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Precursor messenger RNA (Pre-mRNA) splicing is an essential biological process in eukaryotic cells. Genetic mutations in many spliceosome genes confer human eye diseases. Mutations in the pre-mRNA splicing factor,  RP9  (also known as PAP1), predispose autosomal dominant retinitis pigmentosa (adRP) with an early onset and severe vision loss. However, underlying molecular mechanisms of the  RP9  mutation causing photoreceptor degeneration remains fully unknown. Here, we utilize the CRISPR/Cas9 system to generate both the  Rp9  gene knockout (KO) and point mutation knock in (KI) ( Rp9 , c.A386T, P.H129L) which is analogous to the reported one in the retinitis pigmentosa patients ( RP9 , c.A410T, P.H137L) in 661 W retinal photoreceptor cells  in vitro . We found that proliferation and migration were significantly decreased in the mutated cells. Gene expression profiling by RNA-Seq demonstrated that RP associated genes,  Fscn2  and  Bbs2 , were down-regulated in the mutated cells. Furthermore, pre-mRNA splicing of the  Fscn2  gene was markedly affected. Our findings reveal a functional relationship between the ubiquitously expressing  RP9  and the disease-specific gene, thereafter provide a new insight of disease mechanism in  RP9 -related retinitis pigmentosa.

Targeted RP9 ablation and mutagenesis in mouse photoreceptor cells by CRISPR-Cas9