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Heart Rhythm. 2010 Sep;7(9):1246-52. doi: 10.1016/j.hrthm.2010.05.032. Epub 2010 Jun 1.

Novel KCNA5 mutation implicates tyrosine kinase signaling in human atrial fibrillation.

Author information

1
Department of Medicine, Vanderbilt University School of Medicine, Nashville, Tennessee 37323-6602, USA.

Abstract

BACKGROUND:

Emerging evidence has strongly implicated hereditary determinants for atrial fibrillation (AF). Loss-of-function mutations in KCNA5 encoding the ultrarapid delayed rectifier potassium current I(Kur) have been identified in AF families.

OBJECTIVE:

The purpose of this study was to determine the clinical and biophysical phenotypes in a KCNA5 mutation with deletion of 11 amino acids in the N-terminus of the protein, which was identified in patients with lone AF.

METHODS:

Patients with AF confirmed by ECG were prospectively enrolled in the Vanderbilt AF Registry, which comprises clinical and genetic databases. A KCNA5 mutation was generated by mutagenesis for electrophysiologic characterization.

RESULTS:

We identified a novel 33-bp coding region deletion in two Caucasian probands. One proband was part of a kindred that included four other members with AF, and all were mutation carriers. The mutation results in deletion of 11 amino acids in the N-terminus of the protein, a proline-rich region as a binding site for Src homology 3 (SH3) domains associated with Src-family protein tyrosine kinase (TK) pathway. In transfected cells, the mutant caused approximately 60% decreased I(Kur) versus wild-type (WT) (75 +/- 8 pA/pF vs 180 +/- 15 pA/pF, P <.01) and dominant-negative effect on WT current (105 +/- 10 pA/pF, P <.01). Pretreatment with the Src inhibitor PP2 prevented v-Src TK from 90% suppressed WT current. In contrast, the mutant channel displayed no response to v-Src TK.

CONCLUSION:

Our data implicate abnormal atrial repolarization control due to variable TK signaling as a mechanism in familial AF and thereby suggest a role for modulation of this pathway in AF and its treatment.

KEYWORDS:

KCNA5 channel; familial atrial fibrillation; genetics; tyrosine kinase; variants

PMID:
20638934
PMCID:
PMC2932792
DOI:
10.1016/j.hrthm.2010.05.032
[Indexed for MEDLINE]
Free PMC Article
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