Ttn-flox Mouse

Ttn, encoding the giant sarcomere protein titin, is a major determinant of cardiomyocyte stiffness and contributes to cardiac strain sensing. It plays a crucial role in regulating myocardial function, including cardiac filling and output, and is part of the contractile machinery in muscle [1,2].

Mutations in the TTN gene are the most common causes of dilated cardiomyopathy (DCM). TTN truncating variants (tTTN) lead to reduced normal TTN protein levels, production of truncated proteins, and impairment of sarcomere content and function. DCM patients with tTTN have a lower left ventricular ejection fraction and a lower frequency of the left bundle branch block compared to those without or with mutations in other known causal genes, though tTTN are not associated with the composite primary endpoint of cardiac death and heart transplantation during follow-up [3]. The prevalence of TTN mutations in DCM patients is 0.17, with 0.23 in familial DCM and 0.16 in sporadic DCM [4]. TTN truncating mutations occur in approximately 25% of familial cases and 18% of sporadic cases of idiopathic DCM, and incorporation of sequencing for TTN truncations in genetic testing for DCM can increase test sensitivity [5]. Pathogenic variants in TTN can also cause skeletal muscle diseases, with nonsense-mediated decay likely preventing harmful truncated protein accumulation in skeletal muscle in some cases [6].

In conclusion, Ttn is essential for maintaining cardiomyocyte stiffness and normal cardiac function. Studies on TTN mutations, especially in relation to DCM and skeletal muscle diseases, have provided valuable insights into the gene's function and the pathophysiology of these diseases, highlighting the importance of Ttn in understanding muscle-related disorders.