Cystic fibrosis transmembrane conductance regulator (CFTR) mRNA with premature termination codons (CFTR mRNA (PTC))

Cystic fibrosis transmembrane conductance regulator (CFTR) mRNA containing premature termination codons (PTCs) is the primary driver of Class I cystic fibrosis mutations. These nonsense mutations, such as G542X or W1282X, introduce a stop signal prematurely in the genetic sequence, leading to the production of truncated, non-functional proteins (Cystic Fibrosis Foundation). Furthermore, these PTC-containing transcripts are frequently targeted for degradation by the cellular nonsense-mediated mRNA decay (NMD) pathway, which significantly reduces the pool of available mRNA for translation (Linde & Kerem, 2008). This target is unique because therapeutic intervention occurs during the translation process, where small molecules called read-through agents interact with the ribosome. These agents, such as Ataluren or ELX-02, facilitate the bypass of the premature stop signal by promoting the insertion of a near-cognate amino acid at the PTC site (Welch et al., 2007). This process allows the ribosome to continue translation to the natural stop codon, resulting in the synthesis of full-length, functional CFTR protein. Current research also explores the use of NMD inhibitors to stabilize the mRNA, thereby increasing the substrate available for read-through therapy (Sharma et al., 2021). Restoring CFTR function at the cell membrane is essential for normalizing chloride and bicarbonate transport, which alleviates the thick mucus accumulation in the lungs and other organs. Clinical monitoring of this target often involves measuring sweat chloride levels or nasal potential difference to assess the restoration of ion channel activity. Despite challenges such as low read-through efficiency and potential off-target effects, targeting CFTR mRNA remains a critical strategy for treating patients with nonsense mutations who do not benefit from standard CFTR modulators.

Other names

PTC-containing CFTR mRNACFTR mRNA with nonsense mutationsNonsense-mutated CFTR mRNAPremature stop codon CFTR mRNA

Induction of translational read-through at premature termination codons and inhibition of nonsense-mediated mRNA decay (NMD) (Welch et al., 2007; Sharma et al., 2021).