Researchers at Osaka University in Japan have identified specific genetic mutations that can cause dilated cardiomyopathy (DCM).
In an article published in Science Translational Medicine entitled “Loss-of-function mutations in the co-chaperone protein BAG5 cause dilated cardiomyopathy (DCM) requiring heart transplantation,” Hideyuki Hakui, a member of the Osaka University Department of Cardiovascular Medicine, and his colleagues found through whole-genome sequencing that loss-of-function mutations in the gene encoding BAG5 caused DCM with complete penetrance.
These findings are important, as DCM is the leading cause of heart failure, affects 1 in 2,500 individuals, and has no known cure. The majority of DCM inheritance is through an autosomal dominant pattern; however, other inheritance patterns have been identified, such as autosomal recessive, X-linked, and mitochondrial. These new findings are promising for the development of therapies, including gene therapy, as a treatment for this disease.
BAG5, or BAG Cochaperone 5, plays a crucial role in maintaining proteostasis at junctional membrane complexes (JMCs). By comparing transcriptional changes in heart tissue samples from five patients with DCM, the Japanese researchers found that “rare homozygous truncating variants were detected in 15 genes.” But multiple variants were identified only in the BAG5 gene, inherited in a recessive fashion.
They go on to observe that “five patients carrying homozygous BAG5 truncating variants all developed life-threatening DCM.” As DCM requires a heart transplantation for survival, the researchers analyzed the removed diseased hearts of the affected individuals: they concluded that “BAG5 protein expression was not observed in the heart tissue obtained during heart transplantation from the affected individual.”
Adequate proteostasis, or protein homeostasis, is essential for maintaining a healthy heart. Mutations in BAG5 disrupt proteostasis by disrupting co-chaperone activity. The HSP70 and HSC70 genes are important for proteostasis, as they ensure correct protein folding and refolding of misfolded proteins. BAG5 functions as a nucleotide exchange factor for HSP70 and HSC70; consequently, a loss-of-function mutation in BAG5 disrupts this interaction, inhibiting proteostasis.
The Osaka researchers found that “all of the identified BAG5 truncating mutations caused loss-of-function as a co-chaperone for HSC70 in the heart.” The inhibition of HSC70 to act as a ubiquitous molecular chaperone resulting from loss-of-function mutations in BAG5 explains a biological mechanism of DCM.
Aside from disrupting proteostasis, loss-of-function mutations in BAG5 were also found to “disturb transverse tubule morphology and perturb calcium handling in mouse cardiomyocytes” by impairing JMCs. Impaired JMCs—specialized membrane contact sites between the sarcoplasmic reticulum and T-tubules critical for calcium handling—cause abnormal T-tubule structure. These T-tubules, or transverse tubules, are responsible for cardiac muscle cell contraction. T-tubule alterations are common features of heart failure, and the researchers conclude that “upregulation of BAG5 gene expression in failing hearts could be a compensatory mechanism to maintain JMC proteostasis.”
The researchers modeled the effected of these mutations in knock-in mice. When the BAG5 gene was mutated in these animal models, the researchers found that a promotion of the interaction of HSC70 and the JMC protein did not occur. This suggests that “JMC protein changes could be the cause of heart failure in knock-in mice.” Moreover, the impairment of the JMC protein was associated with changes in calcium dynamics, confirmed by the staining of cardiomyocytes in the knock-in mice, specifically decreasing interactions between JMC protein JPH2 and voltage-dependent L-type calcium channels.
Although many of the underlying biological causes of DCM remain unknown, this study reveals a crucial genetic mutation responsible for DCM. These findings allow for a foundation for preventative and corrective treatment. The researchers conclude that genetic testing for BAG5 variants “could be beneficial for clinical risk stratification in DCM”. They also believe that “BAG5/HSC70-mediated proteostasis at JMCs could be a future target for the treatment of heart failure.” The extension of treatment from current small-molecule treatments to targeted gene therapy can potentially save the life of individuals who recessively inherit DCM from gene mutations on BAG5.