Abstract
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.
