Truncations of Titin Causing Dilated Cardiomyopathy

By D. Herman, L. Lam, Matthew R. G. Taylor, Libin Wang, P. Teekakirikul, Danos C. Christodoulou, Lauren Conner, S. DePalma, B. McDonough, E. Sparks and 19 more. New England Journal of Medicine, 2012

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BACKGROUND Dilated cardiomyopathy and hypertrophic cardiomyopathy arise from mutations in many genes. TTN, the gene encoding the sarcomere protein titin, has been insufficiently analyzed for cardiomyopathy mutations because of its enormous size. METHODS We analyzed TTN in 312 subjects with dilated cardiomyopathy, 231 subjects with hyper-trophic cardiomyopathy, and 249 controls by using next-generation or dideoxy sequencing. We evaluated deleterious variants for cosegregation in families and assessed clinical characteristics. RESULTS We identified 72 unique mutations (25 nonsense, 23 frameshift, 23 splicing, and 1 large tandem insertion) that altered full-length titin. Among subjects studied by means of next-generation sequencing, the frequency of TTN mutations was significantly higher among subjects with dilated cardiomyopathy (54 of 203 [27%]) than among subjects with hypertrophic cardiomyopathy (3 of 231 [1%], P = 3×10−16) or controls (7 of 249 [3%], P = 9×10−14). TTN mutations cosegregated with dilated cardiomyopathy in families (combined lod score, 11.1) with high (>95%) observed penetrance after the age of 40 years. Mutations associated with dilated cardiomyopathy were overrepresented in the titin A-band but were absent from the Z-disk and M-band regions of titin (P≤0.01 for all comparisons). Overall, the rates of cardiac outcomes were similar in subjects with and those without TTN mutations, but adverse events occurred earlier in male mutation carriers than in female carriers (P = 4×10−5). CONCLUSIONS TTN truncating mutations are a common cause of dilated cardiomyopathy, occurring in approximately 25% of familial cases of idiopathic dilated cardiomyopathy and in 18% of sporadic cases. Incorporation of sequencing approaches that detect TTN truncations into genetic testing for dilated cardiomyopathy should substantially increase test sensitivity, thereby allowing earlier diagnosis and therapeutic intervention for many patients with dilated cardiomyopathy. Defining the functional effects of TTN truncating mutations should improve our understanding of the pathophysiology of dilated cardiomyopathy. (Funded by the Howard Hughes Medical Institute and others.)

Subfields: Cardiology and Cardiovascular Medicine, Molecular Biology

View Paper: https://www.semanticscholar.org/paper/d7ad2e6b3218a5d8ebbe8e39f2f8da2fe6c6d22a

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In Cardiology and Cardiovascular Medicine

Joseph A. Hill

In Molecular Biology

Citations in the corpus

Cardiovascular toxicity and titin cross-reactivity of affinity-enhanced T cells in myeloma and melanoma. (2013, background): “Titin is a sarcomeric protein expressed in striated muscle,(13) and certain mutations in titin are known to cause dilated cardiomyopathy.(14) Importantly, standard cultured primary cardiomyocyte cells do not express titin, but actively beating cardiac myocytes derived from iPSCs do express titin.”
An international effort towards developing standards for best practices in analysis, interpretation and reporting of clinical genome sequencing results in the CLARITY Challenge (2014, background): “Nevertheless, successful teams recognized the probable causative nature of the TTN variants in Family 1 based on the fact that one was a published pathogenic change previously reported to cause dilated cardiomyopathy [71] and the second mutation was predicted to alter splicing.”
Pathological Ventricular Remodeling: Mechanisms: Part 1 of 2 (2013, background): “Recently, however, mutations in the gene coding for the giant sarcomeric protein titin (TTN) have been identified in 25% of patients with familial idiopathic DCM, whereas only 3 of 231 patients with HCM harbor these mutations.(17) Mutations in this gene can also promote cardiomyocyte stiffness,(18) ”
Dilated Cardiomyopathy: Genetic Determinants and Mechanisms (2017, positive): “Using a TTN-specific array designed to capture all TTN exons, it was shown that truncating variants of TTN contribute to 20% to 25% of nonischemic DCM.(64) Before this, only a few missense TTN variants had been described linked to DCM.”
Settling the score: variant prioritization and Mendelian disease (2017, background): “However, simply ignoring variants in such genes is ill-advised: some TTN mutations, for example, cause autosomal recessive and dominant cardiomyo-pathies 58 , as well as various muscular dystrophies 59,60 .”