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

Previous in vitro studies indicate that CWC27 functions as a splicing factor in the B-act 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 Cwc27(K338fs/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 Cwc27(K338fs/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 Cwc27(K338fs/K338fs) mouse retina provide insight to the potential disease mechanisms, paving the way for targeted therapeutic development.