Submission Details

Retinal degeneration 3 (RD3) is an evolutionarily conserved 23 kDa protein expressed in rod and cone photoreceptor cells. Mutations in the gene encoding RD3 resulting in unstable non-functional C-terminal truncated proteins are responsible for early onset photoreceptor degeneration in Leber congenital amaurosis 12 (MIM#610612). Leber congenital amaurosis (LCA) is the earliest and most severe form of all inherited retinal dystrophies (IRD) and the most frequent cause of inherited blindness in children. Leber congenital amaurosis-12 (LCA12) is an autosomal recessive form of Inherited retinal disease (IRD) and is characterized by congenital nystagmus, low vision, sluggish pupillary reflexes, absence of ocular pursuit from birth (Perrault et al., 2013) RD3 is located at 1q32.3 and consists of 3 exons encoding a basic protein of 195 amino acids that is preferentially expressed in the retina (Aravindan S et al. 2017). It exhibits increasing expression throughout mouse early postnatal development. It is highly expressed in cone and rod outer segments, and colocalizes with GC1 and GC2. In cones, RD3 protein binds the C-terminus of GC1 and mediates its export from the endoplasmic reticulum to endosomal vesicles. GC1 and GC2 loss iis observed n photoreceptor cells of rd3 mice expressing a truncated unstable rd3 protein. RD3 protein promotes accumulation of retinal membrane guanylyl cyclase (RetGC) in the photoreceptor outer segment and suppresses RetGC activation by guanylyl cyclase–activating proteins (GCAPs). Truncating variants in RD3 cause severe retinal disease by preventing the inhibitory interaction of RD3 with the guanylyl cyclase (Chang B et al. 1993; Friedman JS et al., 2006; Zulliger R. et al., 2016; Peshenko IV et al. 2019). RD3 also negatively regulaes RetGC by binding it and blocking activation by GCAPs. This ability of RD3 to bind and suppress RetGC is likely critical for photoreceptor survival (Peshenko IV et al. 2019).

A total of 9 variants have already been identified underlying Leber congenital amaurosis 12. The mutation spectrum in RD3 includes 4 nonsense, 3 frameshifts and 2 splice junction losses (PMID: 17186464, 22531706, 23308101).

In this curation, data from 3 consanguineous families and 2 isolated individuals with 5 unique variants), were collected from 3 publications (Friedman JS, et al., 2006, PMID: 17186464, Preising MN, et al., 2012, PMID: 22531706, Perrault I, et al., 2013, PMID: 23308101).

Experimental evidence for expression, biochemical function and animal model systems were calculated as well (Aravindan S, et al., 2017, PMID: 29030614, Peshenko IV, et al., 2019, PMID: 30559291, Friedman JS, et al., 2006, PMID: 17186464).

In summary, RD3 is definitively associated with RD3-related retinopathy. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This clinical validity classification was approved by the ClinGen Retina Gene Curation Expert Panel on January 4th, 2022 (SOP Version 8).