In a study published in the journal Science Translational Medicine, researchers from Osaka University showed that a previously unknown mutation can lead to a condition called dilated cardiomyopathy, which is one of the main causes of heart failure.
Heart failure refers to an incurable condition where the heart is no longer able to meet the body’s demands in terms of blood supply. It is one of the most common causes of death and affects almost 40 million people worldwide, representing a huge public health problem. One of the leading factors leading to heart failure is a disease called dilated cardiomyopathy (DCM). It is characterised by dilation of the heart’s chambers and a pumping disfunction. Previous research has shown that DCM is often inherited and has a genetic basis.
The research team identified a gene called BAG5 as a novel causative gene for DCM. First, they studied patients from different families, highlighting a correlation between loss of function mutations in the BAG5 gene and DCM. They found that the mutation has a complete penetrance, meaning that 100 per cent of the individuals presenting it will develop the disease.
They then found in a mouse model of dilated cardiomyopathy that mice without BAG5 exhibited the same symptoms of human DCM, such as dilatation of the heart's chambers and irregular heart rhythm. This indicated that mutations that erase the function of BAG5 can cause cardiomyopathy.
“Here we showed that loss of BAG5 perturbs calcium handling in mouse cardiomyocytes,” said Dr. Hideyuki Hakui, lead author of the study. BAG5 is important for calcium handling in the heart muscle cells, and calcium is essential for a regular rhythm and overall health of the cardiac muscle, explaining why a loss of BAG5 leads to cardiomyopathy.
Senior author of the study Dr. Yoshihiro Asian said, “After demonstrating that BAG5 mutations led to loss of functional BAG5 protein. We also showed that the administration of an AAV9-BAG5 vector in a murine model could restore cardiac function. This finding suggests that gene therapy with adeno-associated viruses (AAV) should be further investigated as a possible treatment alternative to heart transplantation for patients who are BAG5 deficient.”
