Submission Details

PRPF3 (Pre-mRNA Processing Factor 3, 1q21.2) encodes a protein integral to the pre-mRNA splicing process, specifically associating with U4 and U6 small nuclear ribonucleoproteins (snRNPs) within the spliceosome complex. This protein plays a crucial role in the removal of introns from pre-mRNA, facilitating the accurate translation of genetic information into functional proteins. The PRPF3 gene is comprised of 16 exons and encodes a protein of 683 amino acids in length with a calculated molecular weight of 77 kDa (Chakarova CF, et al., 2002; Zhong Z, et al., 2016). PRPF3 is ubiquitously expressed across various human tissues, with a predominantly nuclear localization, reflecting its fundamental role in gene expression. Immunohistochemistry data indicate that PRPF3 is mainly localized in the nucleus across most tissues. Notably, studies in murine models have demonstrated that PRPF3 expression is particularly high in retinal cells compared to other tissues, and its expression is developmentally regulated. This elevated retinal expression suggests a critical role for PRPF3 in maintaining retinal function. Additionally, PRPF3 protein was localized to the nuclei of photoreceptor cells, interneurons and ganglion cells. Relatively higher levels were detected in ganglion and inner nuclear layers and lower levels in the outer nuclear layer where photoreceptors are localized (Chakarova CF, et al., 2002; Comitato A, et al., 2007). Pathogenic variants in PRPF3 are predominantly associated with autosomal dominant retinitis pigmentosa (ADRP), specifically classified as retinitis pigmentosa 18 (RP18) (MIM#601414), characterized by progressive photoreceptor degeneration, leading to symptoms such as night blindness, peripheral vision loss, and, in advanced stages, central vision impairment (Chakarova CF, et al., 2002; Meng X, et al., 2017; Zhong Z, et al., 2016; Wang J, et al., 2022). Animal models (zebrafish, mouse) suggested that RP18 is not a result of haploinsufficiency but instead arises from a toxic gain-of-function caused by missense variants in PRPF3 gene (Graziotto JJ et al., 2008). Several disease-causing variants in PRPF3 have been identified in patients with ADRP (7 missense changes and 1 splice site in an in-frame exon). One of the most studied variants is the p.(Thr494Met) substitution, which has been reported in multiple families with ADRP (Chakarova CF, et al., 2002; Meng X, et al., 2017; Zhong Z, et al., 2016; Wang J, et al., 2022). This variant is in exon 11 of PRPF3 and is associated with variable phenotypic expressivity, even among individuals carrying the same variant. Data for this variant suggest that mutant PRPF3 causes mislocalization of splicing factors and forms aggregates that can be detrimental to the photoreceptor cell (Meng X, et al., 2017). Missense PRPF3 variants identified in adRP families are clustered at the highly conserved C-terminal domain for binding to U4/U6 snRNA and splicing factors. The recurrent variant p.(Thr494Met) substantially reduces the phosphorylation of PRPF3 C-terminal region by casein kinase II, thereby suppressing its association with itself, Hprp4p, and U4/U6 snRNA, so all variants in c-terminal exon to 0.5 were upscored, as this appears to be critical region in pathogenicity of disease (Gonzalez-Santos JM et al., 2008; Yang C et al., 2021). Interestingly there was one splice site variant, but it seems this is affecting an in-frame exon (exon 10) and thus skipping of this exon will retain the frame and this variant is not considered as a null variant (this exon is 7% of the total protein) (Wang J et al. et al., 2022). In this curation, data from 7 individuals were collected (Chakarova CF, et al., 2002; Meng X, et al., 2017; Zhong Z, et al., 2016; Wang J, et al., 2022). Supporting segregation evidence was collected from 3 families with the recurrent p.(Thr494Met) variant. Additionally, experimental evidence for expression, biochemical function, animal modelling and function alteration was reviewed (Chakarova CF, et al., 2002; Comitato A, et al., 2007; Farkas MH, et al., 2014). In summary, PRPF3 is definitively associated with PRPF8-related retinopathy. The association with retinopathy has been repeatedly demonstrated in both the research and clinical diagnostic settings and has been upheld over time. The suggested name of the condition is PRPF3-related retinopathy. This classification was approved by the ClinGen Retinal Gene Curation Expert Panel on March 3rd, 2022 (SOP Version 8).