolyte Imbalance / Q000150:complications*
chemical_list: D051638:Ether-A-Go-Go Potassium Channels; C489619:KCNE2 protein, human; D051657:KCNQ1 Potassium Channel; C496909:KCNQ1 protein, human; D024642:Potassium Channels, Voltage-Gated; D002118:Calcium