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Emma M Lessieur, Wei Zhang, Linjing Li, Gabrielle C Nivar, Ellen Piccillo, Ping Song, Brian D Perkins, Hemant Khanna; Mutations in zebrafish cep290 result in age-related cone degeneration. Invest. Ophthalmol. Vis. Sci. 2017;58(8):364.
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© ARVO (1962-2015); The Authors (2016-present)
Mutations in CEP290 cause ciliopathies with multisystemic dysfunction and are frequently observed in isolated cases of retinal degeneration. CEP290 is a component of the ciliary transition zone and is thought to function in ciliary trafficking. To better understand the disease pathogenesis associated with CEP290, we evaluated two zebrafish mutants: cep290fh297 and cep290sa1383 for visual function and photoreceptor structure.
Localization of Cep290 was evaluated by immunohistochemistry of retinal cryosections. Visual function was assessed by the optokinetic response (OKR) at 5 days post fertilization (dpf). Photoreceptors anatomy was investigated using light microscopy, transmission electron microscopy and immunohistochemistry in animals between 5 dpf and 12 months of age.
The cep290fh297 allele encodes a stop codon at amino acid 1217 whereas the cep2901383 allele carries a premature stop codon at residue 1843. None of the mutants exhibit early lethality. At 5 dpf, 90% of cep290fh297 and 100% of cep290sa1383 mutants showed no structural alterations in photoreceptors; however, visual performance was decreased for cep290fh297 but not for cep290sa1383 mutants. Labeling of cone photoreceptors indicated age-related cone degeneration. Rhodopsin mislocalization and thinning of the retinal outer nuclear layer was observed at 3, 6 and 12 months of age in homozygous mutant animals when compared to controls. The cep290sa1383 allele exhibited disorganized outer segments in double cones with progressive loss of outer segments with age.
The zebrafish mutants studied here are viable. Visual behavior is affected in cep290fh297 but not in cep290sa1383 mutants. Homozygous animals have spared photoreceptor development, however, progressive and predominant cone degeneration, accompanied by thinning of the retinal outer nuclear layer and rhodopsin mislocalization was observed from 3-12 months of age in both alleles. Taken together, these results suggest that the cep290fh297 and cep290sa1383 allele may be hypomorphs, and that the domain encoded by residues 1844-2439 of zebrafish Cep290 harbors important photoreceptor functional elements.
This is an abstract that was submitted for the 2017 ARVO Annual Meeting, held in Baltimore, MD, May 7-11, 2017.
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