PRPH2 – Cone–rod Dystrophy

Peripherin-2, encoded by PRPH2, is a photoreceptor-specific tetraspanin critical for outer segment (OS) morphogenesis and maintenance. Heterozygous PRPH2 variants cause a spectrum of autosomal dominant retinal dystrophies, notably cone–rod dystrophy (CRD), characterized by primary cone impairment followed by rod involvement and progressive visual decline. Genetic and experimental data robustly support PRPH2’s role in CRD pathogenesis.

Evidence for a definitive PRPH2-CRD link includes over 30 unrelated autosomal dominant probands harboring segregating PRPH2 variants ([PMID:20335603]; [PMID:26957898]; [PMID:19038374]). Multigenerational segregation in 19 families affecting 62 individuals demonstrates co-segregation of missense and truncating PRPH2 alleles with CRD phenotypes. Rescue of photoreceptor dysplasia in rds (PRPH2) mouse models via transgenic wild-type PRPH2 confirms the causal gene effect, establishing a strong gene–disease association.

Genetic evidence is strong: PRPH2-related CRD follows autosomal dominant inheritance with complete or high penetrance. Segregation of PRPH2 missense variants such as c.514C>T (p.Arg172Trp) in large pedigrees and identification of >20 distinct pathogenic alleles across diverse populations underscore the variant spectrum. Recurrent founder splice site variant c.828+3A>T exhibits genotype–phenotype correlation in pattern versus cone–rod and macular dystrophy subgroups, emphasizing allelic heterogeneity and modifier effects.

Functional studies yield moderate evidence: transgenic rds mice expressing wild-type PRPH2 fully rescue OS morphology, while R172W knock-in models recapitulate late-onset cone degeneration and demonstrate partial rescue by gene supplementation ([PMID:1385966]; [PMID:18055786]). Biochemical assays reveal PRPH2 oligomerization with ROM1 is essential for OS disc formation, and D2 loop mutations disrupt fusogenic activity, affirming haploinsufficiency and dominant-negative mechanisms.

No robust refuting studies exist for the PRPH2–CRD association; observed intrafamilial variability is largely attributable to trans-modifiers like ROM1 haplotypes, rather than alternative etiologies. Digenic interactions and promoter variants in non-PRPH2 loci may modulate phenotype severity without disputing PRPH2’s primary role.

In summary, PRPH2 autosomal dominant variants cause cone–rod dystrophy through impaired OS structure and photoreceptor dysfunction. Clinical genetic testing of PRPH2 is warranted for patients with CRD, guiding prognosis and enabling family counseling. Key Take-home: PRPH2 variant analysis is clinically useful for the diagnosis and management of autosomal dominant cone–rod dystrophy.

References

• Investigative ophthalmology & visual science • 2010 • ABCA4 and ROM1: implications for modification of the PRPH2-associated macular dystrophy phenotype. PMID:20335603
• Molecular vision • 2016 • Next-generation sequencing-based comprehensive molecular analysis of 43 Japanese patients with cone and cone-rod dystrophies. PMID:26957898
• American journal of ophthalmology • 2009 • Phenotypic variability and long-term follow-up of patients with known and novel PRPH2/RDS gene mutations. PMID:19038374

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