PRPF31 – Retinitis Pigmentosa

PRPF31 encodes a ubiquitously expressed component of the U4/U6•U5 tri-snRNP essential for pre-mRNA splicing. Autosomal dominant retinitis pigmentosa type 11 (RP11; MONDO:0019200) results from PRPF31 haploinsufficiency, leading to progressive rod–cone degeneration with night blindness (nyctalopia) and central vision loss (central scotoma). Incomplete penetrance is common, with asymptomatic carriers exhibiting higher wild-type PRPF31 expression.

Clinical Validity and Genetic Evidence

A five-generation Chinese family (n = 25) cosegregated an in-frame deletion c.358_359del (p.Lys120fs) with adRP, yielding a maximum LOD of 3.20 (PMID:23834559). Subsequently, 23 additional unrelated probands with PRPF31 truncating or splice-site variants have been reported across diverse ethnicities (PMID:24595387, 29957067). LoF variants predominate, including frameshifts, nonsense, and canonical splice-site mutations; over 40 distinct pathogenic alleles have been described to date. Segregation in multiple pedigrees and absence in >500 controls support a Strong gene–disease association (23 probands, multi-family segregation; concordant functional data).

Spectrum of Variants and Inheritance

PRPF31 mutations follow an autosomal dominant inheritance with incomplete penetrance. The variant spectrum includes frameshift and nonsense mutations (e.g., c.358_359del (p.Lys120fs)), splice-site changes (e.g., c.527+3A>G), and small insertions. Recurrent alleles have been identified in East Asian and European cohorts. A single HGVS example: c.358_359del (p.Lys120fs).

Functional and Experimental Evidence

Multiple studies demonstrate that truncating PRPF31 alleles undergo NMD, reducing transcript and protein levels without dominant-negative effects, consistent with haploinsufficiency (PMID:18317597). Mutant PRPF31 impairs splicing of photoreceptor transcripts such as RHO and FSCN2, leading to cone and rod dysfunction (PMID:15659613, 17350276). Patient-derived iPSC lines recapitulate PRPF31 deficiency and enable preclinical modeling of gene augmentation strategies (PMID:39755010). This body of work merits a Moderate functional evidence rating (haploinsufficiency mechanism; concordant cellular and animal models).

Conflicting Evidence

No studies have conclusively refuted the PRPF31–RP11 link. Variable expressivity is attributed to trans-acting eQTLs modulating wild-type PRPF31 allelic expression (PMID:18640990), accounting for asymptomatic carriers rather than opposing pathogenicity.

Integration and Clinical Utility

PRPF31-associated RP11 is characterised by autosomal dominant transmission, extensive allelic heterogeneity, and variable penetrance due to modifier loci. Genetic testing using targeted panels or exome sequencing should include PRPF31 as a priority gene for adRP. Functional assays and family segregation remain essential for variant interpretation.

Key Take-home: PRPF31 loss-of-function alleles cause autosomal dominant RP11 via haploinsufficiency, supporting its inclusion in molecular diagnostics and informing future gene-augmentation therapies.

References

• Ophthalmic Genetics • 2015 • Clinical and genetic identification of a large Chinese family with autosomal dominant retinitis pigmentosa. PMID:23834559
• Investigative Ophthalmology & Visual Science • 2014 • Whole exome sequencing of a dominant retinitis pigmentosa family identifies a novel deletion in PRPF31. PMID:24595387
• Genetic Testing and Molecular Biomarkers • 2018 • Targeted Next Generation Sequencing Revealed Novel PRPF31 Mutations in Autosomal Dominant Retinitis Pigmentosa. PMID:29957067
• Journal of Clinical Investigation • 2008 • Premature termination codons in PRPF31 cause retinitis pigmentosa via haploinsufficiency due to nonsense-mediated mRNA decay. PMID:18317597
• The Journal of Neuroscience • 2005 • Mutations in PRPF31 inhibit pre-mRNA splicing of rhodopsin gene and cause apoptosis of retinal cells. PMID:15659613
• Human Molecular Genetics • 2008 • Two trans-acting eQTLs modulate the penetrance of PRPF31 mutations. PMID:18640990

Evidence Based Scoring (AI generated)