Human Molecular Genetics Advance Access originally published online on June 13, 2006
Human Molecular Genetics 2006 15(14):2185-2191; doi:10.1093/hmg/ddl143
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Kv1.5 channelopathy due to KCNA5 loss-of-function mutation causes human atrial fibrillation
1 Division of Cardiovascular Diseases, Department of Medicine, 2 Division of Pediatric Cardiology, Department of Pediatric and Adolescent Medicine and 3 Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic College of Medicine, Rochester, MN, USA
* To whom correspondence should be addressed at: Guggenheim 7, Mayo Clinic, 200 First Street SW, Rochester, MN 55905, USA. Tel: +1 5072842747; Fax: +1 5072849111; Email: terzic.andre{at}mayo.edu
Received May 2, 2006; Accepted May 26, 2006
Atrial fibrillation is a rhythm disorder characterized by chaotic electrical activity of cardiac atria. Predisposing to stroke and heart failure, this common condition is increasingly recognized as a heritable disorder. To identify genetic defects conferring disease susceptibility, patients with idiopathic atrial fibrillation, lacking traditional risk factors, were evaluated. Genomic DNA scanning revealed a nonsense mutation in KCNA5 that encodes Kv1.5, a voltage-gated potassium channel expressed in human atria. The heterozygous E375X mutation, present in a familial case of atrial fibrillation and absent in 540 unrelated control individuals, introduced a premature stop codon disrupting the Kv1.5 channel protein. The truncation eliminated the S4–S6 voltage sensor, pore region and C-terminus, preserving the N-terminus and S1–S3 transmembrane domains that secure tetrameric subunit assembly. Heterologously expressed recombinant E375X mutant failed to generate the ultrarapid delayed rectifier current IKur vital for atrial repolarization and exerted a dominant-negative effect on wild-type current. Loss of channel function translated into action potential prolongation and early after-depolarization in human atrial myocytes, increasing vulnerability to stress-provoked triggered activity. The pathogenic link between compromised Kv1.5 function and susceptibility to atrial fibrillation was verified, at the organism level, in a murine model. Rescue of the genetic defect was achieved by aminoglycoside-induced translational read-through of the E375X premature stop codon, restoring channel function. This first report of Kv1.5 loss-of-function channelopathy establishes KCNA5 mutation as a novel risk factor for repolarization deficiency and atrial fibrillation.
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