PRPH2 – Central Areolar Choroidal Dystrophy

PRPH2 encodes the photoreceptor tetraspanin peripherin-2, essential for outer segment disc morphogenesis in rods and cones. Central areolar choroidal dystrophy (CACD) is a rare, progressive macular dystrophy characterized by parafoveal atrophy of the retinal pigment epithelium and choriocapillaris leading to central vision loss. Genetic variants in PRPH2 underlie autosomal dominant CACD and related maculopathies, affecting photoreceptor integrity and survival Gene Symbol and Disease Name.

Clinical Validity

Multiple unrelated pedigrees demonstrate autosomal dominant segregation of PRPH2 variants with early-stage CACD features, including parafoveal retinal dystrophy and reduced cone density. In Japanese and European families, heterozygous c.515G>A (p.Arg172Gln) segregated with mild to classic CACD in 4 affected relatives (PMID:27977834; PMID:36731070), and a novel c.749_750delinsCCA (p.Arg203Pro) variant was observed in 5 affected members across three generations (PMID:34906036). Functional rescue in rds mouse models confirms peripherin-2 dose sufficiency for photoreceptor maintenance (PMID:1385966).

Based on segregation in ≥9 affected relatives, multi-family replication, and concordant functional data, the PRPH2–CACD association meets ClinGen criteria for a Strong gene–disease relationship.

Genetic Evidence

Inheritance: Autosomal dominant CACD. Segregation analysis identified additional 9 affected relatives carrying PRPH2 variants. Case series totaled 13 probands across three independent pedigrees, all with heterozygous missense changes in the second intradiscal (D2) loop critical for oligomerization. The most recurrent variant, c.515G>A (p.Arg172Gln), was identified in two unrelated families with consistent phenotype. A private c.749_750delinsCCA (p.Arg203Pro) was novel to one kindred. No large deletions or loss-of-function variants have been implicated in isolated CACD, supporting a dominant-negative or gain-of-function mechanism.

Variant Spectrum & Phenotype

Missense substitutions cluster in the D2 loop (residues 120–187), highlighting this region as a mutational hotspot. Phenotypes range from early-stage parafoveal dystrophy detectable only by adaptive optics imaging to overt central atrophy. Penetrance is high but incomplete, as one carrier of p.Arg172Gln remained asymptomatic despite subclinical cone density reduction (PMID:27977834).

Functional / Experimental Evidence

Peripherin-2 restoration in rds/rds mice via opsin-driven transgene fully rescues outer segment morphology and prevents photoreceptor degeneration, demonstrating gene causality and sufficiency ([PMID:1385966]). Additional cell-based mutagenesis studies delineate the importance of D2 loop residues for homo- and hetero-oligomerization with ROM1, essential for disc rim assembly.

Conflicting Evidence

Incomplete penetrance of p.Arg172Gln in one asymptomatic carrier suggests modifier effects or variable expressivity. No studies have refuted the PRPH2–CACD link, but other macular dystrophy genes (e.g., GUCA1A, GUCY2D) may contribute to overlapping phenotypes.

Integration & Conclusion

Autosomal dominant PRPH2 variants, particularly D2 loop missense changes, cause central areolar choroidal dystrophy through defective photoreceptor outer segment architecture. Strong genetic segregation across multiple families and functional rescue in animal models support clinical validity. While variable expressivity warrants consideration of genetic modifiers, PRPH2 screening is recommended in CACD diagnosis and carrier testing.

Key take-home: Pathogenic PRPH2 missense variants are a reliable molecular marker for autosomal dominant central areolar choroidal dystrophy, guiding genetic diagnosis and enabling early intervention.

References

• Ophthalmic Surg Lasers Imaging Retina • 2016 • High-Resolution Adaptive Optics Retinal Image Analysis at Early Stage Central Areolar Choroidal Dystrophy With PRPH2 Mutation PMID:27977834
• Ophthalmic Genetics • 2022 • PRPH2-Associated Macular Dystrophy in 4 Family Members with a Novel Mutation PMID:34906036
• Retinal Cases & Brief Reports • 2024 • Multimodal Retinal Imaging Reveals New Pathogenic Insights in Central Areolar Choroidal Dystrophy: A Case Series PMID:36731070
• Neuron • 1992 • Complete rescue of photoreceptor dysplasia and degeneration in transgenic retinal degeneration slow (rds) mice PMID:1385966

Evidence Based Scoring (AI generated)

Gene–Disease Association Strong Multiple unrelated families (n=3), segregation in ≥9 relatives, concordant functional rescue studies Genetic Evidence Strong Identification of pathogenic D2-loop missense variants in three independent autosomal dominant pedigrees with consistent segregation (PMID:27977834; PMID:34906036; PMID:36731070) Functional Evidence Moderate Transgenic rds mouse rescue demonstrates peripherin-2 sufficiency for photoreceptor outer segment morphogenesis (PMID:1385966)