Readthrough Activators and Nonsense-Mediated mRNA Decay Inhibitor Molecules: Real Potential in Many Genetic Diseases Harboring Premature Termination Codons

Abstract

Nonsense mutations that generate a premature termination codon (PTC) can induce both the accelerated degradation of mutated mRNA compared with the wild type version of the mRNA or the production of a truncated protein. One of the considered therapeutic strategies to bypass PTCs is their “readthrough” based on small-molecule drugs. These molecules promote the incorporation of a near-cognate tRNA at the PTC position through the native polypeptide chain. In this review, we detailed the various existing strategies organized according to pharmacological molecule types through their different mechanisms. The positive results that followed readthrough molecule testing in multiple neuromuscular disorder models indicate the potential of this approach in peripheral neuropathies.

Genetic and Clinical Analyses of the KIZ-c.226C>T Variant Resulting in a Dual Mutational Mechanism

“…Translation readthrough is currently being studied and developed as a potential therapy for nonsense mutations that cause a variety of inherited diseases, either by readthrough drugs such as ataluren [ 36 , 37 , 38 ] or by suppressor tRNAs [ 39 , 40 ]. Both methods rely on a substantial number of available transcripts; however, two mechanisms might limit this amount—the nonsense mediated mRNA decay (NMD) that degrades transcripts bearing a PTC [ 41 , 42 ] and the ESE-affecting nonsense mutations, such as KIZ -c.226C>T, leading to aberrant splicing. While NMD does not seem to affect KIZ transcripts in fibroblasts (and potentially in the retina), the effect of c.226C>T on splicing might limit the number of transcripts for readthrough drugs.…”