Study Identifies Strong Link Between Gene Mutation and Cardiomyopathy
By Michael Stephens
A landmark study published in the New England Journal of Medicine has used modern DNA sequencing techniques to demonstrate a significant link between genetic mutation of the gene responsible for encoding titin - the human body’s largest protein - and dilated cardiomyopathy (McNally, 2012).
Dilated cardiomyopathy is a heart-muscle disorder in which the organ becomes weakened and distended, preventing it from pumping blood efficiently or effectively. DCM is frequently manifested as congestive heart failure, a severe and potentially fatal condition arising when the heart cannot pump sufficient blood throughout the organs of the body (Cardiopathy, 2011)
|Figure 1: The components of a sarcomere, including titin, the molecular ruler (McNally, 2012)|
The study reports that mutations in the TTN gene – responsible for encoding the muscle-protein titin – were accountable for 27% of DCM cases by predisposing the heart to those symptoms associated with DCM, namely engorgement and poor function. (Herman et al, 2012)
Sarcomere Animation: http://www.youtube.com/watch?v=-pg09F5V63U
The muscle fibres of the heart are comprised of a series of contractile units called sarcomeres (Figure 1). These are composed of actin, myosin, and other proteins including titn. In the human heart, the protein titin acts as a molecular ruler, measuring the contractions and elongations of the sarcomere by sensing and recording changes in length during movement. (Campbell et al, 2009; pg.1124) The effect of the TTN gene mutation is to disrupt the site of measurement, being the protein kinase domain, labelled TK, in the protein titin. This impairs the protein’s ability to accurately monitor the sarcomere, and causes heart malfunction through false reports (McNally, 2012).
TTN is comprised up roughly 35,000 amino acids, and the complexity and enormous size of the gene have prevented previous attempts to effectively study the effects of its mutations. It is only with the advent of modern sequencing techniques that a comprehensive study such as this is possible.
Analysing 312 patients with DCM and 249 control subjects, the authors identified that 27% of the DCM patients had mutations expected to produce truncated forms of titin. Only 3% of control subjects had similar mutations, substantiating the suggested link (Herman et al, 2012). The authors further identified a strong trend of DCM and TTN-mutation co-inheritance, supporting the suggestion that this mutation plays a key role in cardiomyopathy
While mutations associated with cardiomyopathy have been identified in over 50 different genes, even the most common of these describes only 5% of cases (Herman et al, 2012).. As such, the findings of this study amount to a dramatic increase in biomedical knowledge.
Nevertheless, the study also identified that the actual outcome of TTN-mutations is dependant on the particular genetic constitution of the individual, and exposure to environmental factors (such as alcohol). For example, other heart disorders (such as hypertension) would be expected to exacerbate the effects of protein mutation (McNally, 2012).
Dilated Cardiomyopathy is a devastating disorder which can lead to heart failure, and is generally not amenable to surgery other than transplantation. Some patients remain stable for long periods, though the health of most continues to deteriorate, because it is a condition which cannot effectively be treated if the underlying cause can be identified and corrected. (Cardiopathy, 2011) Thus, diagnosing the genetic basis of DCM has opened the door for more effective genetic counselling, and prevention, which will ultimately have immeasurable benefits to patient therapy.
McNally, E. (15 March 2012). ‘Genetics: Broken giant linked to heart failure’. Nature 483, 281–282
Cardiopathy (2011), accessed 18 March 2012 from PubMed Health: http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0002095/
Herman et al, (2012) ‘Truncations of titin causing dilated cardiomyopathy’. New England Journal of Medicine, 366 (7), 619-628
Campbell et al, 2009. Biology, (8th Ed.), Pearson Australia,