Montazaribarforoushi Saba, Jolly Lachlan A
Robinson Research Institute, The University of Adelaide, Adelaide, SA, Australia; Adelaide Medical School, The University of Adelaide, Adelaide, SA, Australia.
Robinson Research Institute, The University of Adelaide, Adelaide, SA, Australia; School of Biomedicine, The University of Adelaide, Adelaide, SA, Australia.
Curr Opin Genet Dev. 2025 Oct;94:102394. doi: 10.1016/j.gde.2025.102394. Epub 2025 Aug 6.
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.
无义介导的mRNA衰变（NMD）是一种依赖翻译的mRNA衰变机制，其作用是控制mRNA的质量和数量。作为一种质量控制机制，NMD保护生物体免受编码提前终止密码子的mRNA的有害影响，这些提前终止密码子是由转录错误或基因变异产生的。NMD还被用作生理基因表达水平的主要调节因子，在模式生物中，多个NMD基因的完全敲除是胚胎致死的。现在，对导致人类孟德尔疾病的基因的鉴定突出表明，影响NMD功能的基因变异会导致一系列神经发育障碍（NDD）。在这里，我们聚焦于最近的发现，梳理了与NDD相关的NMD基因和基因变异的现状。这项调查突出表明，超过一半的NMD及与NMD相关的基因与NDD有关，这是一个显著的富集现象。NMD受损可能是多种导致NDD的遗传原因的共同致病机制，这使得有必要持续研究NMD在大脑发育中的作用。
