Table 2.
Animal models of CSNB
| Species | defective gene | source | mutation type | disease phenotype | ref |
|---|---|---|---|---|---|
| Cat | Rdh5 | naturally occurring |
Missense mutations in Rdh5 c.542G > T;p.Gly181Val |
Thinning of central retinal area. | [79] |
| Dog | Lrit3 | naturally occurring |
A base deletion that occurs in Lrit3 c.762_763delG |
The b-wave disappears in dark-adapted ERG images Bright-adapted ERG b-wave reduction. |
[80] |
| Dog | Sag | naturally occurring | Exon 16 c.1216T > C p.*405Rext*25 |
Data not shown, but late onset of initial visual loss in dim light (night blindness), which gradually progress in some cases to total blindness. Thin retinal blood vessels, pallid optic nerve head, irregular pattern of tapetal reflectivity. |
[81] |
| Fly | mtt | RNAi interference | Decreasing the expression of mtt gene through RNAi interference | Drosophila eye structures are disrupted, especially in adult flies. | [82] |
| Horse | Grm6 | naturally occurring | Missense mutations in Grm6 c.533 C > T, p.178Thr > Met |
Dark-adapted ERG b-wave disappears, Ming-adapted ERG a-wave amplitude is normal but the trough becomes wider. |
[83] |
| Horse | Trpm1 | naturally occurring | Downregulation of Trpm1, 1378 bp long terminal repeat (LTR) insertion in intron 1 of Trpm1 | Dark and light adapted: b-wave missing. | [84] |
| Mouse | Gpr179 | KO | A gene cassette containing lac Z and neomycin is inserted into intron 1 of Gpr179 | In dark-adapted ERG images, b-wave disappears, light-adapted ERG a and b-waves are delayed, b-wave amplitude is significantly reduced, and RGS7, RGS11 and GNB5 are missing at the dendritic tips of ON-type bipolar cells. | [85] |
| Mouse | Lrit3 | KO |
Knocking out the remaining part of exon 3 (21 bp) of exon 4 and inserting c.611_2046delinsGCCCATAG resulted in premature termination. p.Phe204Trpfs*3 |
In dark-adapted ERG images, b-wave disappears, light-adapted ERG a and b-waves are delayed, b-wave amplitude is significantly reduced, and the INL layer becomes thinner. | [86] |
| Mouse | Cacna1f | naturally occurring | A single base change and a 10 bp insertion occurred between exons 1, 3 and 14 of the Cacna1f gene. The insertion resulted in a frameshift mutation in exon 14. | The b-wave of dark-adapted ERG images is severely reduced, the OPL layer becomes thinner, and retinal M and S proteins decrease with age. In addition, there is miss localization of retinal proteins. | [87] |
| Mouse | Grm6 | naturally occurring |
Missense mutation in Grm6 gene p.Met66Leu |
Dark adaptation ERG b-wave weakening The b-wave of ERG is severely weakened during bright adaptation. |
[88] |
| Mouse | Rho | naturally occurring | Exon 1 c.269G > A and c.270 A > C p. Gly90Asp | Loss of rod sensitivity. Depending on the amount of endogenous rhodopsin and p. Gly90Asp allele retinal degeneration. | [89] |
| Mouse | Gnat1 | genetically modified | Exon 2 probably c.113G > A p.Gly38Asp | Reduced rod photoreceptor responses. | [90] |
| Mouse | Gnat1 | genetically modified | Exon 6 not clear p.Gln200Leu | Not clear if in Gnat1þ/ background. But in high levels of transgene reduced rod photoreceptor responses. | [91] |
| Mouse | Gnat1 | genetically modified | In exon 4–5 neomycin selection cassette inserted | Gnat1/ no rod b-wave, no a wave (from rods) but normal cone b-wave Gnat1þ/ morphology normal; Gnat1/ mild age dependent retinal degeneration. | [92] |
| Mouse | Pde6b | genetically modified | Exon 4 c.772 C > A p.His258Asn |
Selective loss of b-wave or a and b-wave reduction. ERG findings dependent on genetic background. |
[35] |
| Mouse | Rdh5 | KO | In exon 1, 2 and 3 neomycin selection cassette inserted | Delayed dark adaptation. Delayed 11-cis-retinal regeneration, delayed dark adaption kinetics no other ERG abnormalities in dark adapted KO mice in fully dark-adapted mice. | [93] |
| Mouse | Sag | KO | In 5’promoter elements and in the first two exons neomycin selection cassette inserted | Prolonged Photoresponses Increased susceptibility to light damage, fundus abnormalities not investigated. | [94] |
| Mouse | Grk1 | KO | In exon 1 neomycin selection cassette inserted | Prolonged Photoresponses Increased susceptibility to light damage, fundus abnormalities not investigated. | [94] |
| Mouse | Cacna1f |
Cacna1fDEx7 Total KO |
In exon 7 self-excising Cre-loxneo cassette inserted p.Gly305* | No CACNA1F in the OPL, thinner than normal OPL, develop ectopic neurites from DBCs and horizontal cells, absence of optokinetic responses Severe icCSNB or cone-rod dystrophy. | [95] |
| Mouse | Cacna1f | Spontaneous (nob2) in AXB-6/PgnJ strain, incomplete KO | In exon 2 transposon insertion leading to 2 transcripts: 90%:* in exon 2, 10%: | light adapted: b-wave, cone responses are reduced No CACNA1F in the OPL, thinner than normal OPL, develop ectopic neurites from DBCs and horizontal cells, but normal optokinetic responses. | [96] |
| Mouse | Cacna1f | KO | In exon 14–17 neomycin cassette inserted | Dark adapted: a-wave normal, b-wave absent, light adapted: b-wave absent cone function reduced by behavioural tests; heterozygous mice reduction of b-wave and cone function in between WT and hemizygous mice consistent with X-inactivation, No CACNA1F in the OPL, and the IPL, develop ectopic neuritis from DBCs and horizontal cells; heterozygous mice patchy pattern probably due to mosaic defects. | [97] |
| Mouse | Cacna1f | Knock-in mimicking gain of function human mutation Exon 17 c.2234T > C p.Ile745Th | Exon 17 c.2267T > C p.Ile756Thr | Dark adapted: reduced b waves, light adapted: b-wave, cone responses are reduced Disperse staining of CACNA1F, extending into ONL. Most synapses immature but some mature, thinner OPL, ONL, cones were shorter and few cones sprout, develop ectopic neurites from DBCs, reduction in expression of Cacna1f, β2 and α2δ-4. | [98] |
| Mouse | Cabp4 | Cabp4DEx1-2 KO | In exon 1 and part of exon 2 neomycin cassette inserted, protein is not detectable |
Dark adapted: a-wave reduced, b-wave missing, light adapted, a- slightly reduced, b-wave severely reduced Thinner OPL, reduction in the number of synaptic ribbons and photoreceptor terminals and deflation of rod spherules and cone pedicles. Formation of ectopic synapses between rods and rod bipolar or horizontal cells in the outer nuclear layer. |
[99] |
| Mouse | Cacna2d4 | naturally occurring | In exon 25 c.2451dup p.Gly818Argfs*15 reduced RNA | a-wave reduced, b-wave missing, cone ERG absent Thinner OPL, loss of ribbon synpases, degeneration of rods. | [74] |
| Mouse | Nyx | naturally occurring | Exon 4 c.567_651del p.Ile189Metfs171* | Dark and light adapted: b-wave missing heterozygous mice reduction of b-wave consistent with X-inactivation. | [100] |
| Mouse | Grm6 | KO | In Exon 8, neomycin selection cassette inserted | Dark and light adapted: b-wave missing. | [101] |
| Mouse | Grm6 | naturally occurring | Mutation in intron 2 leads to splice site with larger transcript: c.486þ648C > T, r.486_487þ486ins582_6446, p.Ile163Glyfs*103 | Dark and light adapted: b-wave missing. | [102] |
| Mouse | Grm6 | N-ethyl-N-nitrosourea (ENU) induced (nob4) |
Exon 3 c.553T > C, p.Ser185Pro |
Dark and light adapted: b-wave missing. | [102] |
| Mouse | Trpm1 | KO | In exons 4–6 neomycin selection cassette inserted | Dark and light adapted: b-wave missing. | [62] |
| Mouse | Trpm1 | ENU induced | Exon 23 c.3202G > A, p.Ala1068Thr | Dark and light adapted: b-wave missing Heterozygous mice show reduction of b-wave. | [100] |
| Mouse | Gpr179 | naturally occurring | Transposon insertion (~ 6.5 kb) in intron 1 | Dark adapted: b-wave missing, light adapted: severely reduced till missing. | [103] |
| Mouse | Grm6 | naturally occurring | A G > A transition occurred at the last position of Grm6 exon 8, resulting in incorrect splicing and extending exon 8 by 28 base pairs. | The b-wave is missing in both dark-adapted and light-adapted ERGs, and mGluR6 protein is missing at the tips of DBC dendrites. | [104] |
| Mouse | Rho | KI | A DNA fragment of approximately 1.3 kb containing the G90D-Rho cDNA was inserted before the start codon of the arrestin-1 gene in mice. | Mutant G90D-rhodopsin produces dark continuous noise. | [105] |
| Rat | Cacna1f | naturally occurring | Exon 23 c.2941 C > T p.Arg981* | a-wave reduced, b-wave missing, cone responses reduce Rod bipolar and horizontal cells reduced, but neither rod bipolar nor horizontal cells dendrites were observed to extend beyond the OPL in the rat, behavioral differences. | [106] |
| Zebrafish | Cacnafa | ENU induced | Exon 5 c.626T > A p.Leu209* c.3430 C > T p.Gln1144* | Reduced a-wave, delayed and reduced b-wave Thinner OPL. | [107, 108] |
| Zebrafish | Nyx | KO | Morpholino against the translation site | b-wave missing. | [109] |
| Zebrafish | Grm6b | KO | Morpholino against the translation site | b-wave missing. | [110] |
| Zebrafish | Gpr179 | KO | Morpholino against the translation site | b-wave missing. | [103] |