Kv1.5 Channelopathy Due to KCNA5 Loss-Of-Function Mutation Causes Human Atrial Fibrillation

Hum Mol Genet. 2006 Jul 15;15(14):2185-91. doi: 10.1093/hmg/ddl143. Epub 2006 Jun 13.

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.

Publication types

  • Case Reports
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

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

Substances

  • Codon, Nonsense
  • KCNA5 protein, human
  • Kv1.5 Potassium Channel
  • Recombinant Proteins