Abstract
Mutations in the RPGR-interacting protein 1 (RPGRIP1) gene cause recessive Leber congenital amaurosis (LCA), juvenile retinitis pigmentosa (RP) and cone-rod dystrophy. RPGRIP1 interacts with other retinal disease-causing proteins and has been proposed to have a role in ciliary protein transport; however, its function remains elusive. Here, we describe a new zebrafish model carrying a nonsense mutation in the rpgrip1 gene. Rpgrip1homozygous mutants do not form rod outer segments and display mislocalization of rhodopsin, suggesting a role for RPGRIP1 in rhodopsin-bearing vesicle trafficking. Furthermore, Rab8, the key regulator of rhodopsin ciliary trafficking, was mislocalized in photoreceptor cells of rpgrip1 mutants. The degeneration of rod cells is early onset, followed by the death of cone cells. These phenotypes are similar to that observed in LCA and juvenile RP patients. Our data indicate RPGRIP1 is necessary for rod outer segment development through regulating ciliary protein trafficking. The rpgrip1 mutant zebrafish may provide a platform for developing therapeutic treatments for RP patients.
Highlights
Mutations in the RPGR-interacting protein 1 (RPGRIP1) gene cause recessive Leber congenital amaurosis (LCA), juvenile retinitis pigmentosa (RP) and cone-rod dystrophy
The N-terminal coiled-coil domain of RPGRIP1 interacts with SPATA7, which is mutated in LCA3 and juvenile RP18,19, the central C2 domain interacts with NPHP4 and notably disease-associated mutations in RPGRIP1 or NPHP4 disrupt this interaction[20]; the RPGR-interacting domain (RID) domain interacts with RPGR3–5 and Nek[4] serine/threonine kinase[15]
We predicted that the nonsense mutation would lead to either a truncated 735 amino acids polypeptide and/or nonsense-mediated RNA decay (NMD)
Summary
Mutations in the RPGR-interacting protein 1 (RPGRIP1) gene cause recessive Leber congenital amaurosis (LCA), juvenile retinitis pigmentosa (RP) and cone-rod dystrophy. Required for ciliary targeting of NPHP4 and SDCCAG8, which are associated with renal-retinal ciliopathy[22] These data suggest RPGRIP1 plays a critical role in ciliary protein trafficking and ciliopathies presenting with the photoreceptor cell death. An RPGRIP1 knock-out (KO) mouse model exhibited early retinal degeneration with almost complete loss of photoreceptor cells by three months of age. The photoreceptors of these KO mice initially developed with a normal structure of the connecting cilium, but the outer segments were disorganized with oversized outer segment disks[21]. A few photoreceptors remained by 45 weeks of age[24]
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