Cardiovascular Research Advance Access [Accepted Manuscript] published online on October 4, 2007
Cardiovascular Research, doi:10.1093/cvr/cvm030
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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
2 Department of Pharmacology, Cornell University, Weill Medical College, 520 East 70th Street, New York, NY, 10021
3 Departments of Pediatrics and Medicine, Columbia University, 1150 St Nicholas Avenue, New York, NY, 10032
4 Departments of Pediatrics, Pathology and Medicine, New York University School of Medicine, 550 First Avenue, New York, NY, 10016
* To whom correspondence should be addressed: Dr. Geoffrey W. Abbott, Tel: 212 7466275; Fax: 212 7467984; email: gwa2001{at}med.cornell.edu Dr. Wendy Chung, email: wkc15{at}columbia.edu
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 hypomagnesemia and hypocalcemia after completing a marathon, followed by subsequent VF with hypokalemia. The patient was found to harbor 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 analyzed here and was previously described only once - in an LQTS patient - but not functionally characterized.
METHODS: T10M-MiRP1-hERG currents were assessed using whole-cell voltage clamp of transfected CHO cells.
RESULTS: T10M-MiRP1-hERG channels showed =80 % reduced tail current, left-shifted steady-state inactivation and 50% slower recovery from inactivation compared to 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: The 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 (hypokalemia) or otherwise lower the ventricular threshold for fibrillation (hypomagnesemia, hypocalcemia). This first example of a MiRP1 mutation associated with auditory stimulus-induced arrhythmia is supportive of the hypothesis that MiRP1 regulates hERG in human heart.
Time for primary review: 30 days