Abstract
Retinitis pigmentosa (RP) is one of the most common forms of inherited retinal degeneration with 1/4,000 people being affected. The vision alteration primarily begins with rod photoreceptor degeneration, then the degenerative process continues with cone photoreceptor death. Variants in 71 genes have been linked to RP. One of these genes, PDE6a is responsible for RP43. To date no treatment is available and patients suffer from pronounced visual impairment in early childhood. We used the novel zebrafish pde6aQ70X mutant, generated by N-ethyl-N-nitrosourea at the European Zebrafish Resource Centre, to better understand how PDE6a loss of function leads to photoreceptor alteration. Interestingly, zebrafish pde6aQ70X mutants exhibited impaired visual function at 5 dpf as evidenced by the decrease in their visual motor response (VMR) compared to pde6aWT larvae. This impaired visual function progressed with time and was more severe at 21 dpf. These modifications were associated with an alteration of rod outer segment length at 5 and 21 dpf. In summary, these findings suggest that rod outer segment shrinkage due to Pde6a deficiency begins very early in zebrafish, progresses with time. The zebrafish pde6aQ70X mutant represents an ideal model of RP to screen relevant active small molecules that will block the progression of the disease.
Highlights
Ocular diseases, such as photoreceptor dystrophy, retinitis pigmentosa (RP), glaucoma, cataract or corneal dystrophy, lead to visual impairment
To determine the role of Pde6a in photoreceptor function, we analyzed pde6aQ70X mutant zebrafish, generated using the ENU method, at the European Zebrafish Resource Centre (EZRC)
The genotypes of the fish were assessed by PCR and Mwo1 endonuclease digestion, as the recognition of the restriction site is disrupted by the pde6aQ70X mutation
Summary
Ocular diseases, such as photoreceptor dystrophy, retinitis pigmentosa (RP), glaucoma, cataract or corneal dystrophy, lead to visual impairment. Variants in 71 different genes, have been associated with RP so far, among which PDE6a gene encodes the alpha subunit of cyclic
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