How the giant protein titin causes cardiomyopathy

Dissecting disease pathways in a mouse model of titin-related cardiomyopathy

Dr Katja Gehmlich and her colleagues at the University of Oxford are trying to find out how a faulty gene leads to an inherited heart condition called dilated cardiomyopathy, where the heart enlarges and cannot pump effectively. Dr Gehmlich’s team has discovered that a family with dilated cardiomyopathy has a fault in a gene encoding the largest human protein titin. Normally, this protein acts as a molecular ‘spring’ in the contracting units of the heart muscle. Dr Gehmlich believes the gene fault interferes with the front end of the protein, mainly affecting how the titin spring responds to stretch (when the heart gets filled with blood). The fault could also make the titin spring more fragile. In this project, Dr Gehmlich will study a mouse with a gene fault that mimics the faulty human titin gene to find out more about the disease. She will observe how the heart of these mice develops reduced pumping capacity, and which functions of the titin spring and associated proteins are faulty in these mice. This research will help to understand how this particular gene fault causes cardiomyopathy and how the titin spring works in the healthy heart. Results from this study could help to develop new treatments for cardiomyopathy in the future.