Decreased Levels of BAG3 in a Family With a Rare Variant and in Idiopathic Dilated Cardiomyopathy

Abstract

The most common cause of dilated cardiomyopathy and heart failure (HF) is ischemic heart disease; however, in a third of all patients the cause remains undefined and patients are diagnosed as having idiopathic dilated cardiomyopathy (IDC). Recent studies suggest that many patients with IDC have a family history of HF and rare genetic variants in over 35 genes have been shown to be causative of disease. We employed whole-exome sequencing to identify the causative variant in a large family with autosomal dominant transmission of dilated cardiomyopathy. Sequencing and subsequent informatics revealed a novel 10-nucleotide deletion in the BCL2-associated athanogene 3 (BAG3) gene ((Ch10:del 121436332_12143641: del. 1266_1275 [NM 004281]) that segregated with all affected individuals. The deletion predicted a shift in the reading frame with the resultant deletion of 135 amino acids from the C-terminal end of the protein. Consistent with genetic variants in genes encoding other sarcomeric proteins there was a considerable amount of genetic heterogeneity in the affected family members. Interestingly, we also found that the levels of BAG3 protein were significantly reduced in the hearts from unrelated patients with end-stage HF undergoing cardiac transplantation when compared with non-failing controls. Diminished levels of BAG3 protein may be associated with both familial and non-familial forms of dilated cardiomyopathy.

Loss-of-function mutations in co-chaperone BAG3 destabilize small HSPs and cause cardiomyopathy

“…Decreased levels of BAG3 protein are found in failing human hearts (14). To ascertain whether failing mouse hearts, like their human counterparts, exhibit decreased BAG3, we performed Western blot analysis on cardiac tissue from 2 mouse models of cardiomyopathy.…”

“…While it is clear that mutations in BAG3 result in human cardiac myopathies (12)(13)(14)(15)(16)(17), little is known about the role of BAG3 in cardiomyocytes or the adult heart, or about the mechanisms by which the BAG3 E455K missense mutation leads to the progression of cardiomyopathy. The present study demonstrated an essential role of BAG3 in cardiomyocytes for the maintenance of normal heart function, with loss of BAG3 leading to DCM.…”

“…Mutations in the co-chaperone protein BCL-2-associated athanogene 3 (BAG3) are associated with cardiac myopathies (12)(13)(14)(15)(16)(17). A GWAS, involving multiple families with heart failure due to dilated cardiomyopathy (DCM), identified associated mutations in BAG3 (17).…”

“…Decreased levels of BAG3 have also been described in a family with idiopathic DCM and in unrelated patients with end-stage heart failure (14). BAG3 is a member of an evolutionarily conserved family of molecular co-chaperones (20) that interact with chaperones of the HSP family, including HSP70, to modulate their function (18,(21)(22)(23).…”

BAG3 plays a central role in proteostasis in the heart

“…Finally, BAG3 is downregulated in response to heart failure in both mice and humans, as well as in a subset of patients with idiopathic DCM (14,21). Although heart failure is often accompanied by attenuation of the PQC mechanisms and increased protein misfolding, it remains to be determined whether downregulation of BAG3 substantially contributes to decreased PQC during heart failure.…”