| Model name/type | Species | Genetic modification / mutation | Phenotype recapitulation (key features) | Disease modeled | Key findings | References |
|---|---|---|---|---|---|---|
| CrxE168d2 knock-in mouse | Mouse (*Mus musculus*) | Knock-in of human-equivalent **c.503_504del (p.Glu168fs)** truncating effector-domain variant | Heterozygotes retain only **6–8 ONL rows by 3 months**, have **no detectable cone function**, **severely impaired rod function by 1 month**, and complete rod function loss by 3 months; homozygotes have **3–4 ONL rows by 1 month** and never develop visual function | Dominant **LCA7** / severe early-onset CRX retinopathy | Demonstrated that C-terminal truncating variants act largely through **dominant-negative effects** with **allelic overexpression** of mutant transcript/protein, increasing mutant:WT ratio and disrupting downstream photoreceptor gene regulation | (pqac-00000024, pqac-00000032) |
| CrxRip mouse | Mouse (*Mus musculus*) | Spontaneous **c.763del (p.Gly255Alafs*133)** frameshift causing extended non-homologous C-terminus | **Completely blind at 1 month**, but **ONL thickness largely preserved up to at least 18 months**; incomplete photoreceptor differentiation and severe functional loss without rapid structural degeneration | Congenital blindness / **LCA-like** CRX-associated retinopathy | Showed that extended effector-domain variants can cause severe dysfunction by altering **cofactor recruitment** and transcriptional regulation, distinct from rapid-degeneration truncation models | (pqac-00000024, pqac-00000025, pqac-00000032) |
| CrxR90W knock-in mouse | Mouse (*Mus musculus*) | Knock-in **p.Arg90Trp** homeodomain missense variant | Phenotype similar to **Crx-null** retina in homozygotes, with major photoreceptor dysfunction/degeneration due to failure of normal terminal differentiation | Recessive **LCA** and mild late-onset dominant **CoRD** | Established a **hypomorphic** mechanism: markedly reduced DNA-binding affinity and weak transactivation of photoreceptor promoters; severity tracks with loss of DNA-binding strength | (pqac-00000009, pqac-00000025, pqac-00000031) |
| CrxE80A knock-in mouse | Mouse (*Mus musculus*) | Knock-in **p.Glu80Ala** homeodomain missense variant | **No detectable cone-mediated responses**, defective rod-mediated responses at 1 month, **shortened outer segments**, ONL disorganization, but **no obvious early photoreceptor degeneration** | Severe early-onset dominant **cone-rod dystrophy** | Demonstrated a **gain-of-function / antimorphic** mechanism in which CRX retains target preference but loses selectivity, causing promiscuous binding and **hyperactivation** of early target genes with developmental asynchrony | (pqac-00000009, pqac-00000025, pqac-00000031) |
| CrxK88N knock-in mouse | Mouse (*Mus musculus*) | Knock-in **p.Lys88Asn** homeodomain missense variant | Severe dominant retinopathy phenotype in knock-in models; mechanistically distinct from hypomorphic variants | Severe dominant **CoRD/LCA-spectrum** retinopathy | Showed that some homeodomain mutants alter **DNA-binding specificity** rather than merely affinity, redirecting CRX to ectopic non-cognate sites and severely perturbing the photoreceptor gene network | (pqac-00000009, pqac-00000014, pqac-00000017) |
| Crx knockout mouse | Mouse (*Mus musculus*) | **Crx null / deletion** | Photoreceptors are produced, but phototransduction gene expression is reduced; heterozygous deletion produces only **very mild phenotypes** | Loss-of-function reference model for CRX deficiency | Important comparator showing that **haploinsufficiency alone is usually insufficient** to explain severe dominant CRX disease; therefore not an ideal model for dominant CRX retinopathies | (pqac-00000015, pqac-00000024) |
| CrxRdy cat (spontaneous model) | Cat (*Felis catus*) | Spontaneous **1-bp deletion** causing truncating Class III CRX mutation with intact DNA-binding domain but defective transactivation | **Severe cone-led retinal dystrophy** / early childhood-onset blindness analog; documented as a spontaneous large-animal model | **LCA7** / severe CRX-associated retinal degeneration | Earliest documented large-animal CRX model; supported **allelic overexpression** and truncation-based pathogenicity, and provides translational advantages because feline retina better approximates human cone-rich specializations than rodent retina | (pqac-00000004, pqac-00000024, pqac-00000029) |
| CRX monoallelic knockout retinal organoids | Human retinal organoids | **Monoallelic CRX knockout / haploinsufficiency** in hESC-derived retinal organoids | **Delayed ONL stratification**, **thinner ONL**, major **loss of outer segments**, downregulation of phototransduction and inner/outer-segment genes; **arrested translocation** of CRX+ precursors and actomyosin over-tension during early differentiation | Dominant CRX-associated retinopathy due to **haploinsufficiency** | Provided direct human-model evidence that **CRX haploinsufficiency can impair precursor translocation and differentiation**, revealing a pathogenic mechanism not fully captured in mouse systems | (pqac-00000016, pqac-00000012) |
| CRX-LCA patient iPSC-derived retinal organoids | Human iPSC-derived retinal organoids | Patient-derived organoids carrying dominant **CRX-LCA** mutation(s) | Retinal organoid phenotypes used to assess rescue of photoreceptor development/function in a human context | Dominant **CRX-LCA** | Demonstrated feasibility of testing **AAV-mediated gene therapy** in patient stem-cell-derived retinal tissue; supports organoids as a precision preclinical platform for CRX therapeutic development | (pqac-00000017, pqac-00000019) |
| Tet-On-hCRX transgenic augmentation model | Mouse (*Mus musculus*) | Inducible **human CRX transgene** under Tet-On control for augmentation in mutant/null CRX backgrounds | Allows **quantitative and temporal control** of augmented CRX during the developmental window; CRX expression inducible in null retinae | Preclinical therapeutic model for CRX-associated retinopathies | Proof-of-concept model showing photoreceptors retain **neuroplasticity** and can respond to CRX augmentation, though rescue is **partial**; informed development of **AAV2/5** photoreceptor-directed augmentation strategies | (pqac-00000016, pqac-00000018, pqac-00000026) |


*Table: This table summarizes the principal animal and cellular models used to study CRX-related retinopathy, spanning mouse, cat, and human organoid systems. It highlights how each model captures distinct mechanisms such as haploinsufficiency, dominant-negative truncation, and altered DNA-binding specificity, and why these models are useful for therapeutic development.*