In affected members of a 3-generation Chinese family with retinitis pigmentosa (RP70; 615922), Chen et al. (2014) identified heterozygosity for a c.944C-T transition in exon 10 of the PRPF4 gene, resulting in a pro315-to-leu (P315L) substitution at a highly conserved residue in the second blade of the 7 repeated blades of PRPF4. The mutation was not found in unaffected family members, in 400 unrelated controls, or in SNP databases. Quantitative PCR analysis of cultured patient fibroblasts showed 2.83-fold upregulation of PRPF4 expression compared to fibroblasts from an unaffected family member. Both the wildtype and mutant alleles were upregulated, indicating a compensatory response, and increased expression levels of other tri-snRNP components were also observed, including PRPF3 (607301), PRPF6 (613979), PRPF8 (607300), PRPF31 (606419), EFTUD2 (603892), and SART1 (605941). In addition, the non-snRNP factor SC35 (SRSF2; 600813) was markedly increased, displaying a diffuse pattern on confocal microscopy rather than the distinctly speckled pattern seen with wildtype. Overexpression of the P315L mutant in zebrafish triggered systemic deformities primarily affecting the retina, with disruption of photoreceptors and inner and outer segments, as well as decreased reactivity of rhodopsin (180380).
