Protein clue to sudden cardiac death
A protein has been shown to have a surprising role in regulating the ‘glue’ that holds heart cells together, a finding that may explain how a gene defect could cause sudden cardiac death.
A team led by Oxford University researchers was looking at how a protein, iASPP, might be involved in the growth of tumours. However, serendipitously they found that mice lacking this gene died prematurely of sudden cardiac death. More detailed investigations showed that these mice had an irregular conductance in the right side of the heart, a condition known as arrhythmogenic right ventricular cardiomyopathy (ARVC).
The researchers discovered that iASPP had a previously unknown role in controlling desmosomes – one of the main structures that ‘glue’ individual heart muscle cells (cardiomyocytes) together. The genetic defect was shown to weaken desmosome function at the junctions of heart muscle cells: this affected the structural integrity of the heart, making mice lacking iASPP prone to ARVC.
Further studies of heart tissue from human patients who had died from ARVC showed that some of them have similar defects in desmosomes as in the mice suggesting that the faulty iASPP gene could also be responsible for ARVC deaths in humans. This finding also explains why a previously reported cattle herd with spontaneous iASPP gene deletion died of sudden cardiac death.
‘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 Professor Xin Lu, Director of the Ludwig Institute for Cancer Research at Oxford University, the lead investigator of the report. ‘It took my DPhil 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. Our studies suggest that these changes can threaten the structural integrity of the heart and predispose humans and animals to AVRC.’
ARVC is uncommon in humans, affecting around 1 in 2000 people in the UK [1], and is a leading cause of sudden cardiac death, which is estimated to kill around 100,000 people a year in the UK [2]. Whilst approximately 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 new study suggests that mutations in the gene encoding the iASPP protein may contribute to the development of ARVC in these previously-unexplained cases. University of Oxford
