SPACR Encoded by IIMPG1/I Is Essential for Photoreceptor Survival by Interplaying between the Interphotoreceptor Matrix and the Retinal Pigment Epithelium

Several pathogenic variants have been reported in the IMPG1 gene associated with the inherited retinal disorders vitelliform macular dystrophy (VMD) and retinitis pigmentosa (RP). IMPG1 and its paralog IMPG2 encode for two proteoglycans, SPACR and SPACRCAN, respectively, which are the main component...

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Published in:Genes 2022-08, Vol.13 (9)
Main Authors: Olivier, Guillaume, Brabet, Philippe, Pirot, Nelly, Broyon, Morgane, Guillou, Laurent, Cazevieille, Chantal, Sar, Chamroeun, Quiles, Melanie, Sarzi, Emmanuelle, Pequignot, Marie, Andreo, Ervann, Roube, Meunier, Isabelle, Muller, Agnès, Kalatzis, Vasiliki, Manes, Gaël
Format: Article
Language:English
Subjects:
Analysis
Development and progression
Genetic disorders
Health aspects
Interphotoreceptor retinoid-binding protein
Retinal diseases
Retinal pigment epithelium
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Summary:Several pathogenic variants have been reported in the IMPG1 gene associated with the inherited retinal disorders vitelliform macular dystrophy (VMD) and retinitis pigmentosa (RP). IMPG1 and its paralog IMPG2 encode for two proteoglycans, SPACR and SPACRCAN, respectively, which are the main components of the interphotoreceptor matrix (IPM), the extracellular matrix surrounding the photoreceptor cells. To determine the role of SPACR in the pathological mechanisms leading to RP and VMD, we generated a knockout mouse model lacking Impg1, the mouse ortholog. Impg1-deficient mice show abnormal accumulation of autofluorescent deposits visible by fundus imaging and spectral-domain optical coherence tomography (SD-OCT) and attenuated electroretinogram responses from 9 months of age. Furthermore, SD-OCT of Impg1[sup.−/−] mice shows a degeneration of the photoreceptor layer, and transmission electron microscopy shows a disruption of the IPM and the retinal pigment epithelial cells. The decrease in the concentration of the chromophore 11-cis-retinal supports this loss of photoreceptors. In conclusion, our results demonstrate the essential role of SPACR in maintaining photoreceptors. Impg1[sup.−/−] mice provide a novel model for mechanistic investigations and the development of therapies for VMD and RP caused by IMPG1 pathogenic variants.
ISSN:2073-4425
2073-4425
DOI:10.3390/genes13091508