Cardiovascular Research Advance Access originally published online on October 4, 2007
Cardiovascular Research 2008 77(1):98-106; doi:10.1093/cvr/cvm030
A KCNE2 mutation in a patient with cardiac arrhythmia induced by auditory stimuli and serum electrolyte imbalance
1 Greenberg Division of Cardiology, Department of Medicine, Weill Medical College, Cornell University, 520 East 70th Street, New York, NY 10021, USA
2 Department of Pharmacology, Weill Medical College, Cornell University, 520 East 70th Street, New York, NY 10021, USA
3 Department of Pediatrics, Columbia University, 1150 St Nicholas Avenue, New York, NY 10032, USA
4 Department of Medicine, Columbia University, 1150 St Nicholas Avenue, New York, NY 10032, USA
5 Department of Pediatrics, New York University School of Medicine, 550 First Avenue, New York, NY 10016, USA
6 Department of Pathology, New York University School of Medicine, 550 First Avenue, New York, NY 10016, USA
7 Department of Medicine, New York University School of Medicine, 550 First Avenue, New York, NY 10016, USA
* Corresponding author. Tel: +1 212 7466275; fax: +1 212 7467984. (G.W.A)E-mail address: gwa2001{at}med.cornell.edu (G.W.A.) or wkc15{at}columbia.edu (W.C.)
Aims: Auditory stimulus-induced long QT syndrome (LQTS) is almost exclusively linked to mutations in the hERG potassium channel, which generates the IKr 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 
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 IKr current reduction by the T10M mutation is exacerbated by superimposition of arrhythmogenic substrates such as auditory stimuli, or electrolyte disturbances that reduce IKr (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.
KEYWORDS MiRP1; KCNE2; hERG; KCNH2; Potassium channel; Long QT syndrome
Time for primary review: 22 days