Pathogenic Mechanisms of Synonymous Mutations and Their Impact on Disease
ZHAI Xiguo1#, WANG Yupei2#, ZHU Jing1, HUI Ling2, HOU Qinzheng1*
Synonymous mutations are DNA coding region variants that do not alter the amino acid sequences of proteins and have long been regarded as phenotypically neutral mutations. However, recent studies have demonstrated that synonymous mutations can exert significant effects on gene expression and protein function through diverse regulatory mechanisms, including transcription, splicing, translation, and protein structural dynamics, thereby contributing to human disease phenotypes. This review systematically summarizes the core pathogenic mechanisms of synonymous mutations, encompassing the modulation of mRNA half-life and epitranscriptomic modifications, remodeling of mRNA secondary structures, disruption of splicing sites and cis-regulatory elements, alterations in codon usage bias and tRNA pairing, as well as perturbations in co-translational protein folding and conformational stability. This review emphasizes the distinct pathogenic modes of synonymous mutations in cancer, monogenic disorders, immunodeficiency syndromes, and other disease contexts. In addition, the developmental trajectory of technologies for synonymous mutation research is summarized, and the current challenges in this field are analyzed, including difficulties in pathogenicity prediction and limitations of functional validation systems. Future research priorities include the development of precision bioinformatics tools based on Chinese population genomic data, establishment of efficient experimental validation systems, and exploration of RNA‑targeted therapeutic strategies. Such efforts will provide a theoretical foundation for diagnosis and treatment of synonymous mutation‑associated diseases within the framework of precision medicine.
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