CRX

Summary

CRX (cone-rod homeobox, HGNC:2383) is a protein-coding gene on chromosome 19q13.33, encoding Cone-rod homeobox protein (O43186). Transcription factor that binds and transactivates the sequence 5’-TAATC[CA]-3’ which is found upstream of several photoreceptor-specific genes, including the opsin genes.

The protein encoded by this gene is a photoreceptor-specific transcription factor which plays a role in the differentiation of photoreceptor cells. This homeodomain protein is necessary for the maintenance of normal cone and rod function. Mutations in this gene are associated with photoreceptor degeneration, Leber congenital amaurosis type III and the autosomal dominant cone-rod dystrophy 2. Several alternatively spliced transcript variants of this gene have been described, but the full-length nature of some variants has not been determined.

Source: NCBI Gene 1406 — RefSeq curated summary.

At a glance

• Gene–disease (curated): cone-rod dystrophy 2 (Definitive, ClinGen) — +5 more curated relationships
• GWAS associations: 2
• Clinical variants (ClinVar): 580 total — 92 pathogenic, 34 likely-pathogenic
• Phenotypes (HPO): 65
• Transcription factor: yes — 33 downstream targets (CollecTRI)
• MANE Select transcript: NM_000554

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:2383
Approved symbol	CRX
Name	cone-rod homeobox
Location	19q13.33
Locus type	gene with protein product
Status	Approved
Aliases	CRD, LCA7, OTX3
Ensembl gene	ENSG00000105392
Ensembl biotype	protein_coding
OMIM	602225
Entrez	1406

Gene structure

Transcript identifiers

Ensembl transcripts: 6 — 3 protein_coding, 2 protein_coding_CDS_not_defined, 1 retained_intron

ENST00000221996, ENST00000556527, ENST00000566686, ENST00000602001, ENST00000604324, ENST00000613299

RefSeq mRNA: 1 — MANE Select: NM_000554 NM_000554

CCDS: CCDS12706

Canonical transcript exons

ENST00000221996 — 4 exons

Exon	Start	End
ENSE00000715896	47834409	47834543
ENSE00000715918	47836243	47836394
ENSE00001206821	47821937	47822010
ENSE00001263348	47839320	47843324

Expression profiles

Bgee: expression breadth broad, 54 present calls, max score 87.08.

FANTOM5 (CAGE): breadth tissue_specific, TPM avg 3.9264 / max 1302.2752, expressed in 93 samples.

FANTOM5 promoters (4 alternative TSS)

Promoter ID	TPM avg	Samples expressed
176732	3.7967	85
176735	0.0772	13
176734	0.0288	12
176733	0.0237	14

Top tissues by expression

182 total, by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
pigmented layer of retina	UBERON:0001782	87.08	gold quality
retina	UBERON:0000966	87.06	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	73.41	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	72.18	silver quality
vena cava	UBERON:0004087	64.27	gold quality
inferior olivary complex	UBERON:0002127	63.48	gold quality
dorsal motor nucleus of vagus nerve	UBERON:0002870	63.34	gold quality
parotid gland	UBERON:0001831	62.94	gold quality
epithelium of nasopharynx	UBERON:0001951	62.28	gold quality
myocardium	UBERON:0002349	56.83	gold quality
pons	UBERON:0000988	56.80	gold quality
vastus lateralis	UBERON:0001379	56.35	gold quality
quadriceps femoris	UBERON:0001377	55.99	gold quality
nasal cavity epithelium	UBERON:0005384	55.38	gold quality
superficial temporal artery	UBERON:0001614	55.05	gold quality
skeletal muscle tissue of biceps brachii	UBERON:0004502	54.70	gold quality
heart right ventricle	UBERON:0002080	54.64	gold quality
cerebellar vermis	UBERON:0004720	54.52	gold quality
biceps brachii	UBERON:0001507	54.43	gold quality
cartilage tissue	UBERON:0002418	53.89	gold quality
choroid plexus epithelium	UBERON:0003911	53.52	silver quality
right lobe of liver	UBERON:0001114	53.27	gold quality
medial globus pallidus	UBERON:0002477	53.01	gold quality
eye	UBERON:0000970	52.51	silver quality
endothelial cell	CL:0000115	52.45	gold quality
mammalian vulva	UBERON:0000997	51.97	gold quality
cardia of stomach	UBERON:0001162	51.90	gold quality
subthalamic nucleus	UBERON:0001906	51.88	gold quality
decidua	UBERON:0002450	51.70	gold quality
globus pallidus	UBERON:0001875	50.97	gold quality

Single-cell (SCXA)

Detected in 4 experiment(s), a significant marker in 3.

Experiment	Marker?	Max mean expression
E-GEOD-137537	yes	1409.45
E-MTAB-8060	yes	99.48
E-MTAB-7316	no	30.57
E-ANND-3	no	0.00

Regulation

Is transcription factor: yes

Downstream targets (CollecTRI)

33 targets.

Target	Regulation
AANAT
ABCA4
ADAM2
ALDH7A1
ASMT
ATXN7
BANF1
BEST1	Activation
BTRC
FSCN2	Activation
GNGT1
GRB10
GUCY2D
IGF2
IGF2BP1
IPO13
KCNV2
KNTC1
NOTCH1
NR2E3	Activation
NRL
OPN1SW
PAX6	Repression
PCNA	Repression
PDE6A	Unknown
PDE6B
POU5F1	Repression
PRPH2
RBP3	Activation
RHO	Repression

Upstream regulators (CollecTRI, top): NR1D1, NR2E3, OTX2, TFAP2A, TFAP2B

miRNA regulators (miRDB)

74 targeting CRX, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-3162-3P	100.00	65.37	363
HSA-MIR-3613-3P	100.00	76.36	7965
HSA-MIR-3646	100.00	73.56	5283
HSA-MIR-4534	99.99	66.58	1907
HSA-MIR-4650-5P	99.98	64.69	999
HSA-MIR-6778-3P	99.96	67.29	2693
HSA-MIR-4725-3P	99.96	69.53	2520
HSA-MIR-6780B-5P	99.96	69.60	2562
HSA-MIR-8082	99.95	67.27	1170
HSA-MIR-1236-3P	99.94	68.04	1695
HSA-MIR-10527-5P	99.91	72.28	3754
HSA-MIR-6780A-5P	99.88	66.69	2776
HSA-MIR-3065-3P	99.87	70.25	1407
HSA-MIR-221-3P	99.86	71.56	1329
HSA-MIR-222-3P	99.86	71.35	1337
HSA-MIR-6745	99.74	65.33	1321
HSA-MIR-4428	99.73	66.41	1733
HSA-MIR-4306	99.72	70.50	3630
HSA-MIR-1827	99.63	68.57	3265
HSA-MIR-548AV-5P	99.60	70.84	2107
HSA-MIR-548K	99.60	70.84	2107
HSA-MIR-1252-3P	99.55	67.71	2862
HSA-MIR-7159-3P	99.51	70.17	1920
HSA-MIR-203A-3P	99.49	70.56	2806
HSA-MIR-8054	99.48	70.81	2084
HSA-MIR-766-5P	99.47	67.91	2225
HSA-MIR-548AV-3P	99.43	68.50	1721
HSA-MIR-103A-2-5P	99.39	67.72	1577
HSA-MIR-103A-1-5P	99.39	67.78	1545
HSA-MIR-4644	99.35	69.12	2514

Literature-anchored findings (GeneRIF, showing 40)

• Two patients with Leber congenital amaurosis who carried heterozygously one of two novel frameshift mutations. (PMID:11748859)
• The frameshift mutation in CRX gene in the patient with Leber congenital amaurosis did not cause impairment in vision (PMID:11910559)
• results support the hypothesis that CRX mutations involved in human photoreceptor degeneration act by impairing CRX-mediated transcriptional regulation of the photoreceptor genes (PMID:11971869)
• A novel frameshift mutation was detected in exon III of the CRX retinal homeobox gene. (PMID:12359607)
• both Nrl and Crx are required for full transcriptional activity of the PDE6A gene (PMID:15001570)
• A 615delC mutation in the CRX gene was identified and found to cosegregate with cone-rod dystrophy (PMID:15531334)
• Nr2e3 is a dual-function transcriptional regulator that acts in concert with Crx to promote and maintain the function of rod photoreceptors. (PMID:15689355)
• description of a 2-generation family with a novel mutation in CRX; the resulting phenotype is that of cone-rod dystrophy with variable age at onset and progression (PMID:17320181)
• Transmission of the disease through three generations provides evidence that Lebers congenital amaurosis is transmitted as an autosomal dominant trait. (PMID:17347810)
• authors identified a novel disease causing mutation, c.636delC, in the CRX gene, associated with autosomal dominant cone-rod dystrophy (PMID:18653602)
• CRX expression in the inner nuclear layer of the retina. (PMID:19686387)
• DNA-binding domain mutations in NR2E3 affect in vivo dimerization and interaction with CRX (PMID:19823680)
• CRX has a role in retinal and pineal lineage tumors (PMID:19936203)
• Data show no interaction of barrier-to-autointegration factor (BAF) with HIV-1 MA, cone-rod homeobox (Crx) or MAN1-C in absence of DNA. (PMID:21966431)
• Photosensitive photoreceptor cells can be generated by combinations of transcription factors. The combination of CRX and RX generate immature photoreceptors: and additional NEUROD promotes maturation. (PMID:22558175)
• These findings suggest that CRX is a useful marker to discriminate metastatic retinoblastoma from other, more common, malignant small round cell tumors of childhood (PMID:22790857)
• In this study, three variations were detected in 3 of 130 families with CORD, including two novel mutations, c.239A>G (p.Glu80Gly) and c.362C>T (p.Ala121Val) (PMID:22960069)
• the potential utility of CRX as a marker of pineal lineage in routine diagnostic neuropathology. (PMID:23235340)
• Data have identified a novel retinal SAM domain protein, Samd7, which could act as a transcriptional repressor involved in fine-tuning of Crx-regulated gene expression. (PMID:23565263)
• Two de novo mutations in CRX were found in Chinese patients with Leber congenital amaurosis. The CRX mutation might create a dominantly inherited trait. (PMID:24001014)
• Mutations involving the CRX gene may demonstrate an autosomal dominant inheritance pattern for leber congenital amaurosis. (PMID:24093488)
• CRX could be useful in surgical neuropathology for the differential diagnosis of pineal region tumors, in particular to discriminate pineal tumors from glial tumors (PMID:24555912)
• Mutations in CRX demonstrate significant phenotypic heterogeneity both between and within pedigrees. A novel, adult-onset, macular dystrophy phenotype is characterized, further extending our knowledge of the etiology of dominant macular dystrophies. (PMID:25270190)
• Con rod homeobox protein mRNA is a novel marker for retinoblastoma at extraocular sites. (PMID:25928893)
• Loss of OTX2 expression resulted in decreased expression of C-MYC and CRX, genes previously implicated in retinoblastoma tumorigenesis. Loss of OTX2 expression increased the phosphorylation of RB, a potential mechanism of modulating cell proliferation (PMID:26397460)
• data demonstrate the successful application of ZFN technology to generate CRX-GFP labeled hESC lines, which can be used to study and isolate photoreceptor precursors during hESC differentiation. (PMID:26608863)
• analysis of a homozygous nonsense mutation in SAMD11 in five individuals diagnosed with adult-onset retinitis pigmentosa; SAMD11 interacts with CRX and is expressed in retina (PMID:27734943)
• CRX mutations are associated with a variety of clinical phenotypes, including an adult-onset macular dystrophy that simulates benign concentric annular macular dystrophy with a bull’s eye macular lesion and fairly well preserved visual acuity. (PMID:28945142)
• A sensitive and simple method of tumour cell assessment has been developed that can be used in the clinics to assess for potential extraocular dissemination after intravitreal injections to assure its performance. (PMID:29089355)
• that two photoreceptor-specific transcription factors, NRL and CRX, are master regulators of this program and are required for tumor maintenance in this subgroup (PMID:29533784)
• Study in Lebanese family with 3 affected individuals report for a first time a novel, complete homozygous 56,000 bp deletion of CRX in Leber congenital amaurosis. (PMID:29568065)
• Mutation in CRX gene is associated with macular dystrophy with intrafamilial variable expressivity. (PMID:30067412)
• A novel CRX pathogenic variant has been identified in our patients. The novel pathogenic variant seems to have a different effect on the phenotype of cone-rod dystrophy. (PMID:30078014)
• we revealed a novel frameshift mutation (NM_000554.4:c.538dupG:p.Val180fs) in exon 4 of the CRX gene in a Chinese family with Cone-rod dystrophy. This study broadens the known pathogenic mutation spectrum of the CRX gene and contributes to improved genetic counseling for Cone-rod dystrophy patients. (PMID:30095615)
• A heterozygous nonsense variant c.292C > T (p.R98X) of CRX gene was identified in a Chinese family with atypical and mild manifestations of Retinitis pigmentosa. (PMID:30460480)
• two known retinal dystrophy genes, PRPH2 and CRX, achieved study-wide significance (p < 1.33 x 10-6) under a dominant disease model (PMID:30926958)
• The five patients with bull’s-eye maculopathy along with a negative ERG had differing genotypes. Mutations were found in the CRX gene (2 patients), the ABCA4 gene (1 patient), and the GUCY2D gene (2 patients). (PMID:30945053)
• Incomplete penetrance of CRX gene for autosomal dominant form is associated cone-rod dystrophy. (PMID:31215831)
• most heterozygous pathogenic variants in CRX are associated with autosomal dominant retinal degeneration, a homozygous c.268C>T (p.Arg90Trp) substitution and homozygous complete deletion of CRX have been reported to cause Leber congenital amaurosis. In conclusion, many rare missense variants and some truncating variants in CRX are likely benign. (PMID:31626798)
• Heterozygous CRX deletion is associated with recurrent arcuate retinopathy in familial cone-rod dystrophy. (PMID:31743059)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	otx5	ENSDARG00000043483
mus_musculus	Crx	ENSMUSG00000041578
rattus_norvegicus	Crx	ENSRNOG00000013890

Paralogs (50): ARX (ENSG00000004848), PAX6 (ENSG00000007372), PAX7 (ENSG00000009709), ALX4 (ENSG00000052850), GSC2 (ENSG00000063515), PITX1 (ENSG00000069011), PAX2 (ENSG00000075891), RHOXF1 (ENSG00000101883), EVX1 (ENSG00000106038), PAX4 (ENSG00000106331), NOBOX (ENSG00000106410), PITX3 (ENSG00000107859), PHOX2B (ENSG00000109132), OTX1 (ENSG00000115507), PRRX1 (ENSG00000116132), VSX2 (ENSG00000119614), ESX1 (ENSG00000123576), PAX8 (ENSG00000125618), PAX1 (ENSG00000125813), RHOXF2 (ENSG00000131721), GSC (ENSG00000133937), RAX (ENSG00000134438), PAX3 (ENSG00000135903), ALX3 (ENSG00000156150), HESX1 (ENSG00000163666), PITX2 (ENSG00000164093), UNCX (ENSG00000164853), PHOX2A (ENSG00000165462), OTX2 (ENSG00000165588), DRGX (ENSG00000165606), PRRX2 (ENSG00000167157), SHOX2 (ENSG00000168779), OTP (ENSG00000171540), RAX2 (ENSG00000173976), EVX2 (ENSG00000174279), PROP1 (ENSG00000175325), ISX (ENSG00000175329), ALX1 (ENSG00000180318), MIXL1 (ENSG00000185155), SHOX (ENSG00000185960)

Protein

Protein identifiers

Cone-rod homeobox protein — O43186 (reviewed: O43186)

All UniProt accessions (3): O43186, A0A087WTS9, H3BUU7

UniProt curated annotations — full annotation on UniProt →

Function. Transcription factor that binds and transactivates the sequence 5’-TAATC[CA]-3’ which is found upstream of several photoreceptor-specific genes, including the opsin genes. Acts synergistically with other transcription factors, such as NRL, RORB and RAX, to regulate photoreceptor cell-specific gene transcription. Essential for the maintenance of mammalian photoreceptors.

Subunit / interactions. Interacts (via the homeobox) with NRL (via the leucine-zipper domain). Interacts with PDC, RAX2, RORB and SCA7.

Subcellular location. Nucleus.

Tissue specificity. Retina.

Disease relevance. Leber congenital amaurosis 7 (LCA7) [MIM:613829] A severe dystrophy of the retina, typically becoming evident in the first years of life. Visual function is usually poor and often accompanied by nystagmus, sluggish or near-absent pupillary responses, photophobia, high hyperopia and keratoconus. The disease is caused by variants affecting the gene represented in this entry. Cone-rod dystrophy 2 (CORD2) [MIM:120970] An inherited retinal dystrophy characterized by retinal pigment deposits visible on fundus examination, predominantly in the macular region, and initial loss of cone photoreceptors followed by rod degeneration. This leads to decreased visual acuity and sensitivity in the central visual field, followed by loss of peripheral vision. Severe loss of vision occurs earlier than in retinitis pigmentosa, due to cone photoreceptors degenerating at a higher rate than rod photoreceptors. The disease is caused by variants affecting the gene represented in this entry. Retinitis pigmentosa (RP) [MIM:268000] A retinal dystrophy belonging to the group of pigmentary retinopathies. Retinitis pigmentosa is characterized by retinal pigment deposits visible on fundus examination and primary loss of rod photoreceptor cells followed by secondary loss of cone photoreceptors. Patients typically have night vision blindness and loss of midperipheral visual field. As their condition progresses, they lose their far peripheral visual field and eventually central vision as well. Retinitis pigmentosa can be inherited as an autosomal dominant, autosomal recessive or X-linked condition. The disease is caused by variants affecting the gene represented in this entry.

Similarity. Belongs to the paired homeobox family.

RefSeq proteins (1): NP_000545* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001356	HD	Domain
IPR009057	Homeodomain-like_sf	Homologous_superfamily
IPR013851	Otx_TF_C	Domain
IPR017970	Homeobox_CS	Conserved_site

Pfam: PF00046, PF03529

UniProt features (23 total): sequence variant 15, helix 4, chain 1, DNA-binding region 1, region of interest 1, compositionally biased region 1

Structure

Experimental structures (PDB)

1 structures.

PDB	Method	Resolution (Å)
9B8U	X-RAY DIFFRACTION	2.9

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-O43186-F1	61.78	0.21

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 193 (showing top): NIKOLSKY_OVERCONNECTED_IN_BREAST_CANCER, GOBP_ANIMAL_ORGAN_MORPHOGENESIS, GOBP_SENSORY_PERCEPTION_OF_LIGHT_STIMULUS, TGACATY_UNKNOWN, GOBP_SENSORY_PERCEPTION, GOBP_SENSORY_ORGAN_DEVELOPMENT, RIZ_ERYTHROID_DIFFERENTIATION_APOBEC2, GOBP_RETINA_DEVELOPMENT_IN_CAMERA_TYPE_EYE, GOCC_RNA_POLYMERASE_II_TRANSCRIPTION_REGULATOR_COMPLEX, GOMF_CHROMATIN_BINDING, GOCC_TRANSCRIPTION_REGULATOR_COMPLEX, GOCC_NUCLEOLUS, GOMF_LEUCINE_ZIPPER_DOMAIN_BINDING, GOMF_LRR_DOMAIN_BINDING, SENGUPTA_EBNA1_ANTICORRELATED

GO Biological Process (9): regulation of DNA-templated transcription (GO:0006355), regulation of transcription by RNA polymerase II (GO:0006357), nervous system development (GO:0007399), visual perception (GO:0007601), animal organ morphogenesis (GO:0009887), cell differentiation (GO:0030154), positive regulation of transcription by RNA polymerase II (GO:0045944), retina development in camera-type eye (GO:0060041), multicellular organism development (GO:0007275)

GO Molecular Function (13): RNA polymerase II transcription regulatory region sequence-specific DNA binding (GO:0000977), RNA polymerase II cis-regulatory region sequence-specific DNA binding (GO:0000978), DNA-binding transcription factor activity, RNA polymerase II-specific (GO:0000981), DNA-binding transcription activator activity (GO:0001216), DNA-binding transcription activator activity, RNA polymerase II-specific (GO:0001228), chromatin binding (GO:0003682), DNA-binding transcription factor activity (GO:0003700), nuclear receptor binding (GO:0016922), leucine zipper domain binding (GO:0043522), RNA polymerase II-specific DNA-binding transcription factor binding (GO:0061629), sequence-specific double-stranded DNA binding (GO:1990837), DNA binding (GO:0003677), protein binding (GO:0005515)

GO Cellular Component (4): chromatin (GO:0000785), nucleus (GO:0005634), RNA polymerase II transcription regulator complex (GO:0090575), transcription regulator complex (GO:0005667)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
transcription cis-regulatory region binding	3
RNA polymerase II transcription regulatory region sequence-specific DNA binding	3
regulation of DNA-templated transcription	2
transcription by RNA polymerase II	2
regulation of transcription by RNA polymerase II	2
positive regulation of DNA-templated transcription	2
anatomical structure development	2
DNA-binding transcription factor activity	2
binding	2
DNA-templated transcription	1
regulation of gene expression	1
regulation of RNA biosynthetic process	1
system development	1
sensory perception of light stimulus	1
anatomical structure morphogenesis	1
animal organ development	1
cellular developmental process	1
camera-type eye development	1
multicellular organismal process	1
cis-regulatory region sequence-specific DNA binding	1
chromatin	1
DNA-binding transcription factor activity, RNA polymerase II-specific	1
DNA-binding transcription activator activity	1
positive regulation of transcription by RNA polymerase II	1
transcription regulator activity	1
RNA polymerase II-specific DNA-binding transcription factor binding	1
LRR domain binding	1
DNA-binding transcription factor binding	1
double-stranded DNA binding	1
sequence-specific DNA binding	1
nucleic acid binding	1
chromosome	1
cellular anatomical structure	1
intracellular membrane-bounded organelle	1
transcription regulator complex	1
nuclear protein-containing complex	1
protein-containing complex	1

Protein interactions and networks

STRING

1414 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
CRX	NRL	P54845	986
CRX	NR2E3	Q9Y5X4	956
CRX	RHO	P08100	927
CRX	RCVRN	P35243	907
CRX	AIPL1	Q9NZN9	906
CRX	TPRX1	Q8N7U7	879
CRX	GUCY2D	Q02846	875
CRX	RPE65	Q16518	875
CRX	FIZ1	Q96SL8	863
CRX	RPGRIP1	Q96KN7	858
CRX	RDH12	Q96NR8	856
CRX	ATXN7	O15265	847
CRX	TULP1	O00294	844
CRX	PDE6B	P35913	837
CRX	IMPDH1	P20839	826

IntAct

380 interactions, top by confidence:

A	B	Type	Score
CRX	GCM2	psi-mi:“MI:0915”(physical association)	0.890
GCM2	CRX	psi-mi:“MI:0915”(physical association)	0.890
CRX	PRKAB2	psi-mi:“MI:0915”(physical association)	0.830
PRKAB2	CRX	psi-mi:“MI:0915”(physical association)	0.830
CA8	CRX	psi-mi:“MI:0915”(physical association)	0.780
CRX	CA8	psi-mi:“MI:0915”(physical association)	0.780
QRICH1	CRX	psi-mi:“MI:0915”(physical association)	0.720
BANP	CRX	psi-mi:“MI:0915”(physical association)	0.720
HGS	CRX	psi-mi:“MI:0915”(physical association)	0.720

BioGRID (282): CRX (Two-hybrid), CRX (Two-hybrid), CRX (Two-hybrid), EIF5A (Two-hybrid), MLLT6 (Two-hybrid), ROR2 (Two-hybrid), PRKAB2 (Two-hybrid), PSMB10 (Two-hybrid), SOX5 (Two-hybrid), STK16 (Two-hybrid), ATG12 (Two-hybrid), GCM2 (Two-hybrid), KIAA0141 (Two-hybrid), SFI1 (Two-hybrid), ABI2 (Two-hybrid)

ESM2 similar proteins: A0PJS5, A1YG01, A2D4R4, A2D649, A2T6H5, A2T6Z0, A3KNJ3, A7Y7W3, A8K830, F6W2R2, F8VPY8, O15353, O42506, O43186, O54751, P14653, P17919, P28322, P31276, P32243, P40646, P43268, P57082, P70056, P80206, P83758, Q00288, Q06710, Q08820, Q16633, Q1KL10, Q28GC4, Q28IU6, Q2KJA4, Q4G112, Q503Z8, Q64693, Q66IK1, Q66IT9, Q7T1C0

Diamond homologs: A0A1W2PPF3, A1YEY5, A1YFI3, A1YG57, A2T733, A2T7P4, A6NLW8, A6NNA5, F1NEA7, G5EBU4, G5EDS1, O18381, O35137, O35160, O42250, O43186, O43316, O43812, O54751, O70137, O73917, O75360, O75364, O95076, P09088, P0CJ85, P0CJ86, P0CJ87, P0CJ88, P0CJ89, P0CJ90, P21711, P22810, P26367, P26630, P29454, P32242, P32243, P34764, P34765

SIGNOR signaling

9 interactions.

A	Effect	B	Mechanism
SP4	“up-regulates activity”	CRX	binding
SP1	“up-regulates activity”	CRX	binding
CRX	“down-regulates quantity by repression”	RHO	“transcriptional regulation”
CRX	“down-regulates quantity by repression”	RBP3	“transcriptional regulation”
CRX	“up-regulates quantity by expression”	RS1	“transcriptional regulation”
CRX	“up-regulates quantity by expression”	RBP3	“transcriptional regulation”
ATXN7	“down-regulates activity”	CRX	binding
FIZ1	“down-regulates activity”	CRX	binding
CRX	“up-regulates quantity by expression”	BEST1	“transcriptional regulation”

Disease & clinical

Clinical variants and AI predictions

ClinVar

580 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	92
Likely pathogenic	34
Uncertain significance	230
Likely benign	88
Benign	45

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1004054	NM_000554.6(CRX):c.728dup (p.Pro244fs)	Pathogenic
1013687	NM_000554.6(CRX):c.660dup (p.Tyr221fs)	Pathogenic
1035273	NM_000554.6(CRX):c.323del (p.Pro108fs)	Pathogenic
1037927	NM_000554.6(CRX):c.426C>A (p.Tyr142Ter)	Pathogenic
1043624	NM_000554.6(CRX):c.592del (p.Ala198fs)	Pathogenic
1046426	NC_000019.9:g.(?48337701)(48343224_?)del	Pathogenic
1056395	NM_000554.6(CRX):c.76_80del (p.Met26fs)	Pathogenic
1071706	NC_000019.9:g.(?48339500)(48343224_?)del	Pathogenic
1172711	NM_000554.6(CRX):c.564del (p.Ala189fs)	Pathogenic
1184468	NM_000554.6(CRX):c.522_523dup (p.Gln175fs)	Pathogenic
1185565	NM_000554.6(CRX):c.570dup (p.Tyr191fs)	Pathogenic
1359713	NM_000554.6(CRX):c.509del (p.Pro170fs)	Pathogenic
1370793	NM_000554.6(CRX):c.324del (p.Gly110fs)	Pathogenic
1385024	NM_000554.6(CRX):c.381del (p.Ser128fs)	Pathogenic
1387234	NM_000554.6(CRX):c.125_128dup (p.Thr44fs)	Pathogenic
1393381	NM_000554.6(CRX):c.365del (p.Gly122fs)	Pathogenic
1399832	NM_000554.6(CRX):c.590del (p.Pro197fs)	Pathogenic
1418367	NM_000554.6(CRX):c.750del (p.Thr251fs)	Pathogenic
1425620	NM_000554.6(CRX):c.176_177del (p.Ala59fs)	Pathogenic
1466734	NM_000554.6(CRX):c.501del (p.Glu168fs)	Pathogenic
1468996	NM_000554.6(CRX):c.108del (p.Arg37fs)	Pathogenic
1478978	NM_000554.6(CRX):c.494del (p.Pro165fs)	Pathogenic
1496447	NM_000554.6(CRX):c.624T>G (p.Tyr208Ter)	Pathogenic
1499937	NM_000554.6(CRX):c.597del (p.Ala200fs)	Pathogenic
1685674	NM_000554.6(CRX):c.545C>G (p.Ser182Ter)	Pathogenic
1685675	NM_000554.6(CRX):c.586_587del (p.Ala196fs)	Pathogenic
2007366	NM_000554.6(CRX):c.541_542del (p.Ala181fs)	Pathogenic
2014678	NM_000554.6(CRX):c.116_127del (p.Gln39_Glu42del)	Pathogenic
2017828	NM_000554.6(CRX):c.591_594dup (p.Ser199fs)	Pathogenic
2033764	NM_000554.6(CRX):c.714del (p.Gly239fs)	Pathogenic

SpliceAI

603 predictions. Top by Δscore:

Variant	Effect	Δscore
19:47834406:CAGGC:C	acceptor_loss	1.0000
19:47834407:A:AG	acceptor_gain	1.0000
19:47834407:AG:A	acceptor_gain	1.0000
19:47834407:AGGC:A	acceptor_loss	1.0000
19:47834408:G:GT	acceptor_gain	1.0000
19:47834408:GG:G	acceptor_gain	1.0000
19:47834408:GGC:G	acceptor_gain	1.0000
19:47834408:GGCC:G	acceptor_gain	1.0000
19:47834408:GGCCC:G	acceptor_gain	1.0000
19:47834539:CCCAA:C	donor_gain	1.0000
19:47834540:CCAA:C	donor_gain	1.0000
19:47834541:CAA:C	donor_gain	1.0000
19:47834541:CAAGT:C	donor_loss	1.0000
19:47834542:AA:A	donor_gain	1.0000
19:47834543:AG:A	donor_loss	1.0000
19:47834544:G:GG	donor_gain	1.0000
19:47836238:CCCA:C	acceptor_loss	1.0000
19:47836239:CCA:C	acceptor_loss	1.0000
19:47836240:CAGGC:C	acceptor_loss	1.0000
19:47836241:A:AC	acceptor_loss	1.0000
19:47836241:A:AG	acceptor_gain	1.0000
19:47836242:G:A	acceptor_loss	1.0000
19:47836242:G:GG	acceptor_gain	1.0000
19:47836242:GGC:G	acceptor_gain	1.0000
19:47836353:G:GT	donor_gain	1.0000
19:47836376:GCC:G	donor_gain	1.0000
19:47836378:C:CG	donor_gain	1.0000
19:47834492:GCCC:G	donor_gain	0.9900
19:47834545:T:A	donor_loss	0.9900
19:47834547:A:AG	donor_gain	0.9900

AlphaMissense

1909 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
19:47836269:C:A	R43S	1.000
19:47836269:C:T	R43C	1.000
19:47836273:C:T	T44I	1.000
19:47836278:T:A	F46I	1.000
19:47836278:T:C	F46L	1.000
19:47836278:T:G	F46V	1.000
19:47836279:T:C	F46S	1.000
19:47836279:T:G	F46C	1.000
19:47836280:C:A	F46L	1.000
19:47836280:C:G	F46L	1.000
19:47836292:A:C	Q50H	1.000
19:47836292:A:T	Q50H	1.000
19:47836294:T:C	L51P	1.000
19:47836303:T:A	L54Q	1.000
19:47836303:T:C	L54P	1.000
19:47836312:T:C	L57P	1.000
19:47836314:T:A	F58I	1.000
19:47836314:T:C	F58L	1.000
19:47836314:T:G	F58V	1.000
19:47836315:T:C	F58S	1.000
19:47836315:T:G	F58C	1.000
19:47836316:T:A	F58L	1.000
19:47836316:T:G	F58L	1.000
19:47836329:T:C	Y63H	1.000
19:47836330:A:G	Y63C	1.000
19:47836332:C:T	P64S	1.000
19:47836333:C:A	P64Q	1.000
19:47836347:C:A	R69S	1.000
19:47836360:C:A	A73D	1.000
19:47836375:T:C	L78P	1.000

dbSNP variants (sampled 300 via entrez): RS1000101914 (19:47825474 C>A), RS1000285785 (19:47824432 C>G,T), RS1000299028 (19:47820997 C>A,T), RS1000398136 (19:47824277 C>T), RS1000413298 (19:47830219 A>G), RS1000604732 (19:47835410 G>A), RS1000608221 (19:47831287 A>G), RS1000699432 (19:47828744 C>T), RS1001151383 (19:47839330 A>G), RS1001292066 (19:47843742 G>T), RS1001330063 (19:47834181 G>T), RS1001509483 (19:47827928 T>G), RS1001570124 (19:47819953 T>A), RS1001582950 (19:47829783 C>A,T), RS1001679585 (19:47824488 T>C)

Disease associations

OMIM: gene MIM:602225 | disease phenotypes: MIM:120970, MIM:613829, MIM:268000, MIM:248200, MIM:153870, MIM:204000, MIM:276900, MIM:117000

GenCC curated gene-disease

Disease	Classification	Inheritance
cone-rod dystrophy 2	Definitive	Autosomal dominant
Leber congenital amaurosis 7	Definitive	Semidominant
hereditary macular dystrophy	Definitive	Autosomal dominant
cone-rod dystrophy	Supportive	Autosomal dominant
Leber congenital amaurosis	Supportive	Autosomal dominant
retinitis pigmentosa	Supportive	Autosomal dominant

ClinGen Gene-Disease Validity (1)

Expert-panel classifications — Definitive > Strong > Moderate > Limited > Disputed > Refuted.

Disease	Classification	Inheritance
cone-rod dystrophy 2	Definitive	AD

Mondo (13): cone-rod dystrophy 2 (MONDO:0007362), Leber congenital amaurosis 7 (MONDO:0013449), retinitis pigmentosa (MONDO:0019200), inherited retinal dystrophy (MONDO:0019118), Stargardt disease (MONDO:0019353), prostate cancer (MONDO:0008315), benign concentric annular macular dystrophy (MONDO:0007934), Leber congenital amaurosis (MONDO:0018998), cone-rod dystrophy (MONDO:0015993), Leber congenital amaurosis 1 (MONDO:0008764), Usher syndrome (MONDO:0019501), central core myopathy (MONDO:0007294), hereditary macular dystrophy (MONDO:0020242)

Orphanet (9): Cone rod dystrophy (Orphanet:1872), Leber congenital amaurosis (Orphanet:65), Retinitis pigmentosa (Orphanet:791), OBSOLETE: Inherited retinal disorder (Orphanet:71862), Stargardt disease (Orphanet:827), Familial prostate cancer (Orphanet:1331), Benign concentric annular macular dystrophy (Orphanet:251287), Usher syndrome (Orphanet:886), Central core disease (Orphanet:597)

HPO phenotypes

65 total (30 of 65 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000007	Autosomal recessive inheritance
HP:0000365	Hearing impairment
HP:0000405	Conductive hearing impairment
HP:0000407	Sensorineural hearing impairment
HP:0000501	Glaucoma
HP:0000505	Visual impairment
HP:0000510	Rod-cone dystrophy
HP:0000512	Abnormal electroretinogram
HP:0000518	Cataract
HP:0000529	Progressive visual loss
HP:0000533	Chorioretinal atrophy
HP:0000540	Hypermetropia
HP:0000543	Optic disc pallor
HP:0000546	Retinal degeneration
HP:0000548	Cone/cone-rod dystrophy
HP:0000550	Undetectable electroretinogram
HP:0000551	Color vision defect
HP:0000563	Keratoconus
HP:0000602	Ophthalmoplegia
HP:0000603	Central scotoma
HP:0000613	Photophobia
HP:0000618	Blindness
HP:0000639	Nystagmus
HP:0000648	Optic atrophy
HP:0000662	Nyctalopia
HP:0000729	Autistic behavior
HP:0000842	Hyperinsulinemia
HP:0001105	Retinal atrophy
HP:0001133	Constriction of peripheral visual field

GWAS associations

2 associations (top):

Study	Trait	p-value
GCST012020_539	Serum metabolite levels	4.000000e-11
GCST90093092_6	DHEAS levels	6.000000e-06

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0007001	dehydroepiandrosterone sulphate measurement

MeSH disease descriptors (9)

Descriptor	Name	Tree numbers
D000071700	Cone-Rod Dystrophies	C11.270.152; C11.768.585.658.250; C16.320.290.152
D057130	Leber Congenital Amaurosis	C11.270.516; C11.768.364
D020512	Myopathy, Central Core	C05.651.575.300; C10.668.491.550.300
D011471	Prostatic Neoplasms	C04.588.945.440.770; C12.100.500.260.750; C12.100.500.565.625; C12.200.294.260.750; C12.200.294.565.625; C12.200.758.409.750; C12.900.619.750
D058499	Retinal Dystrophies	C11.768.585.658
D012174	Retinitis Pigmentosa	C11.270.684; C11.768.585.658.500; C16.320.290.684
D000080362	Stargardt Disease	C11.270.872; C11.768.585.439.339; C16.320.290.724
D052245	Usher Syndromes	C09.218.458.341.186.500.500; C09.218.458.341.887.886; C10.597.751.418.341.186.500.500; C10.597.751.418.341.887.886; C10.597.751.941.162.625.500; C11.768.585.658.500.813; C11.966.075.375.500; C16.131.077.299.500; C16.320.290.684.500; C23.888.592.763.393.341.887.886
C537833	Macular dystrophy, concentric annular (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

PharmGKB: 1 entry (VIP=true, CPIC=false)

CTD chemical–gene interactions

16 total (human), top 16 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
tetrabromobisphenol A	decreases expression	2
Benzo(a)pyrene	increases methylation, affects methylation, decreases methylation	2
tetrabromobisphenol S	decreases expression	1
propionaldehyde	decreases expression	1
bisphenol A	decreases expression	1
benzo(e)pyrene	increases methylation	1
aflatoxin B2	decreases methylation	1
CGP 52608	affects binding, increases reaction	1
Resveratrol	affects cotreatment, decreases expression, increases expression	1
Camptothecin	decreases response to substance	1
Formaldehyde	increases expression	1
Methapyrilene	increases methylation	1
Phthalic Acids	increases methylation	1
Plant Extracts	decreases expression, increases expression, affects cotreatment	1
Aflatoxin B1	affects methylation	1
Particulate Matter	increases expression	1

Cellosaurus cell lines

6 cell lines: 4 embryonic stem cell, 2 induced pluripotent stem cell

First 10 cell lines (id-ordered, not curated):

Cellosaurus	Name	Category	Sex
CVCL_A0S6	SEES3-1V human CRX, clone1	Embryonic stem cell	Male
CVCL_A0S7	SEES3-1V human CRX, clone2	Embryonic stem cell	Male
CVCL_A0S8	SEES3-1V human CRX, clone3	Embryonic stem cell	Male
CVCL_B5ZJ	WA09 CRX+/tdTomato	Embryonic stem cell	Female
CVCL_WR01	INMi003-A	Induced pluripotent stem cell	Male
CVCL_WR02	INMi004-A	Induced pluripotent stem cell	Male

Clinical trials (associated diseases)

307 trials via MONDO — disease-level, not drug-specific.

Trial	Phase	Status	Title
NCT00717080	PHASE4	COMPLETED	The Role of Capsular Tension Ring (CTR) in Anterior Capsular Contraction
NCT00999609	PHASE3	ACTIVE_NOT_RECRUITING	Safety and Efficacy Study in Subjects With Leber Congenital Amaurosis
NCT06891443	PHASE3	RECRUITING	Study to Evaluate Sepofarsen in Subjects With Leber Congenital Amaurosis (LCA) Type 10 (HYPERION)
NCT00000114	PHASE3	COMPLETED	Randomized Trial of Vitamin A and Vitamin E Supplementation for Retinitis Pigmentosa
NCT00000116	PHASE3	COMPLETED	Randomized Trial of DHA for Retinitis Pigmentosa Patients Receiving Vitamin A
NCT00346333	PHASE3	COMPLETED	Clinical Trial of Lutein for Patients With Retinitis Pigmentosa Receiving Vitamin A
NCT01786395	PHASE3	TERMINATED	Phase III Efficacy and Safety Clinical Study of UF-021 for Treatment of Retinitis Pigmentosa
NCT04224207	PHASE3	COMPLETED	Management of Retinitis Pigmentosa by Mesenchymal Stem Cells by Wharton’s Jelly Derived Mesenchymal Stem Cells
NCT04636853	PHASE3	COMPLETED	CB-PRP in Retinitis Pigmentosa and Dry Age-related Macular Degeneration
NCT05537220	PHASE3	ACTIVE_NOT_RECRUITING	Oral N-acetylcysteine for Retinitis Pigmentosa
NCT05800301	PHASE3	COMPLETED	Management of Retinitis Pigmentosa Via Combination of Wharton’s Jelly-derived Mesenchymal Stem Cells and Magnovision
NCT05926583	PHASE3	ACTIVE_NOT_RECRUITING	A Study of AAV5-hRKp.RPGR for the Treatment of Japanese Participants With X-linked Retinitis Pigmentosa
NCT06388200	PHASE3	ACTIVE_NOT_RECRUITING	A Phase 3 Study Of OCU400 Gene Therapy for the Treatment Of Retinitis Pigmentosa
NCT07082855	PHASE3	NOT_YET_RECRUITING	A Multicenter, Randomized, Double-Blind, Controlled Clinical Study of Minocycline for the Treatment of Retinitis Pigmentosa
NCT07290530	PHASE3	NOT_YET_RECRUITING	24-Month Trial of NPI-001 for the Preservation of Photoreceptors in Retinitis Pigmentosa Associated With Usher Syndrome
NCT03772665	PHASE3	COMPLETED	Safety and Efficacy of Emixustat in Stargardt Disease
NCT05244304	PHASE3	COMPLETED	Phase 3, Randomized, Placebo-Controlled Study of Tinlarebant to Explore Safety and Efficacy in Adolescent Stargardt Disease
NCT07419334	PHASE3	RECRUITING	Study of ALK-001 on the Progression of Stargardt Disease
NCT01773278	PHASE2	RECRUITING	Cholesterol and Antioxidant Treatment in Patients With Smith-Lemli-Opitz Syndrome (SLOS)
NCT00100230	PHASE2	COMPLETED	DHA and X-Linked Retinitis Pigmentosa
NCT00447980	PHASE2	COMPLETED	A Study of Encapsulated Cell Technology (ECT) Implant for Participants With Early Stage Retinitis Pigmentosa
NCT00447993	PHASE2	COMPLETED	A Study of Encapsulated Cell Technology (ECT) Implant for Patients With Late Stage Retinitis Pigmentosa
NCT01233609	PHASE2	COMPLETED	Trial of Oral Valproic Acid for Retinitis Pigmentosa
NCT01399515	PHASE2	COMPLETED	Efficacy and Safety of Oral Valproic Acid for Retinitis Pigmentosa
NCT01530659	PHASE2	COMPLETED	Retinal Imaging in CNTF -Releasing Encapsulated Cell Implant Treated Patients for Early-stage Retinitis Pigmentosa
NCT01560715	PHASE2	COMPLETED	Autologous Bone Marrow-Derived Stem Cells Transplantation For Retinitis Pigmentosa
NCT02609165	PHASE2	COMPLETED	Nerve Growth Factor Eye Drops Treatment in Patients With Retinitis Pigmentosa and Cystoid Macular Edema
NCT02661711	PHASE2	COMPLETED	Aflibercept for Macular Oedema With Underlying Retinitis Pigmentosa (AMOUR) Study
NCT02804360	PHASE2	UNKNOWN	Intravitreal Dexamethasone Implant in Retinitis Pigmentosa-related Macular Edema- a Retrospective Study
NCT02837640	PHASE2	UNKNOWN	Studying a Potential Protective Effect of L-Dopa on Retinitis Pigmentosa
NCT03073733	PHASE2	COMPLETED	Safety and Efficacy of Intravitreal Injection of Human Retinal Progenitor Cells in Adults With Retinitis Pigmentosa
NCT04068207	PHASE2	COMPLETED	Minocycline Treatment in Retinitis Pigmentosa
NCT04356716	PHASE2	COMPLETED	Sildenafil for Treatment of Choroidal Ischemia
NCT04604899	PHASE2	COMPLETED	Safety of Repeat Intravitreal Injection of Human Retinal Progenitor Cells (jCell) in Adult Subjects With Retinitis Pigmentosa
NCT04763369	PHASE2	UNKNOWN	Investigation of Therapeutic Efficacy and Safety of UMSCs for the Management of Retinitis Pigmentosa (RP)
NCT04864496	PHASE2	UNKNOWN	Effects of Treatment With N- Acetylcysteine on Visual Outcomes in Patients With Retinitis Pigmentosa
NCT04945772	PHASE2	COMPLETED	Efficacy and Safety of MCO-010 Optogenetic Therapy in Adults With Retinitis Pigmentosa [RESTORE]
NCT05085964	PHASE2	TERMINATED	An Open-Label Extension Study to Evaluate Safety & Tolerability of QR-421a in Subjects With Retinitis Pigmentosa
NCT05392179	PHASE2	COMPLETED	A Study in Subjects With Retinitis Pigmentosa
NCT06627179	PHASE2	RECRUITING	Study to Evaluate Ultevursen in Subjects With Retinitis Pigmentosa (RP) Due to Mutations in Exon 13 of the USH2A Gene