Submission Details

RP2 was first reported in relation to RP2-related retinopathy, an X-linked retinal dystrophy, in 1998 (Schwahn et al., PMID: 9697692). The RP2 gene (RP2 Activator of ARL3 GTPase) codes for protein XRP2, which is a GTPase-activating protein. RP2-related retinopathy is typically described as an early-onset, severe retinal dystrophy in males with early macular involvement (PMIDs: 20625056, 10520237, 27911705). Childhood-onset nyctalopia and reduced visual acuity are often reported in affected males, with significant vision loss by mid-adulthood. Progressive loss of peripheral vision, and paracentral or pericentral scotomas are also reported. Rod photoreceptor degeneration is a primary feature of RP2-related retinal dystrophy, though notable cone photoreceptor degeneration is also reported. Mild, moderate, and/or high myopia are reported in some families (PMID: 10520237). In addition, choroideremia-like presentation has been reported in affected males (PMID: 20625056). In some families, affected carrier females are reported with similar features of retinitis pigmentosa with macular involvement, but with delayed onset of disease and less severe vision loss (PMIDs: 20625056, 10520237). An estimated 10-15% of X-linked retinitis pigmentosa is due to variants in RP2 (PMIDs: 23745007, 10090907). RP2 is associated with the disease entity retinitis pigmentosa 2 in OMIM (MIM 312600), however the Retina GCEP opted to curate RP2 for RP2-related retinopathy given the atypical features of RP2-associated retinitis pigmentosa. 14 RP2 gene variants (missense, nonsense, frameshift) that have been reported in in 22 probands in 8 publications (PMIDs: 9697692, 20625056, 23150612, 10520237, 10937588, 11462235, 10090907, 28559085) are included in this curation. Nonsense and frameshift variants are most commonly reported, however missense variants have been reported to be disease-causing as well. For example, the missense variant RP2 c.353G>A (p.Arg118His) was reported in multiple probands (PMIDs: 9697692, 20625056, 10520237). More evidence is available in the literature, but the maximum score for genetic evidence (12 pts.) has been reached. The mechanism of pathogenicity is known to be loss of function. This gene-disease association is also supported by animal models, expression studies, and in vitro functional assays (PMIDs: 11847227, 32531192, 12417528, 26358772, 21738648, 23745007). In vitro assays indicate that RP2 binds to GTP-Arl3 (PMID: 11847227). The ARL3 (ADP-ribosylation factor-like 3) gene is a GTP-binding protein involved in cilia signaling that is associated with two retinal dystrophy phenotypes, autosomal recessive Joubert syndrome (MIM 618161) and autosomal dominant retinitis pigmentosa (MIM 618173). An RP2 knockout mouse model shows early-onset cone dysfunction, which can be rescued with an AAV vector carrying human RP2 (PMID: 26358772). In addition, zebrafish morpholino knockout shows a retinopathy phenotype that can be rescued with wild-type human RP2 expression (PMID: 21738648). Knockout iPSCs show photoreceptor cell death and thinning of the outer nuclear layer, phenotypes consistent with the human retinal dystrophy (PMID: 32531192). RP2 is ubiquitously expressed. RP2 is detected in rod and cone photoreceptors and shown to localize to the plasma membrane of all cells in the adult human retina (PMID: 12417528). In summary, RP2 is definitively associated with X-linked retinal dystrophy. This has been repeatedly demonstrated in both the research and clinical diagnostic settings and has been upheld over time. This gene-disease clinical validity classification was approved by the Retina GCEP on August 5, 2021.