Faculty Collaboration Database

Kv1.5 channelopathy due to KCNA5 loss-of-function mutation causes human atrial fibrillation. Hum Mol Genet 2006 Jul 15;15(14):2185-91

Date

06/15/2006

Pubmed ID

16772329

DOI

10.1093/hmg/ddl143

Scopus ID

2-s2.0-33745635351 (requires institutional sign-in at Scopus site)   429 Citations

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 I(Kur) 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.

Author List

Olson TM, Alekseev AE, Liu XK, Park S, Zingman LV, Bienengraeber M, Sattiraju S, Ballew JD, Jahangir A, Terzic A

MESH terms used to index this publication - Major topics in bold

Animals
Atrial Fibrillation
Base Sequence
Cell Line
Codon, Nonsense
DNA Mutational Analysis
Female
Genes, Dominant
Heterozygote
Humans
In Vitro Techniques
Kv1.5 Potassium Channel
Male
Mice
Models, Molecular
Myocytes, Cardiac
Patch-Clamp Techniques
Pedigree
Recombinant Proteins
Risk Factors
Transfection