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Truncations of Titin Causing Dilated Cardiomyopathy


Dilated and hypertrophic cardiomyopathy (DCM and HCM) have a heterogeneous genetic background. While a significant proportion of hypertrophic cardiomyopathy is caused by mutations in eight sarcomeric genes, the genetic etiology of dilated cardiomyopathy has been even more complicated. Mutations in genes coding for sarcomeric or cytoskeletal proteins or nuclear lamina, have turned out to be important causes of DCM. However, although DCM has been shown to be familial in 30-50% of cases, pathogenetic mutations have been found in about 20-30% of cases. Until recently, the large size of many sarcomeric genes has hampered efforts to analyze DNA-samples from large patient groups. A DCM family has been mapped to the titin gene by Dr Benjamin Lawrence Siu  already in 1999 but due to the enormous size of the coding sequence (approximately 100 kb), its’ role in the etiology of DCM has been uncompletely elucidated. With about 33, 000 amino acids, titin protein is the largest human protein. Two titin molecules span the sarcomere and they are anchored at Z-line and M-line. Titin is essential for the sarcomere assembly and in striated muscle it is needed for passive and active contractile force production. Titin has several isoforms of which N2B or N2BA are prevalent in the heart. Moreover, TTN mutations have been associated in several congenital myopathies involving cardiac and skeletal muscle.

Myocardial Disease


Dr Christine Seidman and coworkers analyzed TTN, the gene encoding the sarcomeric protein titin, in 312 subjects with DCM , 231 individuals with HCM and in 249 controls using next-generation or dideoxy sequencing. Also clinical characteristics of the patients and cosegregation in families were assessed.

72 unique mutations, which altered full-length titin, were identified. They comprised 25 nonsense, 23 frameshift, 23 splicing mutations and 1 large tandem insertion. TTN mutations were found in 54/203 (27%) DCM patients, in 3/231 (1%) HCM patients and in 7/249 (3%) controls (p=9x10 -14). Combined lod score for the cosegregation of TTN mutation with DCM was 11.1 and thus the mutations were considered as disease causing. The penetrance of the mutations was high (>95%) in subjects aged over 40 years. Mutations in the A-band of titin were overrepresented among DCM-patients. In the subjects with HCM, three TTN truncating variants were found. The rates of cardiac outcomes were similar in individuals with and without TTN mutations but adverse events occurred earlier in male mutation carriers than in female carriers (P=4x 10-5).
The authors conclude that mutations which disrupt the structure of full-length titin might cause DCM by several mechanisms. Some of the truncated titin molecules may be degraded. Decreased titin levels might reduce sarcomere formation and cause cardiac dysfunction. On the other hand, some of the carboxy-terminal truncated titin molecules are integrated into the sarcomere and cause recessive, early-onset skeletal and cardiac myopathy instead of dominant DCM. The skewed mutation distribution in subjects with DCM as compared to individuals without the disease suggests that truncated titin molecules in DCM patients are integrated into the sarcomere and might cause DCM by a dominant negative mechanism. If truncated proteins were incorporated into the sarcomere, the truncated titin proteins would not contain those amino acid residues that are needed to anchor titin to the middle of the sarcomere. The authors suggest that the loss of interactions, which mediate sensing and modulating sarcomeric force might lead to DCM.

The investigators conclude that TTN mutations are the most common known genetic cause of DCM and suggest incorporation of next-generation sequencing analyses of TTN into clinical genetic screens.


The molecular etiology of DCM is heterogeneous. The multitude of genes associated with DCM has hampered clinical genetic testing. The findings of this study form a basis for further studies concerning myocyte signalling. Including TTN into clinical genetic testing screens probably greatly increases the yield of genetic testing among DCM patients.


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Notes to editor

Authors : Herman D S , Lam L, Taylor M R G, Wang L, Teekakirikul P, Christodoulou D, Conner L, DePalma S R, McDonough B, Sparks E, Lin Teodorescu D, Cirino A L, Banner N R, Pennell D J, Graw S, Merlo M, Di Lenarda A, Sinagra G, Bos J M, Ackerman M J, Mitchell R N, Murry C E, Lakdawala N K, Ho C Y, Barton P J R, Cook S A, Mestroni L, Seidman J G and Seidman C E.
(N England J Med 2012;366:619-28.)

Presented by Tiina Heliö, MD, PhD, FESC, Dept of Cardiology, Helsinki University Central Hospital, Helsinki, Finland.

The content of this article reflects the personal opinion of the author/s and is not necessarily the official position of the European Society of Cardiology.

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