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Ping Song, Emma M Lessieur, Ellen Piccillo, Cabrielle C Nivar, Joseph Fogerty, Brian D Perkins; The Joubert Syndrome cilia proteins arl13b, ahi1 and cc2d2a differentially modify the severity of retinal dysfunction due to loss of cep290 in zebrafish. Invest. Ophthalmol. Vis. Sci. 2018;59(9):960.
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© ARVO (1962-2015); The Authors (2016-present)
Mutations in CEP290 lead to a range of pleiotropic disorders that frequently include retinal degeneration. The presence of genetic modifiers of CEP290 have been hypothesized to explain the variability in disease expression. Zebrafish cep290-/- mutants undergo slow, progressive cone degeneration. Here, we test the hypothesis that heterozygous mutations in the ciliopathy associated genes ahi1, cc2d2a, or arl13b will accelerate degeneration observed in zebrafish cep290-/- mutants.
Retinal cryosections from 5 day post fertilization (dpf) and adult animals were examined by immunohistochemistry. The optokinetic response (OKR) gain of 5 dpf larvae was measured as a function of contrast sensitivity and spatial frequency.
At 3 months of age, cep290-/- mutants show disorganization in cone structure and loss of cone density. Cone loss progressed by 6 months of age and few cones remained by 12 months of age. Rhodopsin partially mislocalized to the inner segments but rod degeneration was not observed. Cone degeneration was not accelerated in cep290-/-;arl13b+/- mutants, cep290-/-;cc2d2a+/- mutants, or cep290-/-;ahi+/- mutants, suggesting that heterozygosity at these loci do not enhance retinal degeneration. At 5 dpf, however, OKR results found that while cep290-/- and cep290-/-;ahi1+/- mutants performed similarly in contrast sensitivity assays, cep290-/-;ahi1+/- mutants had significantly lower OKR gain as a function of spatial frequency. Furthermore, the OKR gain of cep290-/-;arl13b+/- mutants and cep290+/-;arl13b-/- mutants was lower than either single mutant alone. This indicated that cep290 and arl13b function as reciprocal modifiers of each other. Loss of a single allele of cc2d2a did not influence visual function of cep290-/- mutants, suggesting that cc2d2a is not a modifier for cep290 in zebrafish.
The combined data suggest that Cep290 is essential for cone survival in zebrafish. The role of ciliopathy loci as genetic modifiers of cep290 function is complex and variable. We report that ahi1, cc2d2a and arl13b do not enhance cep290-dependent cone degeneration. In tests of visual acuity, ahi1 and arl13b function as modifiers and cep290 was identified as a genetic modifier of arl13b mutants.
This is an abstract that was submitted for the 2018 ARVO Annual Meeting, held in Honolulu, Hawaii, April 29 - May 3, 2018.
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