Novel KCNA5 mutation implicates tyrosine kinase signaling in human atrial fibrillation

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 ∼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.