In an important new study, Chinese researchers have discovered the previously unrecognized role of alternative splicing of the DOC2A gene in schizophrenia.<\/p>\n
The research was conducted by scientists led by LI Ming from the Kunming Institute of Zoology of the Chinese Academy of Sciences and published in Science Advances on January 16.<\/p>\n
Splicing is a process in which RNA is cut and recombined into the final RNA strand that determines how a protein-encoded by DNA-is formed. Different splicing signals for the same RNA strand can generate protein isoforms that function differently. The varied splicing signals may be generated by very small genetic variants in DNA-such as synonymous single nucleotide polymorphisms (SNPs)-that alter a single nucleotide without changing the encoded amino acid sequence.<\/p>\n
Although genome-wide association studies (GWAS) have identified thousands of variants associated with schizophrenia, the biological functions related to most of these statistical associations are poorly understood.<\/p>\n
To address this problem, the researchers sought to understand how different variants affect splicing and thus produce different protein isoforms.<\/p>\n
Using splicing quantitative trait locus (sQTL) analyses of human postmortem brain tissues, the researchers identified more than 17,000 schizophrenia-associated sQTLs across the genome. Among them, the SNP rs3935873 showed the strongest prediction for disrupting DOC2A splicing. Experimental validation confirmed that this variant promotes the expression of a truncated protein isoform, DOC2A\u25b3Val217\u2013Pro218, while leaving the full-length transcript unaffected. The isoform was previously unannotated (undocumented).<\/p>\n
In murine models, overexpression of this isoform in the hippocampus recapitulated schizophrenia-like behaviors, including anxiety, impaired sensorimotor gating, and anhedonia. These phenotypes were absent in control mice or in mice that expressed full-length DOC2A.<\/p>\n
Electrophysiological recordings further revealed enhanced excitatory synaptic transmission, and interactome profiling highlighted distinct molecular pathways, such as myosin II complex enrichment, suggesting altered synaptic functions.<\/p>\n
These findings integrate genetic, transcriptomic, and behavioral evidence to underscore the critical role of alternative splicing in the genetic regulation of schizophrenia. They also provide a framework for investigating unannotated isoforms in disease pathogenesis. The study not only describes the functional impact of a specific risk variant but also highlights the significance of isoform-specific mechanisms, suggesting potential avenues for targeted therapeutic strategies.<\/p>\n
Source:<\/p>\n
Chinese Academy of Sciences<\/a><\/p>\n Journal reference:<\/p>\n