PRPF3 – Retinitis Pigmentosa

Pre-mRNA processing factor 3 (PRPF3) is a ubiquitously expressed spliceosomal U4/U6 di-snRNP protein whose heterozygous missense variants cause autosomal dominant Retinitis Pigmentosa, manifesting with night blindness (nyctalopia) and progressive peripheral vision loss, often accompanied by myopia.

The recurrent hotspot variant c.1481C>T (p.Thr494Met) was first described in a five-generation Swiss family with 11 affected members displaying variable age of onset (3–25 years) and progression (PMID:20309403). Subsequent screening identified both p.Thr494Met and c.1477C>T (p.Pro493Ser) in two English families, a Danish family, and three sporadic cases, confirming a mutation cluster in exon 11 (PMID:11773002).

Additional missense variants c.1345C>G (p.Arg449Gly) and c.1532A>C (p.His511Pro) were reported in Chinese ADRP families, each co-segregating with disease and expanding the mutational spectrum (PMID:27886254). The recurring p.Thr494Met allele in diverse populations supports multiple independent origins.

Functional studies show that p.Thr494Met and p.Pro493Ser mutants reduce CKII-mediated phosphorylation of PRPF3 and weaken interactions within the U4/U6 snRNP complex, impairing U4/U6-U5 tri-snRNP assembly (PMID:17932117). In photoreceptor cells, mutant PRPF3 forms large nuclear aggregates that trigger apoptosis, whereas wild-type protein remains soluble and correctly localized (PMID:17517693).

A Prpf3-T494M knock-in mouse model recapitulates key RP features, including RPE vacuolization and decreased rod function by two years of age, whereas heterozygous null mice exhibit normal retinal structure and function, supporting a toxic gain-of-function mechanism rather than haploinsufficiency (PMID:20811066; PMID:18552388).

Together, robust segregation of exon 11 missense variants across ≥7 unrelated ADRP families, recurrent mutation hotspots, and convergent functional data establish that PRPF3 mutants act via a dominant negative/toxic gain-of-function mechanism in photoreceptors. Key take-home: testing for PRPF3 exon 11 variants should be included in genetic panels for autosomal dominant retinitis pigmentosa.

References

• Molecular vision • 2010 • Variable phenotypic expressivity in a Swiss family with autosomal dominant retinitis pigmentosa due to a T494M mutation in the PRPF3 gene. PMID:20309403
• Human molecular genetics • 2002 • Mutations in HPRP3, a third member of pre-mRNA splicing factor genes, implicated in autosomal dominant retinitis pigmentosa. PMID:11773002
• Human molecular genetics • 2007 • Mutations in splicing factor PRPF3, causing retinal degeneration, form detrimental aggregates in photoreceptor cells. PMID:17517693
• Human molecular genetics • 2008 • Mutation in the splicing factor Hprp3p linked to retinitis pigmentosa impairs interactions within the U4/U6 snRNP complex. PMID:17932117
• Investigative ophthalmology & visual science • 2008 • Decreased levels of the RNA splicing factor Prpf3 in mice and zebrafish do not cause photoreceptor degeneration. PMID:18552388
• Investigative ophthalmology & visual science • 2011 • Three gene-targeted mouse models of RNA splicing factor RP show late-onset RPE and retinal degeneration. PMID:20811066
• Scientific reports • 2016 • Two novel mutations in PRPF3 causing autosomal dominant retinitis pigmentosa. PMID:27886254

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