RP2’s biological function
The RP2 gene (MIM 312600) is located on the X chromosome (Xp11.3) and encodes RP2 activator of ARL3 GTPase (RP2), a 350–amino acid transmembrane protein that is ubiquitously expressed and particularly enriched in the retina at the ciliary apparatus, the basal body and periciliary membranes. RP2 is a structural component of the photoreceptor outer segment disc membranes and is involved in the biogenesis and organization of these discs, which are essential for the phototransduction process. Functionally, RP2 acts as a GTPase-activating protein for the small GTPase ARL3, thus participating in the assembly and trafficking of proteins to photoreceptor outer segments. Beyond this, RP2 is assumed to play a role in actin cytoskeleton organization and other cellular processes; however, the full functional spectrum of RP2 has not yet been revealed.
Pathogenesis of RP2-associated RP
The pathogenesis of RP2-associated RP is linked to the disruption of photoreceptor outer segment structure and function due to loss-of-function or misfolding of the RP2 protein. More than 130 disease-associated RP2variants have been identified, including missense, splice site variations, nonsense, and insertion/deletion variants. Most truncating variants result in loss of function due to protein instability or nonsense-mediated decay. Some missense variants reduce protein stability and impair membrane targeting. The exact mechanisms by which RP2variants cause photoreceptor degeneration are still unknown. Studies using Rp2-null mice revealed gradual decline in rod and cone function, progressive degeneration of photoreceptor membrane discs, and mislocalization of cone opsins.
Molecular diagnostics
Disease-causing RP2variants can be identified using molecular genetic testing, either directly by sequencing, multi-gene panel testing or by exome/genome sequencing.
RP2