Gain-of-function mutation of Nav1.5 in atrial fibrillation enhances cellular excitability and lowers the threshold for action potential firing

A Contemporary Review on the Genetic Basis of Atrial Fibrillation

“…a second study from our group involving a mother and son with lone af identified a lys1493arg mutation involving a highly conserved residue within the diii-iv linker located 6 amino acids downstream from the fast inactivation motif of sodium channels. 46 Biophysical studies demonstrated a significant positive shift in the voltage dependence of inactivation and a large ramp current near resting membrane potential, consistent with a gain of function. When expressed in hl-1 atrial cardiomyocytes, enhanced cellular excitability was observed in the form of spontaneous action potential depolarizations and a lower threshold for action potential firing as compared to wild-type cells.…”

“…the depolarizing shift in steady-state inactivation increases the probability that the channel will be in the open conformation and capable of conducting current. 46 this alteration in the gating of the nav1.5-mediated current will presumably result in a predisposition for cells to reach threshold potential and fire, consistent with enhanced automaticity. this increase in focal discharges has the potential to serve as the trigger for af.…”

Genetic Discoveries in Atrial Fibrillation and Implications for Clinical Practice

“…Both gain-of-function and loss-of-function mutations in genes encoding potassium and sodium channel subunits have been reported to underlie familial AF. [2][3][4][5][6][7][8][9][11][12][13]25,26,[29][30][31]43 Gain-offunction potassium channel mutations are predicted to influence AF by shortening the atrial effective refractory period, an effect that would be predicted to promote atrial re-entry. 44 Loss-of-function potassium channel mutations are predicted to promote triggered activity in the atrium, which is also an important contributor to the genesis of AF.…”

“…8 Gain-of-function sodium channel mutations are predicted to promote triggered activity. 25 Loss-of-function sodium channel mutations are predicted to shorten the wavelength of an impulse circulating around a re-entry circuit. 45 The potential mechanistic links between non-ion channel mutations and AF pathogenesis are less clearly understood.…”

Differentiation of Human Atrial Myocytes From Endothelial Progenitor Cell-Derived Induced Pluripotent Stem Cells

“…In recent years, familial forms of atrial fibrillation have been explored using sophisticated molecular approaches. One such study demonstrated a causative role mutation in the potassium channels responsible for the slow re-polarization of atrial myocytes (KCNQ1, KCNE2, KCNJ2) [320][321][322]. However, the vast majority of atrial fibrillation is sporadic and non-familial.…”