Ultrafast sequencing shows defects in Titin protein
“We have gone from a walking pace to working at the speed of light,” says CSC Group Head Stuart Cook of a new gene sequencing technology his team has used to investigate heart disease. “…even twelve months ago it could have taken up to a year to analyse genes in one patient – in this study we could do this in two weeks.”
Cardiovascular disease kills more people than cancer every year. Dilated cardiomyopathy (DCM) – one of the leading causes of heart failure – affects more than 30,000 people in the UK. The condition leads to scarring of heart wall and damage to the muscle, with consequent enlargement that compromises effective pumping. Stuart Cook (Molecular Cardiology Group Head, MRC Clinical Sciences Centre) and collaborators have just discovered that defects in a protein called Titin are the leading cause of the disorder.
“We used to think it [DCM] was caused by a viral infection or by drinking too much,” explains Stuart, “but now we know that defects in the Titin gene account for 25% of cases of human dilated cardiomyopathy.” This more than doubles the number of cases for which a genetic cause can be identified and means that relatives can be effectively screened for the condition for the first time.
“The results will help us find new treatment targets for developing drugs for patients with heart failure,” says Stuart. A collaboration between researchers at the Royal Brompton in London and Harvard Medical School in the US, the study – published in The New England Journal of Medicine – looked at more than 300 patients. Using ultrafast next generation sequencing technology, the scientists uncovered new mutations in the gene.
Titin is the biggest protein in the body, spanning half the sarcomere and tethering it all together. Made from the Titin gene, as Stuart explains, “it’s so massive, it’s been difficult to test. There are so many possible mutations that can arise, so the difficulty has been to figuring out which ones might be causative.” His team at the CSC is collaborating with researchers in Europe and the US as part of a transatlantic network, supported by a $6 million Leducq award, which is using next-generation sequencing and animal models to uncover other potential causes.
Heart failure is not limited to humans. And neither is the Titin protein. Naturally occurring mutations occur in rodents that lead to heart failure. Knocking out the gene in mice generates a similar phenotype. And research on animal models including fish and fruit flies supports an increased understanding of the molecular mechanisms underlying heart failure. However, “most discovery has been done in humans,” reveals Stuart.
His research collaboration will use model organism data together with knowledge from human studies. “We’re going to do targeted re-sequencing of all genes that we think might be important in the human condition.” Once the gene candidates have been identified, model organisms will help to elucidate the molecular pathways in which these genes play out.
Current treatments for heart failure were actually developed several decades ago to treat high blood pressure. Examples include beta-blockers, angiotensin-receptor blockers and diuretics, but these are not specific to the causes of disease in individual patients. Physical interventions such as the pacemaker have been very effective, but they’re costly and not without risk. New approaches to genetic diagnostics are an extremely important development, since they offer the possibility of moving towards early prevention, which would give patients a much better prognosis and alleviate an enormous burden on the NHS. Screening for Titin defects could support better treatment plans for tens of thousands of patients in the UK.
BM
Reference:
Herman, D. S., Lam, L., Taylor, M. R. G., Wang, L., Teekakirikul, P., Christodoulou, D., Conner, L., DePalma, S. R., McDonough, B., Sparks, E., Teodorescu, D. L., Cirino, A. L., Banner, N. R., Pennell, D. J., Graw, S., Merlo, M., Di Lenarda, A., Sinagra, G., Bos, J. M., Ackerman, M. J., Mitchell, R. N., Murry, C. E., Lakdawala, N. K., Ho, C. Y., Barton, P. J. R., Cook, S. A., Mestroni, L., Seidman, J. G., Seidman, C. E. (2012). Truncations of titin causing dilated cardiomyopathy. New England Journal of Medicine 366, 619–628.
http://dx.doi.org/10.1056/NEJMoa1110186
