Age- and sex-dependent retinal degeneration in peripherin-2 mutant mice, a model of central areolar choroidal dystrophy

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 (Prph2 KI/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.