Age-related macular degeneration (AMD) is a progressive degenerative eye disease that is the most common cause of blindness among elderly humans. AMD is characterized by early atrophy of the choriocapillaris and retinal pigment epithelium (RPE). Although AMD is a multifactorial disease with many environmental and genetic risk factors, a hallmark of the disease is the origination of extracellular deposits, or drusen, between the RPE and Bruch’s membrane. The human RGR gene (OMIM 600342) generates an exon-skipping splice variant of RGR-opsin (RGR-d) (NP_001012740), that is a persistent component of small and large drusen. Here, the findings prove that abnormal RGR proteins, including RGR-d, are pathogenic in an animal retina with degeneration of the choriocapillaris, RPE, and photoreceptors. A frameshift truncating mutation resulted in severe retinal degeneration with a continuous band of basal deposits along Bruch’s membrane. RGR-d produced less severe disease with choriocapillaris and RPE atrophy, including focal accumulation of abnormal RGR-d protein at the basal boundary of the RPE. Degeneration of the choriocapillaris was marked by decrease in the endothelial CD31 protein and choriocapillaris breakdown at the ultrastructural level. Fundus lesions with patchy depigmentation were characteristic of old RGR-d mice. In cultured cells, RGR-d is mislocalized and causes a strong cell growth defect. These results uphold the notion of a potential hidden linkage between AMD and a high-frequency RGR allele.
Copyright © 2021. Published by Elsevier Inc.

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