Background:
Cardiomyopathy is a leading cause of heart failure and is highly heritable. One common form of cardiomyopathy is dilated cardiomyopathy (DCM), which currently has over 70 identified 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 DCM. Here, we employed whole genome sequencing (WGS) in a family with DCM and heart block who had previously undergone unrevealing genetic testing. We identified a premature stop codon in the
MYBPHL
gene, a gene that has not previously been linked to DCM as a likely cause of DCM in this family. Myosin binding protein H Like (MyBP-HL) is a muscle-expressed protein bearing structural similarity to myosin binding protein C (MyBP-C), which is commonly mutated gene in cardiomyopathies.
Objective:
Determine the physiological and pathophysiological role of
Mybphl
.
Results:
RNA-seq and qPCR from mouse hearts revealed that
Mybphl
is highly expressed in the right and left atria with lower expression in the ventricle and virtually no expression in skeletal muscle. As MyBP-HL shares a high homology with the myofilament proteins cardiac myosin binding protein-C and H, we investigated if MyBP-HL is also myofilament-associated. We determined that MyBP-HL protein is myofilament-associated in the atria although not clearly so in ventricle. To assess the requirement of MyBP-HL in cardiac function, we used a mouse model with an insertional disruption of the
Mybphl
gene. These mice have deficits in
in vivo
cardiac function, with reduced fractional shortening. In addition, ECG recordings from the
Mybphl
null mice show conduction system abnormalities affecting atrioventricular conduction.
Conclusions:
WGS identified a premature stop codon in
MYBPHL
in human DCM. A mouse model with a disrupted
Mybphl
gene showed similar pathophysiological features as the humans with reduced ventricular function and cardiac conduction system abnormalities. MyBP-HL is an important protein for normal cardiac function.
Impact of Hypertrophic Cardiomyopathy Mutations and the Role of Myosin Binding Protein-C on the Sequestered State of Myosin
