Experimental Modeling Supports a Role for MyBP-HL as a Novel Myofilament Component in Arrhythmia and Dilated Cardiomyopathy

• DOI: 10.1161/circulationaha.117.028585
• Publication Date: 2017-08-05T00:40:23Z
• Authors: David Y. Barefield; Megan J. Puckelwartz; Ellis Y. Kim; Lisa D. Wilsbacher; Andy H. Vo; Emily A. Waters; Judy U. Earley; Michele Hadhazy; Lisa Dellefave-Ca...; Lorenzo L. Pesce; Elizabeth M. McNally
• Keywords: Myofilament; Dilated Cardiomyopathy; Component (thermodynamics)

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