Prph2 knock-in mice recapitulate human central areolar choroidal dystrophy retinal degeneration and exhibit aberrant synaptic remodeling and microglial activation

Ruiz-Pastor, María José; Sánchez-Sáez, Xavier; Kutsyr, Oksana; Albertos-Arranz, Henar; Sánchez-Castillo, Carla; Ortuño-Lizarán, Isabel; Martínez-Gil, Natalia; Vidal-Gil, Lorena; Méndez, Lucía; Sánchez-Martín, Manuel; Maneu, Victoria; Lax, Pedro; Cuenca, Nicolás

doi:10.1038/s41419-023-06243-8

Cited by 2 publications

(1 citation statement)

References 52 publications

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“…Finally, a knock-in animal model of CACD due to p.(Arg195Leu) demonstrated a progressive decrease in VA and ERG amplitudes in both scotopic and photopic conditions. 60 Our ERG data for CACD showed a similar trend toward greater cone than rod involvement as reported previously by Hoyng and Deutman. 19 It is intriguing that these animals exhibited evidence of disrupted communication between photoreceptors, bipolar and horizontal cells, supporting the observation of a reduced b:a ratio.…”

Section: Discussionsupporting

confidence: 90%

Retinal Dystrophies Associated With Peripherin-2: Genetic Spectrum and Novel Clinical Observations in 241 Patients

Heath Jeffery,

Thompson,

et al. 2024

Invest. Ophthalmol. Vis. Sci.

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Purpose To describe the clinical, electrophysiological and genetic spectrum of inherited retinal diseases associated with variants in the PRPH2 gene. Methods A total of 241 patients from 168 families across 15 sites in 9 countries with pathogenic or likely pathogenic variants in PRPH2 were included. Records were reviewed for age at symptom onset, visual acuity, full-field ERG, fundus colour photography, fundus autofluorescence (FAF), and SD-OCT. Images were graded into six phenotypes. Statistical analyses were performed to determine genotype–phenotype correlations. Results The median age at symptom onset was 40 years (range, 4–78 years). FAF phenotypes included normal (5%), butterfly pattern dystrophy, or vitelliform macular dystrophy (11%), central areolar choroidal dystrophy (28%), pseudo-Stargardt pattern dystrophy (41%), and retinitis pigmentosa (25%). Symptom onset was earlier in retinitis pigmentosa as compared with pseudo-Stargardt pattern dystrophy (34 vs 44 years; P = 0.004). The median visual acuity was 0.18 logMAR (interquartile range, 0–0.54 logMAR) and 0.18 logMAR (interquartile range 0–0.42 logMAR) in the right and left eyes, respectively. ERG showed a significantly reduced amplitude across all components ( P < 0.001) and a peak time delay in the light-adapted 30-Hz flicker and single-flash b-wave ( P < 0.001). Twenty-two variants were novel. The central areolar choroidal dystrophy phenotype was associated with 13 missense variants. The remaining variants showed marked phenotypic variability. Conclusions We described six distinct FAF phenotypes associated with variants in the PRPH2 gene. One FAF phenotype may have multiple ERG phenotypes, demonstrating a discordance between structure and function. Given the vast spectrum of PRPH2 disease our findings are useful for future clinical trials.

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Section: Discussionsupporting

confidence: 90%

Retinal Dystrophies Associated With Peripherin-2: Genetic Spectrum and Novel Clinical Observations in 241 Patients

Heath Jeffery,

Thompson,

et al. 2024

Invest. Ophthalmol. Vis. Sci.

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A new mouse model for PRPH2 pattern dystrophy exhibits functional compensation prior and subsequent to retinal degeneration

Cavanaugh,

Milstein,

Boucher

et al. 2024

Human Molecular Genetics

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Mutations in PRPH2 are a relatively common cause of sight-robbing inherited retinal degenerations (IRDs). Peripherin-2 (PRPH2) is a photoreceptor-specific tetraspanin protein that structures the disk rim membranes of rod and cone outer segment (OS) organelles, and is required for OS morphogenesis. PRPH2 is noteworthy for its broad spectrum of disease phenotypes; both inter- and intra-familial heterogeneity have been widely observed and this variability in disease expression and penetrance confounds efforts to understand genotype–phenotype correlations and pathophysiology. Here we report the generation and initial characterization of a gene-edited animal model for PRPH2 disease associated with a nonsense mutation (c.1095:C>A, p.Y285X), which is predicted to truncate the peripherin-2 C-terminal domain. Young (P21) Prph2Y285X/WT mice developed near-normal photoreceptor numbers; however, OS membrane architecture was disrupted, OS protein levels were reduced, and in vivo and ex vivo electroretinography (ERG) analyses found that rod and cone photoreceptor function were each severely reduced. Interestingly, ERG studies also revealed that rod-mediated downstream signaling (b-waves) were functionally compensated in the young animals. This resiliency in retinal function was retained at P90, by which time substantial IRD-related photoreceptor loss had occurred. Altogether, the current studies validate a new mouse model for investigating PRPH2 disease pathophysiology, and demonstrate that rod and cone photoreceptor function and structure are each directly and substantially impaired by the Y285X mutation. They also reveal that Prph2 mutations can induce a functional compensation that resembles homeostatic plasticity, which can stabilize rod-derived signaling, and potentially dampen retinal dysfunction during some PRPH2-associated IRDs.

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Prph2 knock-in mice recapitulate human central areolar choroidal dystrophy retinal degeneration and exhibit aberrant synaptic remodeling and microglial activation

Cited by 2 publications

References 52 publications

Retinal Dystrophies Associated With Peripherin-2: Genetic Spectrum and Novel Clinical Observations in 241 Patients

Retinal Dystrophies Associated With Peripherin-2: Genetic Spectrum and Novel Clinical Observations in 241 Patients

A new mouse model for PRPH2 pattern dystrophy exhibits functional compensation prior and subsequent to retinal degeneration

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