Cwc27, associated with retinal degeneration, functions as a splicing factor in vivo.

TitleCwc27, associated with retinal degeneration, functions as a splicing factor in vivo.
Publication TypeJournal Article
Year of Publication2022
AuthorsBertrand, RElaine, Wang, J, Li, Y, Cheng, X, Wang, K, Stoilov, P, Chen, R
JournalHum Mol Genet
Date Published2022 Apr 22
KeywordsAlternative Splicing, Animals, Introns, Mice, Peptidylprolyl Isomerase, Retinal Degeneration, RNA Splice Sites, RNA Splicing, RNA Splicing Factors, Spliceosomes

Previous in vitro studies indicate that CWC27 functions as a splicing factor in the Bact spliceosome complex, interacting with CWC22 to form a landing platform for eIF4A3, a core component of the exon junction complex. However, the function of CWC27 as a splicing factor has not been validated in any in vivo systems. CWC27 variants have been shown to cause autosomal recessive retinal degeneration, in both syndromic and non-syndromic forms. The Cwc27K338fs/K338fs mouse model was shown to have significant retinal dysfunction and degeneration by 6 months of age. In this report, we have taken advantage of the Cwc27K338fs/K338fs mouse model to show that Cwc27 is involved in splicing in vivo in the context of the retina. Bulk RNA and single cell RNA-sequencing of the mouse retina showed that there were gene expression and splicing pattern changes, including alternative splice site usage and intron retention. Positive staining for CHOP suggests that ER stress may be activated in response to the splicing pattern changes and is a likely contributor to the disease mechanism. Our results provide the first evidence that CWC27 functions as a splicing factor in an in vivo context. The splicing defects and gene expression changes observed in the Cwc27K338fs/K338fs mouse retina provide insight to the potential disease mechanisms, paving the way for targeted therapeutic development.

Alternate JournalHum Mol Genet
PubMed ID34726245
PubMed Central IDPMC9029344
Grant ListR01 EY022356 / EY / NEI NIH HHS / United States
R01 EY025536 / EY / NEI NIH HHS / United States
S10 OD023469 / OD / NIH HHS / United States

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