ArticleFASEB journal : official publication of the Federation of American Societies for Experimental Biology2020
Novel molecular mechanisms for Prph2-associated pattern dystrophy.
Article in FASEB journal : official publication of the Federation of American Societies for Experimental Biology, 2020. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 20 papers.
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Who cites it
20 citing papers in PubMed, 29 citations in OpenAlex.
- Advancing genetic pathogenicity prediction with three-dimensional proteoform-phenotype analysis.medRxiv : the preprint server for health sciences · 2026Article
- Transient Knockdown of RORB with Cell-Penetrating siRNA Improves Visual Function in a Proteotoxic Mouse Model of Retinitis Pigmentosa.Biomedicines · 2025Article
- Genotype-Phenotype Correlations inGenes · 2025Article
- Expanding Genetic and Clinical Spectra of Inherited Retinal Dystrophies: Identification of Three NovelBiomedicines · 2025Article
- The PRPH2 D2 Loop: Biochemical Insights and Implications in Disease.Advances in experimental medicine and biology · 2025Review
- Downregulation of rhodopsin is an effective therapeutic strategy in ameliorating peripherin-2-associated inherited retinal disorders.Nature communications · 2024Article
- Review
- Prph2 knock-in mice recapitulate human central areolar choroidal dystrophy retinal degeneration and exhibit aberrant synaptic remodeling and microglial activation.Cell death & disease · 2023Article
- Primary versus Secondary Elevations in Fundus Autofluorescence.International journal of molecular sciences · 2023Review
- Comparative study of PRPH2 D2 loop mutants reveals divergent disease mechanism in rods and cones.Cellular and molecular life sciences : CMLS · 2023Article
- Visualization of automatically combined disease maps and pathway diagrams for rare diseases.Frontiers in bioinformatics · 2023Article
- Delineating the Clinical Phenotype of Patients With the c.629C>G, p.Pro210Arg Mutation in Peripherin-2.Investigative ophthalmology & visual science · 2022Article
- Prph2 disease mutations lead to structural and functional defects in the RPE.FASEB journal : official publication of the Federation of American Societies for Experimental Biology · 2022Article
- Increased Susceptibility to Cerebral Microhemorrhages Is Associated With Imaging Signs of Microvascular Degeneration in the Retina in an Insulin-Like Growth Factor 1 Deficient Mouse Model of Accelerated Aging.Frontiers in aging neuroscience · 2022Article
- PRPH2 mutation update: In silico assessment of 245 reported and 7 novel variants in patients with retinal disease.Human mutation · 2021Article
- Gene Therapy to the Retina and the Cochlea.Frontiers in neuroscience · 2021Review
- ROM1 contributes to phenotypic heterogeneity in PRPH2-associated retinal disease.Human molecular genetics · 2020Article
- Observational
- Review
- Photoreceptor Disc Enclosure Occurs in the Absence of Normal Peripherin-2/rds Oligomerization.Frontiers in cellular neuroscience · 2020Article
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Authors and funding
7 authors at 2 institutions in 1 country.
Funding
Abstract
Mutations in peripherin 2 (PRPH2) have been associated with retinitis pigmentosa (RP) and macular/pattern dystrophies, but the origin of this phenotypic variability is unclear. The majority of Prph2 mutations are located in the large intradiscal loop (D2), a region that contains seven cysteines involved in intra- and intermolecular disulfide bonding and protein folding. A mutation at cysteine 213, which is engaged in an intramolecular disulfide bond, leads to butterfly-shaped pattern dystrophy in humans, in sharp contrast to mutations in the adjacent cysteine at position 214 which result in RP. To help understand this unexpected phenotypic variability, we generated a knockin mouse line carrying the C213Y disease mutation. The mutant Prph2 protein lost the ability to oligomerize with rod outer segment membrane protein 1 (Rom1), but retained the ability to form homotetramers. C213Y heterozygotes had significantly decreased overall Prph2 levels as well as decreased rod and cone function. Critically, supplementation with extra wild-type Prph2 protein elicited improvements in Prph2 protein levels and rod outer segment structure, but not functional rescue in rods or cones. These findings suggest that not all interruptions of D2 loop intramolecular disulfide bonding lead to haploinsufficiency-related RP, but rather that more subtle changes can lead to mutant proteins stable enough to exert gain-of-function defects in rods and cones. This outcome highlights the difficulty in targeting Prph2-associated gain-of-function disease and suggests that elimination of the mutant protein will be a pre-requisite for any curative therapeutic strategy.
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