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PRPF4 – Retinitis Pigmentosa

PRPF4 encodes a core U4/U6.U5 tri-snRNP spliceosomal component whose dysfunction leads to autosomal dominant retinitis pigmentosa (MONDO:0019200; HGNC:17349). Variants in PRPF4 compromise pre-mRNA splicing in photoreceptors, resulting in progressive degeneration.

Genetic Evidence

Autosomal dominant inheritance is supported by three unrelated probands. A heterozygous missense variant, c.572G>A (p.Arg191His), was identified in a simplex RP case and shown to abolish PRPF4 function in zebrafish in vivo (PMID:25383878). In a separate adRP pedigree, a promoter deletion (c.-114_-97del) and a missense variant c.941C>T (p.Pro314Leu) co-segregated with disease and were absent from 400 controls (PMID:24419317). Altogether, these findings in three probands and segregation in one family establish robust genetic association.

Functional Evidence

Biochemical assays demonstrate that p.Arg191His disrupts PRPF4 binding to PRPF3 and prevents integration into the tri-snRNP in human cells and zebrafish embryos, confirming a loss-of-function effect (PMID:25383878). Luciferase reporter studies show that c.-114_-97del reduces promoter activity and PRPF4 expression, consistent with haploinsufficiency. Zebrafish models recapitulate photoreceptor defects, supporting a pathogenic mechanism combining haploinsufficiency and dominant-negative effects (PMID:24419317).

Conflicting Evidence

A mutational screen of 303 adRP patients did not identify clearly pathogenic PRPF4 variants, indicating rare allelic heterogeneity and low prevalence in certain populations (PMID:24959063).

Conclusion

Integration of genetic segregation data, detailed functional assays, and in vivo modeling supports a Strong association between PRPF4 variants and autosomal dominant retinitis pigmentosa driven by spliceosomal dysfunction. PRPF4 genetic testing aids diagnosis and informs genetic counseling in RP.

References

  • PLoS One • 2014 • Identification of a PRPF4 loss-of-function variant that abrogates U4/U6.U5 tri-snRNP integration and is associated with retinitis pigmentosa. PMID:25383878
  • Human molecular genetics • 2014 • PRPF4 mutations cause autosomal dominant retinitis pigmentosa. PMID:24419317
  • Molecular vision • 2014 • Mutational screening of splicing factor genes in cases with autosomal dominant retinitis pigmentosa. PMID:24959063

Evidence Based Scoring (AI generated)

Gene–Disease Association

Strong

3 probands, segregation in one family, concordant functional data

Genetic Evidence

Strong

Identified in 3 probands with 2 distinct missense and 1 regulatory variants; promoter deletion and c.941C>T co-segregate in an adRP pedigree; AD inheritance ([PMID:25383878]; [PMID:24419317])

Functional Evidence

Moderate

Zebrafish LOF and human cell assays show disrupted tri-snRNP integration and promoter downregulation consistent with haploinsufficiency and dominant-negative effects ([PMID:25383878]; [PMID:24419317])