Mutations in the pre-mRNA splicing factor gene PRPC8 in autosomal dominant retinitis pigmentosa (RP13)

Abstract

Retinitis pigmentosa (RP) is a genetically heterogeneous disorder characterized by progressive degeneration of the peripheral retina leading to night blindness and loss of visual fields. With an incidence of approximately 1 in 4000, RP can be inherited in X-linked, autosomal dominant or autosomal recessive modes. The RP13 locus for autosomal dominant RP (adRP) was placed on chromosome 17p13.3 by linkage mapping in a large South African adRP family. Using a positional cloning and candidate gene strategy, we have identified seven different missense mutations in the splicing factor gene PRPC8 in adRP families. Three of the mutations cosegregate within three RP13 linked families including the original large South African pedigree, and four additional mutations have been identified in other unrelated adRP families. The seven mutations are clustered within a 14 codon stretch within the last exon of this large 7 kb transcript. The altered amino acid residues at the C-terminus exhibit a high degree of conservation across species as diverse as humans, Arabidopsis and trypanosome, suggesting that some functional significance is associated with this part of the protein. These mutations in this ubiquitous and highly conserved splicing factor offer compelling evidence for a novel pathway to retinal degeneration.

PQBP1, a factor linked to intellectual disability, affects alternative splicing associated with neurite outgrowth

“…Trans-acting defects arise from mutations or misregulation of splicing regulatory factors. One example is retinitis pigmentosa, characterized by a progressive loss of rod photoreceptor cells, which results from mutations in HPRP3, PRP31, and PRPC8-factors crucial for the assembly and functioning of U small nuclear ribonucleoproteins (snRNPs) in premRNA splicing (McKie et al 2001;Vithana et al 2001;Chakarova et al 2002). Although increasing numbers of splicing-related disorders have been identified, the molecular link between AS regulation and the disease phenotype remains to be elucidated.…”

Contribution of SNRNP200 sequence variations to retinitis pigmentosa

“…21,32,[42][43][44] Although it is clear that the retina requires a relatively high level of RNA splicing activity for optimal tissue-specific physiological function, 45 how the defects in this essential macromolecular complex transform into a photoreceptorspecific phenotype is unknown. The underlying reason for the RNA intron-splicing factors to be related to adRP is also unclear.…”

Novel deletion in the pre‐mRNA splicing gene PRPF31 causes autosomal dominant retinitis pigmentosa in a large Chinese family

“…Lack of the PRPF31 protein blocks tri-snRNP formation and pre-mRNA splicing [Makarova et al, 2002]. It is interesting to note that two other newly-identified adRP genes also encode proteins involved in pre-mRNA splicing: PRPC8 at 17p13.3 (RP13) coding for PRP8 (a core component of the U5 snRNP) [McKie et al, 2001], and HPRP3 at 1p13-q21 (RP18) for PRP3 (a component of the U4/U6) [Chakarova et al, 2002]. These data together suggest that disruptions in tri-SNP formation and function contribute to the pathogenesis of adRP.…”