PRPF31 – Retinitis Pigmentosa 11

Autosomal dominant retinitis pigmentosa 11 (RP11) is caused by heterozygous mutations in the spliceosome component PRPF31. Disease penetrance is modulated by wild-type allele expression, with insufficient transcript levels leading to rod photoreceptor degeneration and night blindness.

Genetic evidence supports a definitive gene–disease relationship. Over 200 unrelated probands across more than 40 families have been reported with PRPF31 variants in RP11 ([PMID:12444105], [PMID:18317597]). Segregation analyses demonstrate co-segregation of truncating and splice-site alleles with disease in multiple pedigrees, including a large Chinese family with an IVS5-1G>A splice acceptor mutation ([PMID:15162096]).

The variant spectrum in RP11 is dominated by loss-of-function alleles: nonsense, frameshift, and essential splice-site mutations. More than 100 unique truncating variants (e.g., c.1205C>A (p.Ser402Ter)) have been described ([PMID:38542364]). A minority of missense mutations impair nuclear localization and solubility (e.g., p.Ala216Pro) but converge on a haploinsufficiency mechanism.

Functional studies corroborate haploinsufficiency as the primary pathogenic mechanism. Allele-specific expression assays reveal nonsense-mediated mRNA decay of mutant transcripts and a 46% reduction in total PRPF31 mRNA in patient fibroblasts ([PMID:38542364]). Quantitative RT-PCR in lymphoblastoid lines shows symptomatic carriers express 52–77% of wild-type levels versus near-normal levels in nonpenetrant relatives ([PMID:14507862]).

Spliceosome biochemistry and animal models further reinforce pathogenicity. In zebrafish and mouse, heterozygous loss of Prpf31 yields minimal extraocular phenotype but retinal pigment epithelium degeneration by one year, mirroring adult-onset RP11 ([PMID:19578015], [PMID:20811066]). Exon skipping strategies in patient cells restore the open reading frame and increase PRPF31 mRNA 1.7-fold, meeting therapeutic thresholds inferred from nonpenetrant carriers ([PMID:38542364]).

No studies have conclusively refuted the association or proposed an alternative mechanism. Modifier loci on chromosome 14q21-23 act in trans to regulate PRPF31 expression but do not alter the core AD inheritance pattern.

Key Take-home: PRPF31 mutations cause RP11 via haploinsufficiency with variable penetrance, supporting genetic diagnosis, segregation analysis, and emerging antisense oligonucleotide therapies.

References

• International Journal of Molecular Sciences • 2024 • A Precision Therapy Approach for Retinitis Pigmentosa 11 Using Splice-Switching Antisense Oligonucleotides to Restore the Open Reading Frame of PRPF31. PMID:38542364
• Human Molecular Genetics • 2002 • Disease mechanism for retinitis pigmentosa (RP11) caused by mutations in the splicing factor gene PRPF31. PMID:12444105
• The Journal of Clinical Investigation • 2008 • Premature termination codons in PRPF31 cause retinitis pigmentosa via haploinsufficiency due to nonsense-mediated mRNA decay. PMID:18317597
• Investigative Ophthalmology & Visual Science • 2003 • Expression of PRPF31 mRNA in patients with autosomal dominant retinitis pigmentosa: a molecular clue for incomplete penetrance? PMID:14507862
• Molecular Vision • 2004 • A novel PRPF31 splice-site mutation in a Chinese family with autosomal dominant retinitis pigmentosa. PMID:15162096

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