Presenting Author:

David Barefield, Ph.D.

Principal Investigator:

Elizabeth McNally, M.D.

Department:

Medicine

Keywords:

whole genome sequencing, cardiomyopathy, arrhythmia, gene discovery, myofilament, mouse model

Location:

Third Floor, Feinberg Pavilion, Northwestern Memorial Hospital

B27 - Basic Science

Novel myofilament component MYBPHL is implicated in arrhythmia and DCM

Cardiomyopathy is a leading cause of heart failure and is highly heritable. One common form is dilated cardiomyopathy (DCM), currently with over 70 genes that have been described as causative for the disease. Genetic testing for DCM employs gene panels and has a sensitivity of mutation detection less than 50%, indicating that additional genes contribute to disease. Here, we describe a proband with DCM and congenital heart block who succumbed to heart failure in the fourth decade of life. Living relatives also exhibit heart block and DCM. This family had previously undergone unrevealing genetic testing; therefore, we employed whole genome sequencing to identify causative genetic variation. We identified a premature stop codon in the MYBPHL gene as a likely cause of DCM in this family. This gene has not previously been studied or linked to disease. MYBPHL encodes myosin-binding protein-H like (MyBP-HL), which is structurally similar to myosin binding protein H (MyBP-H), a skeletal muscle protein, and myosin binding protein C (MyBP-C), which is well linked to cardiomyopathy. Here we characterize this novel protein and the role it plays in arrhythmia and cardiomyopathy. Gene expression from human and mouse hearts revealed that Mybphl is highly expressed in the atria, with lower expression in the ventricle and virtually no expression in skeletal muscle, opposite of the expression pattern of the closely related homolog Mybph. We established that MyBP-HL also interacts with the myofilament, confirming its similarity with the other myosin binding proteins. We determined that MyBP-HL is myofilament-associated in the atria, though not clearly so in ventricle, and the identified stop variant prevents myofilament incorporation. To assess the requirement of MyBP-HL for cardiac function, we investigated a Mybphl null mouse model. These mice have no overt histopathological defects or aberrant sarcomere structure; however, echocardiography measurements revealed a 30% reduction in fractional shortening and an increased diastolic ventricular chamber size, suggesting dilation and impaired contractility. Atria weight normalized to heart weight was increased in Mybphl heterozygous and null mice. Mybphl LacZ reporter staining shows robust atrial expression and discrete foci of LacZ positive cardiomyocytes in the right ventricular wall and the septum. Conscious ambulatory ECG recordings revealed conduction system abnormalities affecting atrioventricular conduction and an increased rate of arrhythmia in heterozygous and null mice; mirroring the abnormalities identified in the proband and affected relatives. Conclusions: WGS identified a premature stop codon in MYBPHL in human cardiomyopathy. A mouse model with a targeted insertion in the Mybphl gene showed similar pathophysiological features as the humans with reduced ventricular function and cardiac conduction system abnormalities. These findings suggest MyBP-HL is an important protein for normal cardiac function.