Novel mutation implicated in familial AF

10 October 2008

MedWire News: Japanese researchers have identified a novel genetic mutation in the cardiac sodium channel that can give rise to familial atrial fibrillation (AF).

The gain-of-function mutation in the SCN5A gene was found to cause increased atrial excitability in patients without underlying structural heart disease, thereby representing a novel pathogenic mechanism underlying AF.

The research, by Takeru Makiyama (Kyoto University) and colleagues, centered on a Japanese family with autosomal dominant hereditary AF that spanned three generations.

Seven family members presented with AF or frequent premature atrial contraction (PAC) in the absence of structural heart disease. The affected members had a remarkably similar clinical course, the authors comment, exhibiting recurrent atrial arrhythmias that were resistant to ablation or drug therapy.

Mutational analysis of the proband identified a novel missense mutation, M1875T, in the Na+ channel gene SCN5A, which was subsequently identified in all affected family members.

Functional studies revealed a distinct gain-of-function type modulation characterized by a +16.4 mV shift in the steady-state inactivation. “This is, to the best of our knowledge, the greatest depolarization shift in all of the previously reported SCN5A mutants,” remark Makiyama et al.

The researchers propose various mechanisms by which the novel mutation might lead to PAC or AF. However they are unable to explain why the SCN5A mutant is associated with atrial but not ventricular arrhythmias, given that Na+ channels encoded by SCN5A are expressed in both chambers of the heart.

Writing in the Journal of the American College of Cardiology, they conclude: “We identified a novel SCN5A gain-of-function mutation that causes a familial form of AF without any underlying structural heart diseases, which provides us with new insight into the pathogenesis of the commonly occurring form of AF.”

J Am Coll Cardiol 2008; 52: 1326–1334