Abstract
Atrial fibrillation (AF), the most common arrhythmia, is a growing epidemic with substantial morbidity and economic burden. Mechanisms underlying vulnerability to AF remain poorly understood, which contributes to the current lack of highly effective therapies. Recognizing mechanistic subtypes of AF may guide an individualized approach to patient management. Here, we describe a family with a previously unreported syndrome characterized by early-onset AF (age <35 years), conduction disease and signs of a primary atrial myopathy. Phenotypic penetrance was complete in all mutation carriers, although complete disease expressivity appears to be age-dependent. We show that this syndrome is caused by a novel, heterozygous p.Glu11Lys mutation in the atrial-specific myosin light chain gene MYL4. In zebrafish, mutant MYL4 leads to disruption of sarcomeric structure, atrial enlargement and electrical abnormalities associated with human AF. These findings describe the cause of a rare subtype of AF due to a primary, atrial-specific sarcomeric defect.
Highlights
Atrial fibrillation (AF), the most common arrhythmia, is a growing epidemic with substantial morbidity and economic burden
Only a single non-ion channel gene has been identified as a cause of a primary atrial arrhythmia syndrome[7]
We created a zebrafish model expressing the putative mutation, and show that zebrafish harbouring the mutation exhibit a phenotype characteristic of an atrial-specific cardiomyopathy and electrical abnormalities consistent with human AF
Summary
Atrial fibrillation (AF), the most common arrhythmia, is a growing epidemic with substantial morbidity and economic burden. Phenotypic penetrance was complete in all mutation carriers, complete disease expressivity appears to be age-dependent We show that this syndrome is caused by a novel, heterozygous p.Glu11Lys mutation in the atrial-specific myosin light chain gene MYL4. Considerable overlap exists in ion channel genes responsible for causing arrhythmia syndromes, with genetic defects in potassium, sodium and gap junction channel genes recognized to cause episodic arrhythmias arising from either the ventricular or atrial cardiac chambers or both[6]. These channel defects alter the action potential properties or intercellular electrical communication, promoting arrhythmia vulnerability. Genetic diseases of the cardiac sarcomere are known to lead to ventricular cardiomyopathy and associated arrhythmia[8], a primary atrial-specific inherited myopathy presenting as an atrial arrhythmia has never previously been described
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