Identification of a novel causative gene for dilated cardiomyopathy requiring heart transplantation and elucidation of the mechanism of protein homeostasis in cardiomyocytes

Heart failure is an increasingly serious public health issue, affecting more than 37.7 million individuals worldwide. The prognosis of patients with heart failure is still poor, with 5-year survival rates of 45.5%, regardless of advanced medical therapy. Dilated cardiomyopathy (DCM) is a major cause of end-stage heart failure requiring heart transplantation. Identifying a novel causative gene for DCM and elucidating its molecular mechanisms could lead to new insight into the pathogenesis of heart failure. Using the combination approach of whole-exome sequencing and transcriptome analysis of failing hearts, we identified the BAG cochaperone 5 (BAG5) as a novel causative gene for juvenile-onset DCM requiring heart transplantation (Hakui et al. Science Translational Medicine. 2022). All the BAG5 homozygous truncating mutations disrupted the C-terminal functional BAG domain and disabled the protein folding activity of a molecular chaperone heat shock cognate 71 kDa protein. Immunocytochemical analysis revealed that BAG5 localized to the junctional membrane complex (JMC), a critical microdomain for calcium-handling in the heart. Moreover, cardiomyocytes isolated from BAG5 mutant knock-in mice showed specifically decreased JMC protein levels under cardiac stress, disrupted JMC structure, and calcium-handling abnormalities. Our findings highlight the involvement of JMC protein homeostasis in the pathogenesis of heart failure.