title: Kv1.5 channelopathy due to KCNA5 loss-of-function mutation causes human atrial fibrillation.
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.
authors.affiliation: Department of Medicine, Division of Cardiovascular Diseases, Mayo Clinic College of Medicine, Rochester, MN 55905, USA.
authors.forename: Timothy M
authors.initials: TM
authors.lastname: Olson
authors.forename: Alexey E
authors.initials: AE
authors.lastname: Alekseev
authors.forename: Xiaoke K
authors.initials: XK
authors.lastname: Liu
authors.forename: Sungjo
authors.initials: S
authors.lastname: Park
authors.forename: Leonid V
authors.initials: LV
authors.lastname: Zingman
authors.forename: Martin
authors.initials: M
authors.lastname: Bienengraeber
authors.forename: Srinivasan
authors.initials: S
authors.lastname: Sattiraju
authors.forename: Jeffrey D
authors.initials: JD
authors.lastname: Ballew
authors.forename: Arshad
authors.initials: A
authors.lastname: Jahangir
authors.forename: Andre
authors.initials: A
authors.lastname: Terzic
mesh_terms: D000818:Animals; D001281:Atrial Fibrillation / Q000209:etiology / Q000235:genetics* / Q000378:metabolism*; D001483:Base Sequence; D002460:Cell Line; D018389:Codon, Nonsense / Q000235:genetics; D004252:DNA Mutational Analysis; D005260:Female; D005799:Genes, Dominant; D006579:Heterozygote; D006801:Humans; D066298:In Vitro Techniques; D051666:Kv1.5 Potassium Channel / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D008297:Male; D051379:Mice; D008958:Models, Molecular; D032383:Myocytes, Cardiac / Q000378:metabolism; D018408:Patch-Clamp Techniques; D010375:Pedigree; D011994:Recombinant Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D012307:Risk Factors; D014162:Transfection
chemical_list: D018389:Codon, Nonsense; C496981:KCNA5 protein, human; D051666:Kv1.5 Potassium Channel; D011994:Recombinant Proteins