Tuesday, 15 May 2012

Mutations of titin resulting in dilated cardiomyopathy

Figure 1: Normal heart vs. heart suffering from dilated cardiomyopathy (A.D.A.M, 2010)
Thanks to new, high-tech methods of DNA analysis, dilated cardiomyopathy, the disease responsible for the greatest proportion of heart transplantations, has recently been investigated as it has never been before. According to a recent article published by D Herman et al, a considerable proportion of cases of dilated cardiomyopathy (approximately 25%), may be attributed to genetic mutation in TTN, the gene encoding for titin – a protein found within the heart. The disease, associated with congestive heart failure, causes the heart to expand and weaken, consequentially reducing its efficiency in pumping blood throughout the body (Zieve & Chen, 2011). Titin is the largest protein occurring in humans, and is important in ensuring that cells within the heart do not stretch beyond their usual limits. Although other genes and environmental factors are also believed to be able to cause cardiomyopathy, the majority of other genetic factors are rare, and mutation in the titin gene (TTN) is considered to be the most common non-environmental factor discovered to date (McNally, 2012).

Figure 2: Structure of sarcomere (McNally, 2012)
In heart cells, titin and other proteins such as actin and myosin are arranged within small structures termed ‘sarcomeres’, which are crucial to the normal contractions of the heart. Each titin molecule spans approximately half the length of each sarcomere, connecting at the halfway point with another titin molecule. If an individual is affected by the genetic mutations described by Herman, these molecules become distorted, and a carboxyl-terminal kinase domain – part of an amino acid - present in each molecule is disrupted. This impinges upon the molecule’s ability to signal that the cell is abnormally lengthened, and by consequence, the heart expands, and is rendered weak and flaccid (McNally, 2012). As a result, oxygen-rich blood will not be able to reach the tissues of the body as readily, and the individual will begin to feel tired, weak, and faint, in addition to being at increased risk of total heart failure (Zieve & Chen, 2011).

To see the original research paper by D Herman (Truncations of Titin Causing Dilated Cardiomyopathy), click here!
Or, if you would prefer to see the simplified analysis by E McNally of the Nature journal, click here!
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Figure 3: Afflicted heart (DeFrances & Lee, 1998)
Before the modern technique mentioned earlier, termed ‘massively parallel sequencing’ (or ‘next-generation sequencing’ by some scientists), became financially and practically viable in labs, titin, composed of approximately 33000 amino acids, or 145kB of data, had been considered too large to synthesise and study (Herman, 2012). However, massively parallel sequencing has maximised the efficiency of this process, and has allowed such daunting tasks to be accomplished. Therefore, although earlier studies had been able to conclude that cardiomyopathy is sometimes passed down genetically from generation to generation, and some had even guessed that titin might be involved, Herman and his team became the first group of researchers to identify and discuss the exact mechanisms by which the faulty DNA affects human hearts.

In conclusion, Herman’s new study has served to shed light on one of the predominant causes of dilated cardiomyopathy, and to demonstrate the potentials of the technologies and techniques on the rapidly advancing frontier of genetics research. Through the sequencing of TTN - the gene responsible for the production of titin - it was possible to determine a specific mechanism responsible for the disease. This knowledge, in the future, may be allow doctors to treat the disease with the similarly modern technique of gene therapy, potentially saving many lives and improving the quality of  life of many suffering people, in addition to furthering our understanding of human genetic diseases.


A.D.A.M. (2010, December 23). Health Central. Retrieved March 18, 2012, from Alcoholic Cardiomyopathy: http://www.healthcentral.com/heart-disease/h/can-alcohol-cause-cardiomyopathy.html

DeFrances, M., & Lee, R. (1998). Cardiovascular Pathology. Retrieved March 18, 2012, from Marie C DeFrances: http://path.upmc.edu/cases/case161.html

Herman, D. (2012). 'Genetics: Broken giant linked to heart failure'. New England Journal of Medicine , 366 (7), 619-628.

McNally, E. (2012). 'Genetics: Broken giant linked to heart failure'. Nature , 483 (1), 281-282.

Zieve, D., & Chen, M. (2011, May 23). Dilated cardiomyopathy. Retrieved March 18, 2011, from PubMed Health: http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0001221/

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