Prph2 mutant mice generated by CRISPR reproduces human central areolar choroidal dystrophy

Purpose Central choroidal dystrophies are retinal diseases characterized by progressive choriocapillaris atrophy and retinal degeneration that are usually associated with a single mutation in the PRPH2 gene. Thus, the purpose of this work was to generate a mouse model with the same p.Arg195Leu mutation described in diagnosed human patients. Methods Prph2KI/WT and Prph2KI/KI mice have been designed and generated using the CRISPR system to introduce the Arg195Leu mutation. The retinal function was analyzed by electroretinography (ERG) and optomotor test. The structural integrity of the retinas was evaluated using optical coherence tomography and immunohistochemistry. Results Genetic sequencing confirmed that both Prph2KI/WT and Prph2KI/KI mice presented the same codon mutation and degeneration pattern found in humans suffering from this dystrophy. A progressive loss of retinal function was found from 3 months of age, with significantly reduced mice visual acuity, measured by optomotor test. At 6 months of age, decreased a‐ and b‐wave amplitudes of the ERG responses were observed. Moreover, morphological analysis of the retinas correlated with functional findings, showing a decreased number of photoreceptor rows and retinal thickness, also presenting an increased inflammation with activation of microglia and Müller cells Conclusions The new Prph2KI/WT and Prph2KI/KI mouse models show a similar degeneration pattern to human disease and may facilitate the study of the pathophysiological process, also displaying their potential to be a model for evaluation of different therapeutic strategies. Support Ministerio de Ciencia e Innovación (FEDER‐ PID2019‐106230RB‐I00). Ministerio de Universidades (FPU16/04114, FPU18/02964). Instituto Carlos III (RETICS‐FEDER RD16/0008/0016). Retina Asturias/Cantabria. FARPE‐FUNDALUCE. Generalitat Valenciana (IDIFEDER/2017/064, ACIF/2020/203). Es Retina Asturias (2019/00286/001).