Variegated yet non-random rod and cone photoreceptor disease patterns in RPGR-ORF15-associated retinal degeneration

Area of Science:

• Ophthalmology
• Genetics
• Retinal Diseases

Background:

• X-linked retinitis pigmentosa (XLRP) is a common inherited retinal disease.
• Mutations in the RPGR gene's ORF15 exon are a frequent cause of XLRP, leading to severe vision loss.
• Gene augmentation therapy has shown potential in animal models, but human photoreceptor distribution and degeneration rates are unclear.

Purpose of the Study:

• To characterize the structural and functional aspects of XLRP caused by ORF15 mutations in humans.
• To correlate human disease features with those observed in Rpgr-mutant mouse models.
• To identify potential targets for localized gene therapies.

Main Methods:

• Studied 70 individuals with ORF15 mutations in the RPGR gene.
• Correlated patient findings with three mouse models (Rpgr-ko, Rd9, Rpgr-cko).
• Performed longitudinal analysis of photoreceptor dysfunction and progression rates.

Main Results:

• Patients exhibited significant macular disease and inter-individual variability in rod and cone dysfunction, with high inter-ocular symmetry.
• No correlation was found between genotype and disease expression in patients.
• Mouse models showed intra-retinal differences in opsin trafficking and inter-ocular symmetry in degeneration.
• Longitudinal studies revealed localized photoreceptor dysfunction progression (0.8-1.3 log/decade).

Conclusions:

• ORF15 mutations in RPGR cause a spectrum of XLRP with macular involvement and symmetrical progression.
• Peripheral photoreceptors in specific visual field regions remain relatively preserved, indicating potential targets for gene therapy.
• Rpgr-mutant mice offer valuable models for studying XLRP pathogenesis and therapeutic strategies.