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 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.


CONCLUSIONS
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.
Yang
Tao
T
Department of Medicine, Vanderbilt University School of Medicine, Nashville, Tennessee 37323-6602, USA.
Yang
Ping
P
Roden
Dan M
DM
Darbar
Dawood
D
D000293:Adolescent; D000328:Adult; D001281:Atrial Fibrillation / Q000201:enzymology / Q000235:genetics* / Q000503:physiopathology; D004247:DNA / Q000235:genetics*; D004562:Electrocardiography; D005260:Female; D005500:Follow-Up Studies; D020022:Genetic Predisposition to Disease; D006801:Humans; D051666:Kv1.5 Potassium Channel / Q000235:genetics*; D008297:Male; D009154:Mutation; D018408:Patch-Clamp Techniques; D010375:Pedigree; D016133:Polymerase Chain Reaction; D011446:Prospective Studies; D011505:Protein-Tyrosine Kinases / Q000378:metabolism*; D015398:Signal Transduction; D055815:Young Adult
C496981:KCNA5 protein, human; D051666:Kv1.5 Potassium Channel; D004247:DNA; D011505:Protein-Tyrosine Kinases