Titin mRNA premature termination codon (TTN PTC)

Titin (TTN) mRNA premature termination codons (PTCs) are a primary therapeutic target for treating dilated cardiomyopathy (DCM) and other titinopathies caused by nonsense mutations. Titin is the largest known protein and serves as a molecular spring within the sarcomere, providing passive stiffness to cardiac and skeletal muscle (Herman et al., 2012). Truncating variants (TTNtv) lead to the production of truncated proteins or the degradation of mRNA via nonsense-mediated decay, resulting in contractile dysfunction and heart failure (Roberts et al., 2015). Nonsense suppression drugs target the ribosomal decoding center while it is positioned over the TTN PTC, encouraging the ribosome to bypass the stop signal. This process, known as translational read-through, aims to restore the production of full-length, functional titin protein to stabilize the sarcomere and improve heart or muscle function (Finkel, 2010). Small molecules like ELX-02 and ataluren are being investigated for their ability to bind the ribosome and decrease the fidelity of the decoding center specifically at these premature stops (Keeling et al., 2014).

Other names

TTN nonsense mutationTitin truncating variantTTNtvPremature stop codon in Titin mRNATTN mRNA-ribosome complex

Nonsense suppression therapy involves small molecules that bind to the ribosomal decoding center, decreasing the fidelity of codon-anticodon pairing specifically at premature termination codons (PTCs) (Keeling et al., 2014). This allows the recruitment of a near-cognate tRNA, leading to the insertion of an amino acid and the continuation of translation to produce a full-length, functional protein.