Gene defect may explain cardiac death

Studies found that mice lacking the protein iASPP had an irregular conductance in the right side of the heart - a condition known as arrhythmogenic right ventricular cardiomyopathy (ARVC).

The researchers also discovered that iASPP plays an important role in ’gluing’ individual heart muscle cells together.

“Our hearts are pumping every second of our lives so the heart is an organ that is under constant mechanical strain

Oxford University’s Xin Lu

The iASPP gene defect was shown to weaken desmosome function at the junctions of heart muscle cells - affecting the structural integrity of the heart, making the mice lacking iASPP prone to ARVC, the researchers said.

Further studies conducted using the human heart tissue of patients that had died from ARVC showed that some of them have similar defects in desmosomes as in the mice.

The Oxford team has suggested that the faulty iASPP gene in mice could be responsible for ARVC deaths in humans.

“We set out to investigate how this protein might cause cancer and found by chance that it could play a key role in this rare genetic heart condition,” said Xin Lu, director of the Ludwig Institute for Cancer Research at Oxford University.

“It took my [Doctor of Philosophy] student Mario Notari, the lead author of the study, over two years of further detective work, in collaboration with our colleagues in Oxford and London, to show how a single faulty gene can affect the function of desmosomes, one of the main structures that ’glue’ heart muscle cells together,” Lu said.

“Our studies suggest that these changes can threaten the structural integrity of the heart and predispose humans and animals to ARVC.”

Although 50% of human ARVC cases are related to known genetic defects in desmosomes, the cause of the other 50% of cases still remains unknown, the researchers said.

According to the researchers, this study could help determine the unexplained cases.

“Our hearts are pumping every second of our lives so the heart is an organ that is under constant mechanical strain. If you think of these desmosomes as ’gluey’ joints that hold heart cells together, any weaknesses or ’cracks’ that you introduce into these structures weaken the whole organ,” Lu said.

According to Lu, mice with the faulty gene controlling the protein, or that do not have sufficient amount of the protein to maintain the full function of desmosomes, “develop weaknesses in the right ventricle of their hearts at early stages such as embryos”.

“With time, the ’cracks’ get bigger and when they reach a certain level it leads to premature death in adults - and these are strikingly similar to the weaknesses we see in the tissues of human ARVC patients,” Lu said.

Further research is now needed to determine whether the gene controlling iASPP could be used to diagnose those at risk of developing ARVC.

A full account of the study has been published in the journal PNAS.