Gene therapy shines light on congenital stationary night blindness for future cures

Zhang, Yi; Lin, Siqi; Yu, Lingqi; Lin, Xiang; Qu, Shuai; Ye, Qingyang; Yu, Mengting; Chen, Wenfeng; Wu, Wenjie

doi:10.1186/s12967-025-06392-8

Journal of Translational Medicine

Table 2 Animal models of CSNB

From: Gene therapy shines light on congenital stationary night blindness for future cures

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.405Rext25	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]

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