title: Ciliopathy-associated protein CEP290 modifies the severity of retinal degeneration due to loss of RPGR.
abstract: 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/Ymice 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/Ymice. 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.
authors.affiliation: Department of Ophthalmology, Horae Gene Therapy Center, UMASS Medical School, Worcester, MA, USA and.
authors.forename: Kollu N
authors.initials: KN
authors.lastname: Rao
authors.affiliation: Department of Ophthalmology, Horae Gene Therapy Center, UMASS Medical School, Worcester, MA, USA and.
authors.forename: Wei
authors.initials: W
authors.lastname: Zhang
authors.affiliation: Department of Ophthalmology, Horae Gene Therapy Center, UMASS Medical School, Worcester, MA, USA and.
authors.forename: Linjing
authors.initials: L
authors.lastname: Li
authors.affiliation: Department of Ophthalmology and Visual Sciences, John A. Moran Eye Center, University of Utah School of Medicine, Salt Lake City, UT, USA.
authors.forename: Cecinio
authors.initials: C
authors.lastname: Ronquillo
authors.affiliation: Department of Ophthalmology and Visual Sciences, John A. Moran Eye Center, University of Utah School of Medicine, Salt Lake City, UT, USA.
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Baehr
authors.affiliation: Department of Ophthalmology, Horae Gene Therapy Center, UMASS Medical School, Worcester, MA, USA and hemant.khanna@umassmed.edu.
authors.forename: Hemant
authors.initials: H
authors.lastname: Khanna
mesh_terms: D000483:Alleles; D000818:Animals; D000951:Antigens, Neoplasm / Q000096:biosynthesis / Q000235:genetics*; D018797:Cell Cycle Proteins; D002923:Cilia / Q000235:genetics / Q000473:pathology; D000072661:Ciliopathies / Q000235:genetics* / Q000473:pathology; D003598:Cytoskeletal Proteins; D004195:Disease Models, Animal; D005136:Eye Proteins / Q000096:biosynthesis / Q000235:genetics*; D005786:Gene Expression Regulation; D006579:Heterozygote; D006801:Humans; D051379:Mice; D009154:Mutation; D009363:Neoplasm Proteins / Q000096:biosynthesis / Q000235:genetics*; D010786:Photoreceptor Cells / Q000473:pathology; D060066:Protein Interaction Maps / Q000235:genetics; D012160:Retina / Q000378:metabolism / Q000473:pathology; D012162:Retinal Degeneration / Q000235:genetics* / Q000473:pathology; D012720:Severity of Illness Index
chemical_list: D000951:Antigens, Neoplasm; D018797:Cell Cycle Proteins; C493903:Cep290 protein, human; D003598:Cytoskeletal Proteins; D005136:Eye Proteins; D009363:Neoplasm Proteins; C099929:RPGR protein, human