Kv1.5 channelopathy due to KCNA5 loss-of-function mutation causes human atrial fibrillation

Timothy M OLSON; Alexey E ALEKSEEV; Xiaoke K LIU; Sungjo PARK; Leonid V ZINGMAN; Martin BIENENGRAEBER; Srinivasan SATTIRAJU; Jeffrey D BALLEW; Arshad JAHANGIR; Andre TERZIC

doi:10.1093/hmg/ddl143

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Kv1.5 channelopathy due to KCNA5 loss-of-function mutation causes human atrial fibrillation

Journal article

Open access

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Kv1.5 channelopathy due to KCNA5 loss-of-function mutation causes human atrial fibrillation

Timothy M OLSON, Alexey E ALEKSEEV, Xiaoke K LIU, Sungjo PARK, Leonid V ZINGMAN, Martin BIENENGRAEBER, Srinivasan SATTIRAJU, Jeffrey D BALLEW, Arshad JAHANGIR and Andre TERZIC

Human molecular genetics, Vol.15(14), pp.2185-2191

2006

DOI: 10.1093/hmg/ddl143

PMID: 16772329

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Abstract

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.

Heart

Fundamental and applied biological sciences. Psychology

Cardiology. Vascular system

Cardiac dysrhythmias

Biological and medical sciences

Molecular and cellular biology

Genetics of eukaryotes. Biological and molecular evolution

Medical sciences

Details

Title: Subtitle: Kv1.5 channelopathy due to KCNA5 loss-of-function mutation causes human atrial fibrillation
Creators: Timothy M OLSON - Division of Cardiovascular Diseases, Department of Medicine, Mayo Clinic College of Medicine, Rochester, MN, United States
Alexey E ALEKSEEV - Division of Cardiovascular Diseases, Department of Medicine, Mayo Clinic College of Medicine, Rochester, MN, United States
Xiaoke K LIU - Division of Cardiovascular Diseases, Department of Medicine, Mayo Clinic College of Medicine, Rochester, MN, United States
Sungjo PARK - Division of Cardiovascular Diseases, Department of Medicine, Mayo Clinic College of Medicine, Rochester, MN, United States
Leonid V ZINGMAN - Division of Cardiovascular Diseases, Department of Medicine, Mayo Clinic College of Medicine, Rochester, MN, United States
Martin BIENENGRAEBER - Division of Cardiovascular Diseases, Department of Medicine, Mayo Clinic College of Medicine, Rochester, MN, United States
Srinivasan SATTIRAJU - Division of Cardiovascular Diseases, Department of Medicine, Mayo Clinic College of Medicine, Rochester, MN, United States
Jeffrey D BALLEW - Division of Cardiovascular Diseases, Department of Medicine, Mayo Clinic College of Medicine, Rochester, MN, United States
Arshad JAHANGIR - Division of Cardiovascular Diseases, Department of Medicine, Mayo Clinic College of Medicine, Rochester, MN, United States
Andre TERZIC - Division of Cardiovascular Diseases, Department of Medicine, Mayo Clinic College of Medicine, Rochester, MN, United States
Resource Type: Journal article
Publication Details: Human molecular genetics, Vol.15(14), pp.2185-2191
DOI: 10.1093/hmg/ddl143
PMID: 16772329
NLM abbreviation: Hum Mol Genet
ISSN: 0964-6906
eISSN: 1460-2083
Publisher: Oxford University Press
Language: English
Date published: 2006
Academic Unit: Internal Medicine
Record Identifier: 9984094484402771

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