Nonsense Mutations in Rare and Ultra-Rare Human Disorders: An Overview

Over 7000 rare diseases have been described, collectively affecting 350 million people worldwide. Most of these conditions result from nonsense mutations, representing approximately 10% of all genetic mutations associated with human inherited diseases. Nonsense mutations convert a sense codon into a premature termination codon (PTC), leading to premature translation termination and the production of truncated, nonfunctional proteins. This results in a loss-of-function phenotype in many genetic disorders, contributing to the disease's severity and progression. The molecular mechanisms of PTC formation involve various genetic alterations, including single-nucleotide changes, frameshifts, and splicing mutations. The nonsense-mediated mRNA decay (NMD) pathway degrades mRNAs containing premature termination codons (PTCs). In contrast, 25% of PTC mRNAs, depending on the PTC position and cellular context, can evade NMD, resulting in the synthesis of truncated proteins. A termination codon during translation is essential for proper protein synthesis, and translational readthrough—a process in which the ribosome bypasses the PTC and reaches the natural stop codon—may restore some level of protein function. The effectiveness of readthrough depends on the surrounding genetic context and the type of amino acid incorporated at the PTC position. This review aims to explore the molecular characteristics of nonsense-related diseases (NRDs), including cystic fibrosis, hemophilia, Fabry disease, choroideremia, Usher syndrome, Shwachman-Diamond syndrome, and certain hereditary neuropathies and cancers.