A KCNE2 mutation in a patient with cardiac arrhythmia induced by auditory stimuli and serum electrolyte imbalance

Cardiovasc Res. 2008 Jan;77(1):98-106. doi: 10.1093/cvr/cvm030. Epub 2007 Oct 4.


Aims: 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.

Methods and 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.

Conclusion: 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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acoustic Stimulation*
  • Adult
  • Animals
  • CHO Cells
  • Calcium / blood
  • Cricetinae
  • Cricetulus
  • Ether-A-Go-Go Potassium Channels / physiology
  • Female
  • Humans
  • KCNQ1 Potassium Channel / physiology
  • Mutation*
  • Potassium Channels, Voltage-Gated / genetics*
  • Potassium Channels, Voltage-Gated / physiology
  • Ventricular Fibrillation / etiology
  • Ventricular Fibrillation / genetics*
  • Water-Electrolyte Imbalance / complications*


  • Ether-A-Go-Go Potassium Channels
  • KCNE2 protein, human
  • KCNQ1 Potassium Channel
  • KCNQ1 protein, human
  • Potassium Channels, Voltage-Gated
  • Calcium