Genetic disruption of nonsense-mediated mRNA decay in neurodevelopmental disorders.

Nonsense-mediated mRNA decay (NMD) is a translation-dependent mRNA decay mechanism that serves the purpose of controlling both mRNA quality and quantity. As a quality control mechanism, NMD protects organisms against the deleterious effects of mRNAs that encode premature termination codons, which arise through either transcriptional errors or genetic variation. NMD is also employed as a major regulator of physiological gene expression levels, and complete knockouts of multiple NMD genes are embryonic lethal in model organisms. The identification of genes that contribute to human Mendelian disease has now highlighted that gene variants that impact NMD function contribute to a spectrum of neurodevelopmental disorders (NDDs). Here, we capture the current landscape of NMD genes and gene variants implicated in NDDs with a focus on recent discoveries. The survey highlighted the involvement of more than half of all NMD and NMD-related genes in NDDs, representing a significant enrichment. That compromised NMD is a likely convergent pathogenic mechanism across multiple genetic causes of NDDs warrants ongoing investigation into the role of NMD in brain development.