Age- and sex-dependent retinal degeneration in peripherin-2 mutant mice, a model of central areolar choroidal dystrophy.
9 affiliations
- 1Department of Physiology, Genetics and Microbiology, University of Alicante, Alicante, Spain.
- 2Department of Optics, Pharmacology, and Anatomy, University of Alicante, Alicante, Spain.
- 3Alicante Institute for Health and Biomedical Research (ISABIAL), Alicante, Spain.
- 4Department of Biomedical Sciences, Faculty of Health Sciences, Cardenal Herrera-CEU University, Valencia, Spain.
- 5CellSight Ocular Stem Cell and Regeneration Program, Department of Ophthalmology, Sue Anschutz-Rodgers Eye Center, University of Colorado, School of Medicine, Aurora, CO, USA.
- 6Department of Physiology, Genetics and Microbiology, University of Alicante, Alicante, Spain. [email protected].
- 7Alicante Institute for Health and Biomedical Research (ISABIAL), Alicante, Spain. [email protected].
- 8Department of Physiology, Genetics and Microbiology, University of Alicante, Alicante, Spain. [email protected].
- 9Alicante Institute for Health and Biomedical Research (ISABIAL), Alicante, Spain. [email protected].
Abstract
Central areolar choroidal dystrophy (CACD) is a progressive macular dystrophy without treatment. Although PRPH2 mutations are the most common cause of disease, the mechanisms driving their phenotypic variability remain poorly understood. Here, a comprehensive characterization of the pathophysiological consequences of p.Arg195Leu mutation in PRPH2 was carried out in a mouse model (Prph2KI/WT). For evaluating the retinal degeneration, this study combines the analysis of electroretinographic responses together with a complete study of bulk RNA-seq transcriptomics and the key cellular and molecular pathways using confocal imaging, flow-cytometry and western blotting. Results from this work demonstrate that ageing and sex influence retinal degeneration. In young mutant mice, retinal functional impairment and structural disorganization of photoreceptor outer segments were accompanied by a reduced expression of Prph2 and Rom1 genes, together with the activation of the immune system and complement pathways. Middle-age stages represent a critical transition point where the increase of cell death and epithelial barrier dysfunction mark the beginning of retinal degeneration. These pathological events become evident at 9 months of age, where visual pathways-related genes were deregulated. Functional, cellular and molecular alterations observed in the mutant mice do not affect males and females equally. From the earliest stages of the disease, females exhibited greater and sustained inflammatory activation, mainly promoted by complement system upregulation and increased CD11b immunoreactivity, and potentially mediated by IL-6/STAT3/ERK signaling. Moreover, females had greater functional decline and photoreceptor loss. Together, these results could explain the high inter- and intrafamilial variability observed in CACD patients carrying the same mutation. Our findings identify inflammatory biomarkers accompanied by visual function loss, prior to evident retinal degeneration, and demonstrate that age and sex critically shape disease onset and severity. These insights underscore the necessity of incorporating sex-specific biology and early anti-inflammatory treatment into the development of targeted therapies for PRPH2-related dystrophies.
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BibTeX
@article{missonnier2026sexdependent,
title = {{Age- and sex-dependent retinal degeneration in peripherin-2 mutant mice, a model of central areolar choroidal dystrophy.}},
author = {Enola Missonnier and Lorena Vidal-Gil and Carla Sánchez-Castillo and Estela Tébar-Garcerán and Ceren Sahin and Marina Pastor-Mas and Yoel Hernández and Oksana Kutsyr and Laura Fernández-Sánchez and Victoria Maneu and Nicolás Cuenca and Natalia Martínez-Gil},
journal = {Cell death discovery},
year = {2026},
month = jul,
doi = {10.1038/s41420-026-03263-z},
url = {https://europepmc.org/article/MED/42897157},
note = {CC BY},
}
RIS
TY - JOUR
TI - Age- and sex-dependent retinal degeneration in peripherin-2 mutant mice, a model of central areolar choroidal dystrophy.
AU - Enola Missonnier
AU - Lorena Vidal-Gil
AU - Carla Sánchez-Castillo
AU - Estela Tébar-Garcerán
AU - Ceren Sahin
AU - Marina Pastor-Mas
AU - Yoel Hernández
AU - Oksana Kutsyr
AU - Laura Fernández-Sánchez
AU - Victoria Maneu
AU - Nicolás Cuenca
AU - Natalia Martínez-Gil
PY - 2026
DA - 2026/07/01
JO - Cell death discovery
DO - 10.1038/s41420-026-03263-z
UR - https://europepmc.org/article/MED/42897157
AB - Central areolar choroidal dystrophy (CACD) is a progressive macular dystrophy without treatment. Although PRPH2 mutations are the most common cause of disease, the mechanisms driving their phenotypic variability remain poorly understood. Here, a comprehensive characterization of the pathophysiological consequences of p.Arg195Leu mutation in PRPH2 was carried out in a mouse model (Prph2KI/WT). For evaluating the retinal degeneration, this study combines the analysis of electroretinographic responses together with a complete study of bulk RNA-seq transcriptomics and the key cellular and molecular pathways using confocal imaging, flow-cytometry and western blotting. Results from this work demonstrate that ageing and sex influence retinal degeneration. In young mutant mice, retinal functional impairment and structural disorganization of photoreceptor outer segments were accompanied by a reduced expression of Prph2 and Rom1 genes, together with the activation of the immune system and complement pathways. Middle-age stages represent a critical transition point where the increase of cell death and epithelial barrier dysfunction mark the beginning of retinal degeneration. These pathological events become evident at 9 months of age, where visual pathways-related genes were deregulated. Functional, cellular and molecular alterations observed in the mutant mice do not affect males and females equally. From the earliest stages of the disease, females exhibited greater and sustained inflammatory activation, mainly promoted by complement system upregulation and increased CD11b immunoreactivity, and potentially mediated by IL-6/STAT3/ERK signaling. Moreover, females had greater functional decline and photoreceptor loss. Together, these results could explain the high inter- and intrafamilial variability observed in CACD patients carrying the same mutation. Our findings identify inflammatory biomarkers accompanied by visual function loss, prior to evident retinal degeneration, and demonstrate that age and sex critically shape disease onset and severity. These insights underscore the necessity of incorporating sex-specific biology and early anti-inflammatory treatment into the development of targeted therapies for PRPH2-related dystrophies.
SN - 2058-7716
ER -