Leber congenital amaurosis (LCA) is a severe, early-onset form of photoreceptor degeneration involving both rods and cones.
13 14 15 16 17 The severity of these disorders makes them prime candidates for initial clinical trials involving gene replacement therapies. LCA is caused by mutations in at least eight genes, three of which are RPE-specific, the remainder being expressed in photoreceptors,
13 18 which include the gene for RPGRIP. RPGRIP was identified through its interaction with RPGR,
19 20 21 another essential photoreceptor protein encoded by the X-linked RP3 locus.
22 23 Both proteins localize to the connecting cilia of rods and cones.
21 24 Because RPGRIP associated stably with the ciliary axoneme and its localization remained unchanged in photoreceptors lacking RPGR, RPGRIP was proposed to be the primary resident, whereas RPGR depended on RPGRIP for its localization in the connecting cilia.
21 25 Further studies showed that RPGR level was unchanged in the RPGRIP-deficient (
RPGRIP −/−) mice, but that the protein failed to localize in the connecting cilia, thereby confirming that RPGRIP tethers RPGR in the connecting cilia.
26 Thus, RPGRIP is required for the normal localization and for the proposed function of RPGR in regulating protein trafficking across the connecting cilia.
21 Studies of the mutant mice also suggest that RPGRIP may additionally function in nascent disc morphogenesis, because outer segment disc formation was severely disrupted in this mutant. Consistent with the notion that RPGRIP both subserves RPGR function and has an additional role in photoreceptors, loss of RPGRIP in mice leads to a more severe disease than the loss of RPGR.
4 Photoreceptor degeneration is evident in
RPGRIP −/− mice as early as postnatal day 15 and progresses to a substantial loss of most cells by 3 months of age. This course of disease in the
RPGRIP −/− mutant is in line with the clinical manifestations of LCA in which patients have early onset of visual loss and nearly complete loss of vision by early adolescence.