PRPH2 – Inherited Retinal Dystrophy

Peripherin-2 (PRPH2; HGNC:9942) encodes a tetraspanin critical for photoreceptor outer segment morphogenesis. Heterozygous PRPH2 variants typically cause autosomal dominant pattern dystrophy, cone-rod dystrophy or retinitis pigmentosa, while bi-allelic loss-of-function leads to early-onset Leber congenital amaurosis within the broader category of inherited retinal dystrophy (MONDO:0019118). Given extensive allelic heterogeneity, both dominant-negative and haploinsufficiency mechanisms have been described.

Genetic evidence includes a multi-generation family with fundus flavimaculatus, central areolar chorioretinal dystrophy and macular pattern dystrophy in heterozygotes and an LCA-like early-onset retinal dystrophy in one homozygote for c.715C>T (p.Gln239Ter) ([PMID:31618092]). Independent reports of five homozygous probands from two kindreds (three children, two adults) with infantile nystagmus and non-recordable ERGs confirm recessive PRPH2 LCA phenotypes; all available heterozygous parents exhibited macular changes ([PMID:26061163]).

Larger cohorts reinforce the dominant association: 40 Japanese patients from 30 families carried 17 distinct pathogenic or likely pathogenic variants with p.Arg142Trp and p.Val200Glu relatively frequent ([PMID:34828423]). In a Spanish series of 220 patients from 103 families, 56 variants were identified, 64% missense clustering in the D2 loop domain, and founder alleles p.Leu41Pro and p.Pro221_Cys222del were ascertained by haplotype analysis ([PMID:38474159]).

The variant spectrum exceeds 245 unique alleles: missense, frameshift, nonsense, splice-site, deep-intronic and complex indels. Recurrent hotspots include p.Arg172Trp, p.Gly167Ser, p.Cys213Tyr, and the splice-site founder c.828+3A>T, which segregates in 19 families and modifies phenotype severity depending on trans-haplotype ([PMID:26842753]).

Functional studies demonstrate that wild-type PRPH2 rescues photoreceptor dysplasia in rds/rds mice ([PMID:1385966]), while targeted D2-loop mutagenesis uncouples fusogenic activity from biosynthesis and disc targeting ([PMID:15252042]) and defines Cys165–Asn182 as essential for homo-/hetero-oligomerization with ROM1 ([PMID:15779916]). The R172W knock-in model recapitulates late-onset cone degeneration and shows only transient rescue with supplementation, supporting both dominant-negative and haploinsufficiency mechanisms ([PMID:18055786]).

Collectively, definitive genetic and experimental data spanning over 700 index patients from hundreds of families establish PRPH2 as a definitive cause of inherited retinal dystrophy. Comprehensive PRPH2 sequencing is warranted in patients with pattern dystrophy, cone-rod dystrophy or non-recordable ERGs for precise diagnosis, prognostic counseling and eligibility for gene-based therapies.

Key Take-home: PRPH2 exhibits a definitive autosomal dominant association with inherited retinal dystrophy, with dose-sensitive outcomes ranging from pattern dystrophy in heterozygotes to early-onset LCA in homozygotes.

References

• Ophthalmic Genetics | 2019 | PRPH2 mutation as the cause of various clinical manifestations in a family affected with inherited retinal dystrophy. [PMID:31618092]
• British Journal of Ophthalmology | 2016 | Peripherin mutations cause a distinct form of recessive Leber congenital amaurosis and dominant phenotypes in asymptomatic parents heterozygous for the mutation. [PMID:26061163]
• Genes | 2021 | Genetic and Phenotypic Landscape of PRPH2-Associated Retinal Dystrophy in Japan. [PMID:34828423]
• International Journal of Molecular Sciences | 2024 | PRPH2-Related Retinal Dystrophies: Mutational Spectrum in 103 Families from a Spanish Cohort. [PMID:38474159]
• Investigative Ophthalmology & Visual Science | 2016 | Autosomal Dominant Retinal Dystrophies Caused by a Founder Splice Site Mutation, c.828+3A>T, in PRPH2 and Protein Haplotypes in trans as Modifiers. [PMID:26842753]
• 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]
• Biochemistry | 2005 | Role of the second intradiscal loop of peripherin/rds in homo and hetero associations. [PMID:15779916]
• Investigative Ophthalmology & Visual Science | 2007 | Late-onset cone photoreceptor degeneration induced by R172W mutation in Rds and partial rescue by gene supplementation. [PMID:18055786]

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