Physicians' Academy for Cardiovascular Education

Mutation in myosin gene explains early-onset atrial fibrillation

Gudbjartsson et al. en Nattel, Eur Heart J, 2016

A loss-of-function mutation in the myosin gene MYL4 has been identified that, in the homozygous state, is completely penetrant for early-onset AF.
In up to 30% of AF cases, no predisposing condition can be identified. In particular, in early-onset AF, familial clustering is recognised. Previous studies have described 33 rare variants and 14 genetic loci associated with AF. Most of the rare variants are located in ion-channel subunits and transcription factors.
 
Using whole-genome sequencing in a population approach in 8453 Icelanders, Gudbjartsson et al. set out to identify sequence variants linked to early onset AF in 1799 patients who received a diagnosis before 60 years of age (and not present in 337453 controls). They found a rare frameshift deletion in the atrial myosin light-chain gene MYL4 (c.234delC) that associated with early onset AF in recessive inheritance models. This mutation leads to truncation of the encoded protein.
 
Eight homozygous carriers of the variant had early onset AF (six had received the diagnosis by the age of 30, two in their fifties), three required pacemakers for sick sinus syndrome, three suffered strokes in the absence of non-AF-risk factors, and one suffered from sudden death.
Early echocardiograms only showed left atrial dilation in two patients, while late echocardiograms showed disease progression with left atrial enlargement in all, mild ventricular dilation in 4/6 persons and reduced ejection fraction in 2. These findings point to atrial-selective abnormalities associated with conduction-system disease, stroke and eventually mild ventricular dysfunction. Thus an MYL4 mutation appear to represent a newly discovered cause of atrial cardiomyopathy.
 
Nattel speculates about the meaning of these findings. MYL4 encodes for a myosin light chain protein, which, together with the myosin heavy chain are a major component of the sarcomere, that regulates contractile function. While in utero both atrial and ventricular MYL4 expression is seen, in adults MYL4 is normally only expressed in atria. It is, however, detected in ventricles in adults with ventricular dysfunction, often in association with congenital heart disease. Expression of MYL4 has been described to enhance cardiomyocyte contractile properties. The only in vivo studies to date on MYL4 function have been performed in zebrafish, in which loss-of-function of the orthologue of MYL4 resulted in absence of sarcomere function and loss of cardiac contractility.
 
A family has recently been described in which several members had early onset AF, and carried an MYL4 mutation. Affected family members showed depressed atrial contractile function, and evidence of conduction system disease. Large atrial areas of electrical silence were noted and P-wave amplitude became very small prior to AF onset.
These insights reinforce the concept of atrial cardiomyopathy as an underlying pathophysiological mechanism in AF.
 
The atrial-specific contractile function of the MYL4-protein can explain the atrial mechanistic abnormalities in mutation carriers, but the origin of the electrophysiological aberrations is unclear. MYL4 dysfunction is not expected to disrupt ventricular function, and indeed, if seen at all, ventricular dysfunction is a mild and late manifestation in MYL4 mutation carriers. This suggests that the electrical aberrations result from primary atrial contractile dysfunction, rather than that they occur secondary to heart failure. Through affecting atrial cardiomyocyte ultrastructure, and possibly through disrupting the integrity of the macromolecular Z-disk structures, MYL4 dysfunction may ultimately affect electrical function.
 
Discoveries like the role of MYL4 dysfunction in AF have the potential to advance risk prediction, prevention and management. The MYL4 atrial cardiomyopathy is an interesting example of how an electrical dysfunction resulting from a primary abnormality in the contractile apparatus affects cardiac physiology.
 

Sources

A frameshift deletion in the sarcomere gene MYL4 causes early-onset familial atrial fibrillation
Gudbjartsson DF, Holm H, Sulem P, et al., Eur Heart J published 14 October 2016, DOI: http://dx.doi.org/10.1093/eurheartj/ehw379 ehw379
 
Close connections between contraction and rhythm: a new genetic cause of atrial fibrillation/cardiomyopathy and what it can teach us
Nattel S. Eur Heart J published 23 October 2016, 10.1093/eurheartj/ehw457