MYH7B variants cause hypertrophic cardiomyopathy by activating the Ca MK-signaling pathway

摘要

Hypertrophic cardiomyopathy(HCM) is a common genetic disease, predominantly caused by mutations in cardiac sarcomere genes;however, whether MYH7 B causes HCM is not known. In this study, 549 unrelated patients with HCM and 500 healthycontrols were screened using targeted sequencing and whole exome sequencing together. We observed seven variants in MYH7 B causing HCM in 8/549 patients, which accounted for 1.46% of HCM cases. Of these seven variants, three likely pathogenic variants in MYH7 B co-segregating with 5 HCM patients were identified in three HCM pedigrees without other HCM-associated variants. Myh7 b knockout rats were generated and cardiac functions were detected by Millar pressure-volume catheterization and echocardiography. Spontaneous HCM phenotypes, cellular disarray and cardiac fibrosis were observed in both Myh7 b^+/–/Myh7 b^–/–rats. Transcriptome sequencing showed that calcium is the key mediator of cardiac hypertrophy in Myh7 b knockout. Subsequent analysis confirmed over-activation of Ca MK-signaling pathway in cardiomyocytes of Myh7 b^–/–rats.Furthermore, MYH7 B expression in human and rat hearts was identified and micro RNA-208 a and micro RNA-499 levels are unchanged in HCM patients and Myh7 b^+/–/Myh7 b^–/–rats. This study is the first to identify MYH7 B variants as cause of HCM,which account for 1.46% of pathogenesisin HCM patients. Activation of Ca MK-signaling pathway may be involved in its pathophysiology.