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Perkins. J Transl Genet Genom 2022;6:95-110  https://dx.doi.org/10.20517/jtgg.2021.47  Page 97

                                                   [33]
               progressive degeneration of rods and cone . The identity of the nba gene remains unknown, but this was
               the first reported mutant with adult-onset retinal degeneration in zebrafish. As ENU creates numerous
               lesions throughout the genome, it is important that all ENU-induced mutants be outcrossed for several
               generations to ensure the observed phenotypes reflect the mutation of a single locus. Genome editing
               technologies such as CRISPR/Cas9 now permit investigators to generate zebrafish with mutations in genes
               orthologous to human disease genes [41,42]  and other genes of interest. While most zebrafish mutants have
               been investigated primarily at the larval stage, a number of zebrafish mutants are viable into adulthood and
               show progressive photoreceptor degeneration. In contrast to the regeneration observed following acute
               injury, these mutants do not initiate a robust regeneration response to disease. The reasons for this
               difference remain unclear. The purpose of this review is to examine those zebrafish mutants that are adult-
               viable and exhibit progressive retinal degeneration. Studies of zebrafish mutants with photoreceptor
               dysfunction during larval stages have provided valuable information regarding photoreceptor biology;
               however, in order to harness the capacity for regeneration in a diseased retina, it will be critical to
               investigate zebrafish models that mimic the pathology and progressive degeneration observed in human
               IRDs. Several recent reviews provide excellent discussions of regeneration [43-46]  and of zebrafish mutants with
               retinal degeneration [22,27,47-49] .


               ZEBRAFISH MODELS OF RETINAL DEGENERATION
               Several zebrafish models of retinal dystrophy exist. In some cases, retinal degeneration is induced by
                                                                           [14]
                                                                                                 [15]
               damage caused by cytotoxic compounds [16,50,51] , acute light exposure , or mechanical injury  for the
               purposes of studying regeneration. This review will focus on genetic models with progressive retinal
               degeneration in adults and will include both transgenic lines and zebrafish mutants with mutations in genes
               that cause retinal dystrophy in humans.

               Zebrafish mutant models of progressive retinal dystrophy
               Abelson-helper integration site-1
               Mutations in the Abelson-helper integration site-1 (AHI1) gene result in JBTS [52,53] . JTBS is an autosomal
               recessive ciliopathy noted for a characteristic brain-stem abnormality known as the “molar tooth” sign, as
               well as retinal dystrophy. The AHI1 gene encodes a protein component of the ciliary transition zone (TZ)
               that functions as a diffusion barrier between the photoreceptor inner segment and outer segment [54,55] . The
               zebrafish ahi1  mutant exhibited disorganized cone outer segments during larval stages but visual function
                           lri46
               as assessed by OKR assays was not impaired at 5 days post fertilization . More than 95% of zebrafish ahi1
                                                                           [41]
               mutants died before 3 months post fertilization (mpf). Among surviving animals, cone photoreceptor
               structure was normal at 3 mpf but rapidly degenerated by 5 mpf. Rod photoreceptors exhibited rhodopsin
               mislocalization but a net loss of rods was not observed, suggesting that rods were unhealthy but
               degeneration was limited.


               Aryl hydrocarbon receptor interacting protein-like 1
               Mutations in the aryl hydrocarbon receptor interacting protein-like 1 (AIPL1) gene result in LCA, although
               individuals heterozygous for a 12-bp deletion were diagnosed with either a dominant form of juvenile
               retinitis pigmentosa or autosomal dominant cone-rod dystrophy . AIPL1 is expressed in exclusively in rod
                                                                      [56]
                                                                        [57]
               photoreceptors of both the peripheral and central retina in humans . Aipl1 protein functions as part of an
               HSP90 chaperone complex  that facilitates maturation of farnesylated proteins such as the cGMP
                                       [58]
                                               [59,60]
               phosphodiesterase 6 subunits α and β  . The zebrafish gold rush (gosh) mutant was identified in a large-
               scale mutagenesis screen for ENU-induced recessive mutations that disrupt visual behavior in zebrafish
               larvae . Visual  function  was  completely  absent  in  gosh  mutants  and  cone  photoreceptors  were
                    [32]
               disorganized with shorter outer segments at 7 dpf. By 4 wpf, the ONL was thinner and green cones were
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