Nonsense suppression therapies in ocular genetic diseases.

ABSTRACT

Premature termination codons (PTCs) are caused by nonsense mutations and this leads to either degradation of the mutant mRNA template by nonsense-mediated decay (NMD) or the production of a non-functional, truncated polypeptide. PTCs contribute significantly to inherited human diseases including ocular disorders. Nonsense suppression therapy allows readthrough of PTCs, thereby rescuing the production of a full-length functional protein. In this review, we highlight the mechanisms that are involved in discriminating normal translation termination from premature termination codons; the current understanding of nonsense-mediated mRNA decay models (NMD); the association and crosstalk between PTC and the underlying dynamic NMD process; and the suppression therapies that have been employed in nonsense-medicated ocular disease models. Defining the mechanistic complexity of PTC and NMD will be important to improve treatments of the numerous genetic disorders caused by PTC mutations.