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

Hum Mol Genet. 2016 May 15;25(10):2005-2012. doi: 10.1093/hmg/ddw075. Epub 2016 Mar 2.


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 Rpgrko/Y mice with a heterozygous hypomorphic allele of Cep290 (Cep290rd16/+) but not of a heterozygous null allele of Cep290 (Cep290null/+) 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 Rpgrko/Y mice. We also observed disorganized photoreceptor outer-segment morphology and defective trafficking of opsins in the Rpgrko/Y::Cep290rd16/+ 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.

MeSH terms

  • Alleles
  • Animals
  • Antigens, Neoplasm / biosynthesis
  • Antigens, Neoplasm / genetics*
  • Cell Cycle Proteins
  • Cilia / genetics
  • Cilia / pathology
  • Ciliopathies / genetics*
  • Ciliopathies / pathology
  • Cytoskeletal Proteins
  • Disease Models, Animal
  • Eye Proteins / biosynthesis
  • Eye Proteins / genetics*
  • Gene Expression Regulation
  • Heterozygote
  • Humans
  • Mice
  • Mutation
  • Neoplasm Proteins / biosynthesis
  • Neoplasm Proteins / genetics*
  • Photoreceptor Cells / pathology
  • Protein Interaction Maps / genetics
  • Retina / metabolism
  • Retina / pathology
  • Retinal Degeneration / genetics*
  • Retinal Degeneration / pathology
  • Severity of Illness Index


  • Antigens, Neoplasm
  • Cell Cycle Proteins
  • Cep290 protein, human
  • Cytoskeletal Proteins
  • Eye Proteins
  • Neoplasm Proteins
  • RPGR protein, human