Ciliopathy-associated protein CEP290 modifies the severity of retinal degeneration due to loss of RPGR.

Mutations in RPGR (retinitis pigmentosa GTPase regulator) are the most common cause of X-linked RP, a severe blindness disorder. RPGR mutations result in clinically variable disease with early- to late-onset phenotypic presentation. Molecular mechanisms underlying such heterogeneity are unclear. Here we show that phenotypic expression of Rpgr-loss in mice is influenced genetically by the loss of Cep290, a human ciliopathy gene. We found that Rpgr(ko/Y) mice with a heterozygous hypomorphic allele of Cep290 (Cep290(rd16/+)) but not of a heterozygous null allele of Cep290 (Cep290(null/+)) or of other ciliopathy genes, Rpgrip1, Nphp1, Nphp4 and Nphp5, exhibit relatively early onset (by 3 months of age) retinal degeneration and dysfunction when compared with the onset at ∼7 months of age in the Rpgr(ko/Y) mice. We also observed disorganized photoreceptor outer-segment morphology and defective trafficking of opsins in the Rpgr(ko/Y)::Cep290(rd16/+) mice. Together with a physical interaction between RPGR and the C-terminal domain of CEP290, our data suggest that RPGR and CEP290 genetically interact and highlight the involvement of hypomorphic alleles of genes as potential modifiers of heterogeneous retinal ciliopathies.

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