Ttn, encoding the giant sarcomere protein titin, is a major determinant of cardiomyocyte stiffness and contributes to cardiac strain sensing. Titin-based forces are crucial in regulating myocardial function, such as cardiac filling and output. It forms the myofibrillar backbone for the contractile machinery components, playing a vital role in muscle disorders and cardiomyopathies [1,2].

Mutations in the TTN gene are the most common causes of dilated cardiomyopathy (DCM). TTN truncating variants (tTTN) reduce normal TTN protein levels, produce truncated proteins, and impair sarcomere content and function. In a study of 1,041 patients with sporadic DCM, tTTN were detected in 120 (11.5%) patients. DCM patients with tTTN had a lower left ventricular ejection fraction and a lower frequency of the left bundle branch block, but tTTN were not associated with the composite primary endpoint of cardiac death and heart transplantation during the follow-up period [3]. TTN truncating mutations are a common cause of dilated cardiomyopathy, occurring in approximately 25% of familial cases of idiopathic DCM and in 18% of sporadic cases [4].

In conclusion, Ttn is essential for myocardial function, especially in maintaining cardiomyocyte stiffness and contributing to cardiac strain sensing. Studies on TTN mutations, especially truncating variants, have revealed their significant association with dilated cardiomyopathy, highlighting the importance of Ttn in understanding the pathophysiology of this cardiac disorder.

References:

1. Loescher, Christine M, Hobbach, Anastasia J, Linke, Wolfgang A. . Titin (TTN): from molecule to modifications, mechanics, and medical significance. In Cardiovascular research, 118, 2903-2918. doi:10.1093/cvr/cvab328. https://pubmed.ncbi.nlm.nih.gov/34662387/

2. Jolfayi, Amir Ghaffari, Kohansal, Erfan, Ghasemi, Serwa, Maleki, Majid, Kalayinia, Samira. 2024. Exploring TTN variants as genetic insights into cardiomyopathy pathogenesis and potential emerging clues to molecular mechanisms in cardiomyopathies. In Scientific reports, 14, 5313. doi:10.1038/s41598-024-56154-7. https://pubmed.ncbi.nlm.nih.gov/38438525/

3. Xiao, Lei, Li, Chenze, Sun, Yang, Marian, Ali J, Wang, Dao Wen. 2021. Clinical Significance of Variants in the TTN Gene in a Large Cohort of Patients With Sporadic Dilated Cardiomyopathy. In Frontiers in cardiovascular medicine, 8, 657689. doi:10.3389/fcvm.2021.657689. https://pubmed.ncbi.nlm.nih.gov/33996946/

4. Herman, Daniel S, Lam, Lien, Taylor, Matthew R G, Seidman, J G, Seidman, Christine E. . Truncations of titin causing dilated cardiomyopathy. In The New England journal of medicine, 366, 619-28. doi:10.1056/NEJMoa1110186. https://pubmed.ncbi.nlm.nih.gov/22335739/