There is a serious heart condition referred to as dilated cardiomyopathy (DCM) that is a major cause of heart failure and often results in premature death; this disease is found in one in two-hundred and fifty adults (0.4%). DCM can originate either as a result of an underlying vascular problem or can have a genetic origin. This report will focus on the progress that has been made in regards to the genetic implications of this condition.
Through the work of Dr. John T. Hinson at the Division of Cardiovascular Medicine at the Brigham and Women’s Hospital, Boston MA and his colleagues from many diverse institutions, it has been show that mutations of a large protein that constitutes one-half of the sarcomere (a structural unit of a myofibril in striated muscle) are the most common cause for DCM. This protein is referred to as titin (TTN) (see image below) and the mutations involved result in a truncated version of TTN. These genetic variants of TTN are referred to as TTN-truncating variants (TTNtvs).
Since the functional significance of TTN within the muscle sarcomere was unclear, the investigators involved in this research, applied the tools of molecular biology to better define the role played by TTN within heart muscle. To accomplish this, they grew out cardiac micro-tissue cultures comprised of cardiomyocytes derived from pluripotent stem cells (iPS) that were harvested from the patients studied. When these patient-derived cells were compared to those derived from normal individuals (the controls), it was discovered that, “certain missense mutations like TTNtvs diminish contractile performance and are pathogenic.”
Furthermore, these patient-derived cardiomyocytes also demonstrated sarcomere insufficiency, reduced responses to mechanical and biochemical stress as well as impairment in critical cell signaling pathways. All of these results, when taken together, point to TTNtvs as playing a causative role in genetically-induced DCM. This is a significant finding with broad implications.