Wednesday, 23 May 2012

Mutated Titin Gene Causing Dilated Cardiomyopathy


Cardiomyopathy affects 1 in 500 Australians, impairing heart function, in some cases leading to heart failure, and killing 1 in 3 children who develop it. Dilated cardiomyopathy (DCM) is the prevalent form of the disease, in which the muscle tissue, particularly of the left ventricle, becomes weakened and enlarged. This disease can be quite deadly, but if diagnosed there are many available treatments that can be very successful. It has previously been found that mutated genes may be responsible for this condition, but most already described mutations are rare, the most common of which accounts for only 5% of cases.
Titin is the largest known protein in the human body, containing some 34000 amino acids, and depending on the definition of a word, its 189819 letter chemical name is the longest word in the English language. It is also an integral part of cardiac muscle, acting as a cellular yardstick, measuring the contraction or relaxation of the cell. If this protein is malformed, for example shortened or truncated, then its capability will be severely limited, causing the muscle cell to malfunction. Mutations of the titin gene have previously been connected to DCM but the enormity of this gene has hampered a full analysis. Those difficulties have now been overcome and Herman and colleagues examined the titin gene of 792 people; some with DCM, some with hypertrophic cardiomyopathy (another form of the condition) and some control subjects with neither condition. Mutations in the sequenced genes were identified analysed to find relationships with DCM.

The research team used two sequencing methods in their analyses, the Sanger method and massively parallel sequencing. Of the samples analysed by the Sanger method, 17% of subjects with DCM had mutations that would truncate titin. The massively parallel method gave a slightly higher 27%. These are significant proportions compared to 1% in the hypertrophic cardiomyopathy subjects and 3% in the control subjects. These results suggest a strong link between truncating mutations of the titin gene, and some cases of DCM. It should also be noted that some subjects without either disease had a mutated gene, and this was attributed to the fact that there are other factors, either genetic or environmental that increase the potential of mutated genes to result in disease.
The findings of this group could play a significant role in the treatment of DCM in the future. Sequencing an individual’s titin gene could identify if they have a mutation and are therefore at risk to the disease. At risk individuals could be monitored for the development of DCM, allowing treatment to begin before it advances to more serious stages. This illness can have devastating effects, but as more is learnt about how and why a person develops it, more can be done to provide early diagnosis and treatment, increasing the chances of a successful outcome.
 Benjamin O'Sullivan

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