Functional analysis of the CTNS gene exonic variants predicted to affect splicing.

Cystinosis is a severe, monogenic systemic disease caused by variants in CTNS gene. Currently, there is growing evidence that exonic variants in many diseases can affect pre-mRNA splicing. The impact of CTNS gene exonic variants on splicing regulation may be underestimated due to the lack of routine studies at the RNA level. Here, we analyzed 59 exonic variants in the CTNS gene using bioinformatics tools and identified candidate variants that may induce splicing alterations by minigene assays. We identified six exonic variants that induce splicing alterations by disrupting the ratio of exonic splicing enhancers/exonic splicing silencers (ESEs/ESSs) or by interfering with the recognition of classical splice sites, or both. Our results help in the correct molecular characterization of variants in cystinosis and inform emerging therapies. Furthermore, our work suggests that the combination of in silico and in vitro assays facilitates to assess the effects of DNA variants driving rare genetic diseases on splicing regulation and will enhance the clinical utility of variant functional annotation. © 2023 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Citation

Changying Li, Ruixiao Zhang, Fengjiao Pan, Qing Xin, Xiaomeng Shi, Wencong Guo, Dan Qiao, Zhi Wang, Yiyin Zhang, Xuyan Liu, Yan Zhang, Leping Shao. Functional analysis of the CTNS gene exonic variants predicted to affect splicing. Clinical genetics. 2024 Mar;105(3):323-328

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PMID: 38009794

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