Mutation type-specific transcriptomic signatures and readthrough therapy rescue in SMC1A-related developmental and epileptic encephalopathy.

objectiveThis study was undertaken to investigate the molecular consequences of pathogenic variants in the SMC1A gene-particularly those associated with developmental and epileptic encephalopathy (DEE85)-and to evaluate the therapeutic potential of ataluren in restoring SMC1A function and mitigating disease-related transcriptomic and genomic alterations.

methodsThe study analyzed transcriptomic profiles from cell lines derived from individuals with DEE85 and Cornelia de Lange syndrome (CdLS), comparing the effects of different SMC1A variants. Particular focus was placed on nonsense variants and their impact on gene expression. Functional assays were conducted to assess the ability of ataluren to restore SMC1A protein expression, correct transcriptional defects, and reduce genomic instability.

resultsTranscriptomic alterations were strongly dependent on variant type, with nonsense variants causing the most profound gene expression changes. DEE85 and CdLS cell lines exhibited distinct transcriptional signatures. Treatment with ataluren led to successful restoration of SMC1A protein levels, partial correction of gene expression abnormalities, and a reduction in genomic instability in cells harboring nonsense variants. SIGNIFICANCE: These findings demonstrate that SMC1A-related epileptic encephalopathies are driven by variant-specific molecular mechanisms and highlight the therapeutic promise of ataluren for DEE85. The study supports further development of precision medicine strategies targeting nonsense variants in SMC1A, with potential implications for improving diagnosis, treatment, and quality of life in affected individuals.