Myosin-binding protein H-like
myofilament
Experimental Modeling Supports a Role for MyBP-HL as a Novel Myofilament Component in Arrhythmia and Dilated Cardiomyopathy.
<h4>Background</h4>Cardiomyopathy and arrhythmias are under significant genetic influence. Here, we studied a family with dilated cardiomyopathy and associated conduction system disease in whom prior clinical cardiac gene panel testing was unrevealing.<h4>Methods</h4>Whole-genome sequencing and induced pluripotent stem cells were used to examine a family with dilated cardiomyopathy and atrial and ventricular arrhythmias. We also characterized a mouse model with heterozygous and homozygous deletion of <i>Mybphl</i>.<h4>Results</h4>Whole-genome sequencing identified a premature stop codon, R255X, in the <i>MYBPHL</i> gene encoding MyBP-HL (myosin-binding protein-H like), a novel member of the myosin-binding protein family. <i>MYBPHL</i> was found to have high atrial expression with low ventricular expression. We determined that MyBP-HL protein was myofilament associated in the atria, and truncated MyBP-HL protein failed to incorporate into the myofilament. Human cell modeling demonstrated reduced expression from the mutant <i>MYBPHL</i> allele. Echocardiography of <i>Mybphl</i> heterozygous and null mouse hearts exhibited a 36% reduction in fractional shortening and an increased diastolic ventricular chamber size. Atria weight normalized to total heart weight was significantly increased in <i>Mybphl</i> heterozygous and null mice. Using a reporter system, we detected robust expression of <i>Mybphl</i> in the atria, and in discrete puncta throughout the right ventricular wall and septum, as well. Telemetric electrocardiogram recordings in <i>Mybphl</i> mice revealed cardiac conduction system abnormalities with aberrant atrioventricular conduction and an increased rate of arrhythmia in heterozygous and null mice.<h4>Conclusions</h4>The findings of reduced ventricular function and conduction system defects in <i>Mybphl</i> mice support that <i>MYBPHL</i> truncations may increase risk for human arrhythmias and cardiomyopathy.