title: Overlap of abnormal photoreceptor development and progressive degeneration in Leber congenital amaurosis caused by NPHP5 mutation.
abstract: Ciliary defects can result in severe disorders called ciliopathies. Mutations in NPHP5 cause a ciliopathy characterized by severe childhood onset retinal blindness, Leber congenital amaurosis (LCA), and renal disease. Using the canine NPHP5-LCA model we compared human and canine retinal phenotypes, and examined the early stages of photoreceptor development and degeneration, the kinetics of photoreceptor loss, the progression of degeneration and the expression profiles of selected genes. NPHP5-mutant dogs recapitulate the human phenotype of very early loss of rods, and relative retention of the central retinal cone photoreceptors that lack function. In mutant dogs, rod and cone photoreceptors have a sensory cilium, but develop and function abnormally and then rapidly degenerate; L/M cones are more severely affected than S-cones. The lack of outer segments in mutant cones indicates a ciliary dysfunction. Genes expressed in mutant rod or both rod and cone photoreceptors show significant downregulation, while those expressed only in cones are unchanged. Many genes in cell-death and -survival pathways also are downregulated. The canine disease is a non-syndromic LCA-ciliopathy, with normal renal structures and no CNS abnormalities. Our results identify the critical time points in the pathogenesis of the photoreceptor disease, and bring us closer to defining a potential time window for testing novel therapies for translation to patients.
authors: Section of Ophthalmology, Department of Clinical Studies, University of Pennsylvania, Philadelphia, PA 19104, USA.
authors: Louise M
authors: LM
authors: Downs
authors: Section of Ophthalmology, Department of Clinical Studies, University of Pennsylvania, Philadelphia, PA 19104, USA.
authors: Erin M
authors: EM
authors: Scott
authors: Department of Ophthalmology, Scheie Eye Institute, University of Pennsylvania, Philadelphia, PA 19104, USA.
authors: Artur V
authors: AV
authors: Cideciyan
authors: Section of Ophthalmology, Department of Clinical Studies, University of Pennsylvania, Philadelphia, PA 19104, USA.
authors: Simone
authors: S
authors: Iwabe
authors: Section of Ophthalmology, Department of Clinical Studies, University of Pennsylvania, Philadelphia, PA 19104, USA.
authors: Valerie
authors: V
authors: Dufour
authors: Section of Ophthalmology, Department of Clinical Studies, University of Pennsylvania, Philadelphia, PA 19104, USA.
authors: Kristin L
authors: KL
authors: Gardiner
authors: Section of Ophthalmology, Department of Clinical Studies, University of Pennsylvania, Philadelphia, PA 19104, USA.
authors: Sem
authors: S
authors: Genini
authors: Section of Ophthalmology, Department of Clinical Studies, University of Pennsylvania, Philadelphia, PA 19104, USA.
authors: Luis Felipe
authors: LF
authors: Marinho
authors: Department of Ophthalmology, Scheie Eye Institute, University of Pennsylvania, Philadelphia, PA 19104, USA.
authors: Alexander
authors: A
authors: Sumaroka
authors: Department of Ophthalmology, Scheie Eye Institute, University of Pennsylvania, Philadelphia, PA 19104, USA.
authors: Mychajlo S
authors: MS
authors: Kosyk
authors: Department of Ophthalmology, Scheie Eye Institute, University of Pennsylvania, Philadelphia, PA 19104, USA.
authors: Malgorzata
authors: M
authors: Swider
authors: Department of Neurology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
authors: Geoffrey K
authors: GK
authors: Aguirre
authors: Department of Ophthalmology, Scheie Eye Institute, University of Pennsylvania, Philadelphia, PA 19104, USA.
authors: Samuel G
authors: SG
authors: Jacobson
authors: Section of Ophthalmology, Department of Clinical Studies, University of Pennsylvania, Philadelphia, PA 19104, USA, wbeltran@vet.upenn.edu gda@vet.upenn.edu.
authors: William A
authors: WA
authors: Beltran
authors: Section of Ophthalmology, Department of Clinical Studies, University of Pennsylvania, Philadelphia, PA 19104, USA, wbeltran@vet.upenn.edu gda@vet.upenn.edu.
authors: Gustavo D
authors: GD
authors: Aguirre
mesh_terms: D000818:Animals; D002148:Calmodulin-Binding Proteins / Q000235:genetics*; D002923:Cilia / Q000235:genetics* / Q000473:pathology; D004195:Disease Models, Animal; D004285:Dogs; D006801:Humans; D057130:Leber Congenital Amaurosis / Q000235:genetics* / Q000378:metabolism / Q000503:physiopathology; D009154:Mutation; D010786:Photoreceptor Cells / Q000378:metabolism* / Q000473:pathology; D012160:Retina / Q000473:pathology*; D017949:Retinal Cone Photoreceptor Cells / Q000378:metabolism / Q000473:pathology; D017948:Retinal Rod Photoreceptor Cells / Q000378:metabolism / Q000473:pathology
chemical_list: D002148:Calmodulin-Binding Proteins; C498171:IQCB1 protein, human