How do alterations in the giant protein titin increase the risk of sudden death?

A comprehensive approach to the genetic, molecular and functional impact of rare titin variants in hypertrophic cardiomyopathy

Inherited heart muscle diseases, or cardiomyopathies, are frequent causes of heart failure and sudden cardiac death in adults and children. One heart muscle disease, hypertrophic cardiomyopathy (HCM), is often caused by faults in the genetic instruction manual for making sarcomeres – a part of the heart muscle that helps it to contract. Recently scientists found that alterations in the gene that instructs production of a large protein called titin cause several different inherited heart muscle diseases in children and adults. But because titin is so large, genetic testing is not very accurate – it identifies a large number of genetic variations, but not all of them cause disease. We need to correctly identify the genetic variations that cause disease to give an accurate clinical diagnosis. In this project BHF Professor Mathias Gautel is working out how genetic alterations affect titin’s protein structure and function, and how this affects disease progression and the outcomes for people with hypertrophic cardiomyopathy. He will create a new web-based database to show the impact of newly identified titin mutations that is publicly accessible, and that enables clinical geneticists to predict the likely impact of existing or new titin mutations on people. By understanding more about these alterations in titin, this work could ultimately help doctors give more personalised treatment to people with HCM.