Skip to main content
Premium Trial:

Request an Annual Quote

Dilated Cardiomyopathy Gene Mutations Point to Possible Therapeutic Strategy

NEW YORK – A team from Japan has detected loss-of-function mutations in a gene involved in protein homeostasis that appear to contribute to juvenile-onset forms of dilated cardiomyopathy, a heart condition affecting ventricular dilation and systolic dysfunction that can lead to heart failure and the need for a heart transplant.

"Familial DCM is reportedly caused by mutations in more than 50 genes, requiring a precise disease stratification based on genetic information," senior and corresponding author Yoshihiro Asano, a cardiovascular medicine researcher at the Osaka University, and his co-authors explained in Science Translational Medicine on Wednesday, reasoning that "[i]dentifying the further genetic causes of DCM could improve the utility of genetic testing and might lead to new insights into the pathogenesis of heart failure."

As part of the "Genome registry and stratification of cardiovascular disease" (GRAND-STAR) study, the researchers searched for new contributors to inherited DCM, including mutations in genes associated with heart sarcomeres, cytoskeleton, and other structures.

Along with genetic clues found in exome sequence data for more than 1,800 individuals represented in the GRAND-STAR database, they used RNA sequencing to profile transcriptional features in heart tissue samples from three inherited DCM patients and as many unaffected controls.

By focusing on genes containing rare variants that were upregulated in DCM cases with heart failure, the team identified five individuals with severe DCM from four families who carried truncating, loss-of-function mutations affecting both copies of the BAG5 gene, which codes for a heat shock cognate (HSC70) protein nucleotide exchange factor from the Bd-2-associated athanogene, or BAG, protein family.

In mouse model experiments, the group saw signs that the introduction of BAG5 alterations stymied HSC70 activation — a process previously linked to protein homeostasis, or proteostasis — and led to DCM-like symptoms in the mice.

The researchers were able to reverse such features by treating the mutant mice with adeno-associated virus serotype 9, or AAV9, viral vectors containing a wild-type version of BAG5 and a cardiac troponin T promoter. Based on such findings, they suggested that gene therapy strategies may eventually preclude the need for heart transplantation in a subset of inherited DCM patients with mutations that lop out BAG5.

"[W]e demonstrated that BAG5 mutations led to loss of functional BAG5 protein, which could be restored through administration of an AAV9-BAG5 vector in a murine model," the authors reported. "This finding suggests that AAV gene therapy should be further investigated as a possible treatment alternative to heart transplantation for patients who are BAG5 deficient."

The researchers noted that hereditary DCM stems from autosomal recessive inheritance of the BAG5 mutations. Even so, they tracked down truncating mutations affecting one copy of the BAG5 gene in three individuals with a reversible DCM subtype called tachycardia-induced cardiomyopathy. The results hinted that heterozygous BAG5 alterations may contribute to TIC, though they cautioned that "the effect of BAG5 mutations on TIC needs to be analyzed in larger groups of patients."

The Scan

Call for a Different Tack

Experts weigh the value of recent experiments testing genetically modified pig kidneys using brain-dead individuals, according to Nature News.

Wastewater Warning

The New York Times reports that wastewater surveillance in some parts of the US point to a possible surge.

Can't Get in the Program

Due to the Northern Ireland protocol dispute, the European Union is preventing UK researchers from joining the Horizon Europe research program, the Times of London reports.

Science Paper on Spatial-Controlled Genome Editing

In Science this week: approach to enable a CRISPR-Cas13a-based system to be used as a cancer therapy.