title: Centrosomal-ciliary gene CEP290/NPHP6 mutations result in blindness with unexpected sparing of photoreceptors and visual brain: implications for therapy of Leber congenital amaurosis.
abstract: Mutations in the centrosomal-ciliary gene CEP290/NPHP6 are associated with Joubert syndrome and are the most common cause of the childhood recessive blindness known as Leber congenital amaurosis (LCA). An in-frame deletion in Cep290 shows rapid degeneration in the rod-rich mouse retina. To explore the mechanisms of the human retinal disease, we studied CEP290-LCA in patients of different ages (7-48 years) and compared results to Cep290-mutant mice. Unexpectedly, blind CEP290-mutant human retinas retained photoreceptor and inner laminar architecture in the cone-rich central retina, independent of severity of visual loss. Surrounding the cone-rich island was photoreceptor loss and distorted retina, suggesting neural-glial remodeling. The mutant mouse retina at 4-6 weeks of age showed similar features of retinal remodeling, with altered neural and synaptic laminae and Muller glial activation. The visual brain pathways in CEP290-LCA were anatomically intact. Our findings of preserved foveal cones and visual brain anatomy in LCA with CEP290 mutations, despite severe blindness and rapid rod cell death, suggest an opportunity for visual restoration of central vision in this common form of inherited blindness.
authors.affiliation: Scheie Eye Institute, Department of Ophthalmology, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA. cideciya@mail.med.upenn.edu
authors.forename: Artur V
authors.initials: AV
authors.lastname: Cideciyan
authors.forename: Tomas S
authors.initials: TS
authors.lastname: Aleman
authors.forename: Samuel G
authors.initials: SG
authors.lastname: Jacobson
authors.forename: Hemant
authors.initials: H
authors.lastname: Khanna
authors.forename: Alexander
authors.initials: A
authors.lastname: Sumaroka
authors.forename: Geoffrey K
authors.initials: GK
authors.lastname: Aguirre
authors.forename: Sharon B
authors.initials: SB
authors.lastname: Schwartz
authors.forename: Elizabeth A M
authors.initials: EA
authors.lastname: Windsor
authors.forename: Shirley
authors.initials: S
authors.lastname: He
authors.forename: Bo
authors.initials: B
authors.lastname: Chang
authors.forename: Edwin M
authors.initials: EM
authors.lastname: Stone
authors.forename: Anand
authors.initials: A
authors.lastname: Swaroop
mesh_terms: D000293:Adolescent; D000328:Adult; D000818:Animals; D000951:Antigens, Neoplasm / Q000235:genetics*; D001766:Blindness / Q000235:genetics* / Q000503:physiopathology / Q000628:therapy*; D001921:Brain / Q000503:physiopathology*; D018797:Cell Cycle Proteins; D002648:Child; D003598:Cytoskeletal Proteins; D005260:Female; D006801:Humans; D008252:Macaca fascicularis; D008279:Magnetic Resonance Imaging; D008297:Male; D051379:Mice; D008817:Mice, Mutant Strains; D008875:Middle Aged; D009154:Mutation; D009363:Neoplasm Proteins / Q000235:genetics*; D020419:Photoreceptor Cells, Vertebrate / Q000502:physiology*; D014795:Visual Pathways
chemical_list: D000951:Antigens, Neoplasm; D018797:Cell Cycle Proteins; C493903:Cep290 protein, human; D003598:Cytoskeletal Proteins; D009363:Neoplasm Proteins