PRPH2 – Retinitis Pigmentosa

Peripherin-2, encoded by PRPH2 (HGNC:9942), is a photoreceptor-specific tetraspanin required for outer segment morphogenesis. Autosomal-dominant retinitis pigmentosa (RP) was first linked to a heterozygous c.629C>G (p.Pro210Arg) variant in a large pedigree and two unrelated families exhibiting peripheral and macular degeneration (PMID:7862413).

Segregation analysis across multiple kindreds demonstrates clear autosomal-dominant inheritance. The c.748T>G (p.Cys250Gly) variant co-segregated with RP in eight affected members of four Japanese families, three of which shared a common haplotype (PMID:29630435). A founder splice-donor alteration c.828+3A>T was identified in 97 individuals from 19 independent families, accounting for ~2% of AD RP cases (PMID:25675413).

The PRPH2 mutation spectrum exceeds 200 unique variants, predominantly missense substitutions clustered within the second intradiscal (D2) loop, but also includes splice-site, frameshift, and nonsense alleles. Digenic RP arises when PRPH2 p.Leu185Pro co-occurs with ROM1 variants in four patients, underscoring critical PRPH2–ROM1 interactions (PMID:9331261).

Functional studies confirm pathogenicity through concordant animal and cellular models. Transgenic expression of wild-type PRPH2 completely rescues retinal dysplasia in rds/rds mice, restoring normal outer segment architecture (PMID:1385966). Targeted neutralization of charged residues Glu321 and Lys324 in the D2 loop abolishes lipid-mixing fusogenic activity without disrupting subunit assembly, linking D2 loop integrity to membrane fusion (PMID:15252042).

Not all variants are pathogenic: c.148G>C (p.Asp50His) failed to co-segregate with disease in a Chinese pedigree and is likely benign (PMID:22567862).

References

• Ophthalmology • 1995 • A peripherin/retinal degeneration slow mutation (Pro-210-Arg) associated with macular and peripheral retinal degeneration. PMID:7862413
• Investigative ophthalmology & visual science • 1997 • Dominant and digenic mutations in the peripherin/RDS and ROM1 genes in retinitis pigmentosa. PMID:9331261
• Neuron • 1992 • Complete rescue of photoreceptor dysplasia and degeneration in transgenic retinal degeneration slow (rds) mice. PMID:1385966
• The Journal of Biological Chemistry • 2004 • Uncoupling of photoreceptor peripherin/rds fusogenic activity from biosynthesis, subunit assembly, and targeting: a potential mechanism for pathogenic effects. PMID:15252042
• Ophthalmic genetics • 2018 • Autosomal dominant retinitis pigmentosa with macular involvement associated with a disease haplotype that included a novel PRPH2 variant (p.Cys250Gly). PMID:29630435
• Genetika • 2012 • Gene mapping and mutation screening in candidate genes in a Chinese family of autosomal dominant retinitis pigmentosa. PMID:22567862

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