NR2E3

Summary

NR2E3 (nuclear receptor subfamily 2 group E member 3, HGNC:7974) is a protein-coding gene on chromosome 15q23, encoding Photoreceptor-specific nuclear receptor (Q9Y5X4). Orphan nuclear receptor of retinal photoreceptor cells.

This protein is part of a large family of nuclear receptor transcription factors involved in signaling pathways. Nuclear receptors have been shown to regulate pathways involved in embryonic development, as well as in maintenance of proper cell function in adults. Members of this family are characterized by discrete domains that function in DNA and ligand binding. This gene encodes a retinal nuclear receptor that is a ligand-dependent transcription factor. Defects in this gene are a cause of enhanced S cone syndrome. Alternatively spliced transcript variants encoding different isoforms have been identified.

Source: NCBI Gene 10002 — RefSeq curated summary.

At a glance

• Gene–disease (curated): inherited retinal dystrophy (Definitive, ClinGen) — +4 more curated relationships
• GWAS associations: 5
• Clinical variants (ClinVar): 865 total — 61 pathogenic, 58 likely-pathogenic
• Phenotypes (HPO): 50
• Druggable target: yes
• Transcription factor: yes — 16 downstream targets (CollecTRI)
• MANE Select transcript: NM_014249

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:7974
Approved symbol	NR2E3
Name	nuclear receptor subfamily 2 group E member 3
Location	15q23
Locus type	gene with protein product
Status	Approved
Aliases	PNR, rd7, RP37
Ensembl gene	ENSG00000278570
Ensembl biotype	protein_coding
OMIM	604485
Entrez	10002

Gene structure

Transcript identifiers

Ensembl transcripts: 4 — 3 protein_coding, 1 protein_coding_CDS_not_defined

ENST00000563709, ENST00000617575, ENST00000621098, ENST00000621736

RefSeq mRNA: 2 — MANE Select: NM_014249 NM_014249, NM_016346

CCDS: CCDS73750, CCDS73751

Canonical transcript exons

ENST00000617575 — 8 exons

Exon	Start	End
ENSE00003714382	71812336	71812511
ENSE00003718725	71811955	71812176
ENSE00003719192	71814012	71814117
ENSE00003721589	71811483	71811609
ENSE00003723408	71810554	71810861
ENSE00003730110	71813389	71813635
ENSE00003737244	71811766	71811869
ENSE00003896159	71817552	71818253

Expression profiles

Bgee: expression breadth ubiquitous, 156 present calls, max score 90.47.

FANTOM5 (CAGE): breadth tissue_specific, TPM avg 0.1081 / max 71.0706, expressed in 8 samples.

FANTOM5 promoters (2 alternative TSS)

Promoter ID	TPM avg	Samples expressed
147551	0.0991	8
147552	0.0090	3

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
buccal mucosa cell	CL:0002336	90.47	silver quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	86.41	gold quality
secondary oocyte	CL:0000655	72.86	gold quality
oocyte	CL:0000023	71.06	gold quality
diaphragm	UBERON:0001103	69.38	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	68.00	gold quality
myocardium	UBERON:0002349	66.46	gold quality
olfactory bulb	UBERON:0002264	65.44	gold quality
pigmented layer of retina	UBERON:0001782	65.00	gold quality
skeletal muscle tissue of biceps brachii	UBERON:0004502	64.88	gold quality
cardiac muscle of right atrium	UBERON:0003379	64.62	gold quality
left ventricle myocardium	UBERON:0006566	64.39	gold quality
skeletal muscle tissue of rectus abdominis	UBERON:0004511	63.13	gold quality
mucosa of sigmoid colon	UBERON:0004993	62.87	gold quality
blood vessel layer	UBERON:0004797	62.73	silver quality
decidua	UBERON:0002450	62.55	gold quality
biceps brachii	UBERON:0001507	60.95	gold quality
lower esophagus mucosa	UBERON:0035834	60.89	gold quality
trabecular bone tissue	UBERON:0002483	60.67	gold quality
right uterine tube	UBERON:0001302	60.31	gold quality
mucosa of paranasal sinus	UBERON:0005030	59.75	gold quality
germinal epithelium of ovary	UBERON:0001304	58.98	gold quality
tendon of biceps brachii	UBERON:0008188	58.98	silver quality
quadriceps femoris	UBERON:0001377	58.87	gold quality
vastus lateralis	UBERON:0001379	58.74	gold quality
prostate gland	UBERON:0002367	58.41	gold quality
fundus of stomach	UBERON:0001160	58.38	gold quality
esophagus squamous epithelium	UBERON:0006920	58.37	gold quality
oviduct epithelium	UBERON:0004804	57.99	silver quality
cerebellar vermis	UBERON:0004720	57.95	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-GEOD-137537	yes	2736.63
E-MTAB-7316	yes	2483.92
E-GEOD-98556	yes	568.10
E-ANND-3	no	0.00

Regulation

Is transcription factor: yes

Downstream targets (CollecTRI)

16 targets.

Target	Regulation
ADAM2
CRX	Activation
ESR1	Unknown
HLA-E
NRL	Activation
NUPR1
OTX2
PIAS3
PRPH2
RARRES2
RCVRN
RGR
RHO	Activation
RLBP1
RS1	Unknown
TP53

Upstream regulators (CollecTRI, top): CRX, NRL

miRNA regulators (miRDB)

37 targeting NR2E3, 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-4283	100.00	66.42	2097
HSA-MIR-495-3P	99.96	72.81	4197
HSA-MIR-335-3P	99.93	73.36	4958
HSA-MIR-4760-3P	99.93	70.50	2385
HSA-MIR-8063	99.91	69.76	3146
HSA-MIR-106A-5P	99.90	73.94	2683
HSA-MIR-4731-5P	99.89	67.23	2537
HSA-MIR-17-5P	99.89	73.83	2665
HSA-MIR-106B-5P	99.88	74.72	2795
HSA-MIR-20A-5P	99.88	74.76	2769
HSA-MIR-20B-5P	99.88	74.01	2621
HSA-MIR-519D-3P	99.88	73.97	2607
HSA-MIR-526B-3P	99.88	74.06	2587
HSA-MIR-93-5P	99.88	73.98	2606
HSA-MIR-320A-3P	99.77	69.73	2107
HSA-MIR-320B	99.77	69.73	2107
HSA-MIR-320C	99.77	69.73	2107
HSA-MIR-320D	99.77	69.73	2107
HSA-MIR-4429	99.77	69.62	2111
HSA-MIR-4261	99.59	70.30	3415
HSA-MIR-4489	99.50	65.56	785
HSA-MIR-147B-5P	99.45	70.62	2432
HSA-MIR-183-3P	99.41	69.41	1598
HSA-MIR-4528	99.18	69.77	1936
HSA-MIR-1228-3P	99.00	66.53	857
HSA-MIR-5701	98.97	69.54	1502
HSA-MIR-936	98.87	70.51	1124
HSA-MIR-29B-1-5P	98.86	68.35	1364
HSA-MIR-4260	98.78	65.37	848
HSA-MIR-222-5P	98.75	69.17	1242

Literature-anchored findings (GeneRIF, showing 40)

• In a mouse model, Nr2e3 may function by regulating genes involved in cone cell proliferation. Mutations in this gene lead to retinal dysplasia and degeneration by disrupting normal photoreceptor cell topography as well as cell-cell interactions. (PMID:11487564)
• In 16 ESCS patients with the most common NR2E3 mutation, R311Q, we documented an abnormal ratio of S to L/M cone function and progressive retinal degeneration. We studied the postmortem retina of an ESCS patient homozygous for NR2E3 R311Q (PMID:11773633)
• We found that enhanced S-cone syndrome, Goldmann-Favre syndrome and clumped pigmentary retinal degeneration can all have the same genetic basis. (PMID:12963616)
• involved in regulating the expression of rod photoreceptor-specific genes at the transcriptional level (PMID:15190009)
• A role for NR2E3 in the rod developmental pathway is suggested. (PMID:15277507)
• Fifteen different mutations were identified, including six not previously reported, in patients with Enhanced S Cone Syndrome (PMID:15459973)
• These experiments show that in mature vertebrate retina Nr2e3 is expressed exclusively in rods and that Nr2e3 functions as a repressor of cone-specific genes in rod photoreceptor cells. (PMID:15634773)
• Nr2e3 is a dual-function transcriptional regulator that acts in concert with Crx to promote and maintain the function of rod photoreceptors. (PMID:15689355)
• Our study suggests that the expression of these 2 mutants of NR2E3, acting as a dimer, is correlated with a mild form of ESCS (enhanced S-cone syndrome) (PMID:16225923)
• We describe the localization and identification of the photoreceptor cell-specific nuclear receptor gene NR2E3 as a novel disease locus and gene for autosomal dominant retinitis pigmentosa. (PMID:17564971)
• Gly56Arg mutation in NR2E3 accounts for approximately 1%-2% of adRP, making it one of the more common single mutations in autosomal dominant retinitis pigmentosa. (PMID:17982421)
• NR2E3 gene mutational analyses were carried out in 103 unrelated subjects with different retinal diseases. A total of 14 different sequence variants were identified, including 3 mutations, 6 rare sequence variants and five polymorphisms (PMID:18294254)
• The phenotype in enhanced S-cone syndrome is variable, both in fundus appearance and in the severity of the electrophysiological abnormalities. (PMID:18436841)
• Functional analysis determined the dominant negative activity of the p.G56R mutant protein as the molecular mechanism of autosomal dominant retinitis pigmentosa (adRP). (PMID:19006237)
• Two novel NR2E3 mutations are described that are associated with Goldmann-Favre syndrome and enhanced S-cone syndrome. (PMID:19139342)
• Patients with NR2E3 mutations may manifest variable phenotypes. Moreover, patients who are homozygous for the same NR2E3 mutation have variable expression of retinal disease, suggesting the involvement of modifier genes. (PMID:19273793)
• A review of disease-associated NR2E3 mutations. (PMID:19718767)
• DNA-binding domain mutations in NR2E3 affect in vivo dimerization and interaction with CRX (PMID:19823680)
• This study was undertaken to determine biochemical as well as functional consequences of reported sequence variants and disease-causing mutations in NR2E3. (PMID:19898638)
• In this study, NR2E3 mutations were found to be responsible for approximately 2.9% of overall retinitis pigmentosa (RP) in Chinese patients, NRL was not associated with RP. (PMID:19933183)
• Helicoid subretinal fibrosis is another potential phenotypic manifestation of recessive NR2E3 mutation. (PMID:20212206)
• This homozygous mutation is likely to affect binding to target DNA sites, resulting in a non-functional behavior of NR2E3 protein. (PMID:20725840)
• The purpose of this study was to compare the nature and implications of mutations in NR2E3 in two subjects with enhanced S Cone Syndrome who have significantly different degrees of degenerative damage. (PMID:21364904)
• In HeLa cells, PNR stimulated tumor suppressor p53-responsive promoters in a tumor suppressor p53-dependent fashion and induced apoptosis in several cell types. (PMID:22025681)
• NR2E3 is essential for expression of ESR1 in ER-positive breast cancer cells by binding directly to the proximal region of the ESR1 promoter. (PMID:22174013)
• Homozygous autosomal recessive retinitis pigmentosa-causing mutations have been found in three Indian families. These included a deletion-cum-insertion in NR2E3. (PMID:22605927)
• The presence of a double concentric hyperautofluorescent ring of FAF may represent a highly penetrant early phenotypic marker of NR2E3-p.G56R-linked autosomal dominant retinitis pigmentosa (PMID:22661467)
• The diagnosis of enhanced S-cone syndrome was suggested by the uniquely abnormal electroretinographic pattern and was confirmed by the finding of homozygous NR2E3 mutations. (PMID:23039133)
• we report novel mutations in the NR2E3 gene that were discovered in 2 cases with enhanced S-cone syndrome. (PMID:23374571)
• Genetic screening confirmed the presence of two disease-causing mutations in the NR2E3 gene in each study patient, as well as identified a novel mutation (202 A > G, S68G). (PMID:23604511)
• PNR/NR2E3 and related NRs such as TLX and COUPTFs can selectively associate with the developmental corepressor BCL11A via a conserved motif F/YSXXLXXL/Y within the RID1 domain. (PMID:23975195)
• Study presents evidence that PNR could promote ERalpha-negative breast cancer metastasis through activation of IL-13Ralpha2-mediated signaling pathway. (PMID:24747967)
• Molecular genetic studies helped to identify a novel p.D406G mutation in NR2E3 of the Goldmann-Favre syndrome (GFS) and vasoproliferative tumors of the retina affected members. (PMID:24891813)
• Direct sequencing of NR2E3 identified 3 previously described mutations and 4 novel mutations in Enhanced S-cone syndrome (ESCS) forms (PMID:25079116)
• NR2E3 is a novel epigenetic regulator that helps to maintain a normal epigenetic status in response to benzo(a)pyrene mediated toxic injury. NR2E3 may be a potential target for cancer prevention. (PMID:26149760)
• Autosomal dominant retinitis pigmentosa due to p.Gly56Arg mutation in the NR2E3 gene (PMID:26910043)
• The frameshift mutation found in patient 1, p.I307LfsX33, is a new causative mutation for ESCS; it is located in exon 6. This mutation truncates the 410 amino acids in the normal NR2E3 protein into 306 amino acids and causes the synthesis of a protein lacking more than half of the ligand-binding domain. (PMID:27522502)
• The patient presented characteristic symptoms, morphology and electrophysiological characteristics for S-cone deficiency syndrome and presented heterozygous for two mutations, one of which (c.790G>A; p.G264R in NR2E3), to our knowledge, has not been previously reported. (PMID:27573156)
• Photoreceptor-specific nuclear receptor (PNR/NR2E3) and Tailless homolog (TLX/NR2E1) are human orthologs of the NR2E group. (PMID:28300834)
• our work revealed the novel role of NR2E3 as a positive upstream transcriptional regulator of AHR. Loss of NR2E3 caused repression of AHR by epigenetic reprogramming, which altered the active H3K4me2 status by modulating LSD1 distribution and activity. (PMID:28878246)

Cross-species orthologs

6 orthologs

Organism	Symbol	Gene ID
danio_rerio	nr2e3	ENSDARG00000045904
mus_musculus	Nr2e3	ENSMUSG00000032292
rattus_norvegicus	Nr2e3	ENSRNOG00000050690
drosophila_melanogaster	Hr51	FBGN0034012
caenorhabditis_elegans		WBGENE00001400
caenorhabditis_elegans		WBGENE00003701

Paralogs (11): HNF4A (ENSG00000101076), NR2E1 (ENSG00000112333), NR2C1 (ENSG00000120798), RXRG (ENSG00000143171), NR2F6 (ENSG00000160113), HNF4G (ENSG00000164749), NR2F1 (ENSG00000175745), NR2C2 (ENSG00000177463), NR2F2 (ENSG00000185551), RXRA (ENSG00000186350), RXRB (ENSG00000204231)

Protein

Protein identifiers

Photoreceptor-specific nuclear receptor — Q9Y5X4 (reviewed: Q9Y5X4)

Alternative names: Nuclear receptor subfamily 2 group E member 3, Retina-specific nuclear receptor

All UniProt accessions (3): F1D8Q9, Q8IVZ9, Q9Y5X4

UniProt curated annotations — full annotation on UniProt →

Function. Orphan nuclear receptor of retinal photoreceptor cells. Transcriptional factor that is an activator of rod development and repressor of cone development. Binds the promoter region of a number of rod- and cone-specific genes, including rhodopsin, M- and S-opsin and rod-specific phosphodiesterase beta subunit. Enhances rhodopsin expression. Represses M- and S-cone opsin expression.

Subunit / interactions. Homodimer. Interacts with PIAS3; the interaction sumoylates NR2E3 and promotes repression of cone-specific gene transcription and activation of rod-specific genes. Component of a complex that includes NR2E3, NRL, CRX and NR1D1. Interacts with NR1D1. Interacts (via the DNA-binding domain) with CRX (via its DNA binding domain); the interaction represses S- and M-cone opsin expression. Interacts with SAMD7.

Subcellular location. Nucleus.

Tissue specificity. Eye specific; found solely in the outer nuclear layer of the adult neurosensory retina, where the nuclei of cone and rod photoreceptors reside.

Post-translational modifications. Di- and tri-sumoylated in developing retina. PIAS3-mediated sumoylation promotes repression of cone-specific gene expression and activation of rod-specific genes. Sumoylation on Lys-185 appears to be the main site.

Disease relevance. Enhanced S cone syndrome (ESCS) [MIM:268100] Autosomal recessive retinopathy in which patients have increased sensitivity to blue light; perception of blue light is mediated by what is normally the least populous cone photoreceptor subtype, the S (short wavelength, blue) cones. ESCS is also associated with visual loss, with night blindness occurring from early in life, varying degrees of L (long, red)- and M (middle, green)-cone vision, and retinal degeneration. The disease is caused by variants affecting the gene represented in this entry. Retinitis pigmentosa 37 (RP37) [MIM:611131] 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. The disease is caused by variants affecting the gene represented in this entry.

Similarity. Belongs to the nuclear hormone receptor family. NR2 subfamily.

Isoforms (2)

UniProt ID	Names	Canonical?
Q9Y5X4-1	Long	yes
Q9Y5X4-2	Short

RefSeq proteins (2): NP_055064, NP_057430 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000003	Retinoid-X_rcpt/HNF4	Family
IPR000536	Nucl_hrmn_rcpt_lig-bd	Domain
IPR001628	Znf_hrmn_rcpt	Domain
IPR001723	Nuclear_hrmn_rcpt	Family
IPR013088	Znf_NHR/GATA	Homologous_superfamily
IPR035500	NHR-like_dom_sf	Homologous_superfamily
IPR050274	Nuclear_hormone_rcpt_NR2	Family

Pfam: PF00104, PF00105

UniProt features (55 total): sequence variant 26, helix 12, cross-link 3, zinc finger region 2, mutagenesis site 2, strand 2, region of interest 2, compositionally biased region 2, chain 1, domain 1, splice variant 1, DNA-binding region 1

Structure

Experimental structures (PDB)

1 structures.

PDB	Method	Resolution (Å)
4LOG	X-RAY DIFFRACTION	2.7

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9Y5X4-F1	75.59	0.44

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Post-translational modifications (3): 330, 337, 185

Mutagenesis-validated functional residues (2):

Position	Phenotype
372	reduces transcription repressor activity.
375	reduces transcription repressor activity.

Function

Pathways and Gene Ontology

Reactome pathways

1 pathways

ID	Pathway
R-HSA-383280	Nuclear Receptor transcription pathway

MSigDB gene sets: 176 (showing top): GOBP_CELLULAR_RESPONSE_TO_LIPID, GOBP_PHOTOTRANSDUCTION, GOBP_NEUROGENESIS, GOBP_HORMONE_MEDIATED_SIGNALING_PATHWAY, GOBP_ANIMAL_ORGAN_MORPHOGENESIS, GOBP_EYE_PHOTORECEPTOR_CELL_DIFFERENTIATION, GOBP_CELLULAR_RESPONSE_TO_HORMONE_STIMULUS, MODULE_379, GOBP_SENSORY_PERCEPTION_OF_LIGHT_STIMULUS, GOBP_PHOTORECEPTOR_CELL_DEVELOPMENT, GOBP_RESPONSE_TO_RADIATION, GOBP_RESPONSE_TO_STEROID_HORMONE, GOBP_RESPONSE_TO_HORMONE, GOBP_RESPONSE_TO_LIPID, GOBP_DETECTION_OF_LIGHT_STIMULUS

GO Biological Process (14): negative regulation of transcription by RNA polymerase II (GO:0000122), signal transduction (GO:0007165), visual perception (GO:0007601), phototransduction (GO:0007602), cell population proliferation (GO:0008283), negative regulation of cell population proliferation (GO:0008285), positive regulation of gene expression (GO:0010628), neuron differentiation (GO:0030182), eye photoreceptor cell development (GO:0042462), positive regulation of transcription by RNA polymerase II (GO:0045944), retina development in camera-type eye (GO:0060041), regulation of DNA-templated transcription (GO:0006355), nuclear receptor-mediated steroid hormone signaling pathway (GO:0030518), intracellular receptor signaling pathway (GO:0030522)

GO Molecular Function (10): RNA polymerase II cis-regulatory region sequence-specific DNA binding (GO:0000978), DNA-binding transcription activator activity, RNA polymerase II-specific (GO:0001228), nuclear steroid receptor activity (GO:0003707), nuclear receptor activity (GO:0004879), zinc ion binding (GO:0008270), sequence-specific DNA binding (GO:0043565), DNA binding (GO:0003677), DNA-binding transcription factor activity (GO:0003700), protein binding (GO:0005515), metal ion binding (GO:0046872)

GO Cellular Component (3): nucleus (GO:0005634), nucleoplasm (GO:0005654), transcription regulator complex (GO:0005667)

Reactome top-level categories

Rollup of top-1 pathways:

Category	Pathways
Generic Transcription Pathway	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
regulation of transcription by RNA polymerase II	2
transcription by RNA polymerase II	2
cellular process	2
regulation of gene expression	2
RNA polymerase II transcription regulatory region sequence-specific DNA binding	2
DNA-binding transcription factor activity, RNA polymerase II-specific	2
negative regulation of DNA-templated transcription	1
cell communication	1
signaling	1
regulation of cellular process	1
cellular response to stimulus	1
sensory perception of light stimulus	1
signal transduction	1
detection of light stimulus	1
cell population proliferation	1
regulation of cell population proliferation	1
negative regulation of cellular process	1
gene expression	1
positive regulation of macromolecule biosynthetic process	1
cell differentiation	1
generation of neurons	1
eye photoreceptor cell differentiation	1
photoreceptor cell development	1
positive regulation of DNA-templated transcription	1
camera-type eye development	1
anatomical structure development	1
DNA-templated transcription	1
regulation of RNA biosynthetic process	1
steroid hormone receptor signaling pathway	1
nuclear receptor-mediated signaling pathway	1
intracellular signal transduction	1
cis-regulatory region sequence-specific DNA binding	1
DNA-binding transcription activator activity	1
positive regulation of transcription by RNA polymerase II	1
nuclear receptor activity	1
nuclear receptor-mediated steroid hormone signaling pathway	1
intracellular receptor signaling pathway	1
signaling receptor activity	1
ligand-modulated transcription factor activity	1
transition metal ion binding	1

Protein interactions and networks

STRING

1277 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
NR2E3	CRX	O43186	956
NR2E3	NRL	P54845	936
NR2E3	RHO	P08100	827
NR2E3	PRPH2	P23942	792
NR2E3	RPE65	Q16518	770
NR2E3	PRPF31	Q8WWY3	764
NR2E3	PDE6A	P16499	759
NR2E3	EYS	Q5T1H1	759
NR2E3	CERKL	Q49MI3	754
NR2E3	TULP1	O00294	745
NR2E3	IMPG2	Q9BZV3	742
NR2E3	PRCD	Q00LT1	742
NR2E3	RDH12	Q96NR8	735
NR2E3	OTX2	P32243	735
NR2E3	CNGA1	P29973	733

IntAct

16 interactions, top by confidence:

A	B	Type	Score
WDR5	NR2E3	psi-mi:“MI:0915”(physical association)	0.560
NR2E3	DDI1	psi-mi:“MI:0915”(physical association)	0.400
ELAVL2	NR2E3	psi-mi:“MI:0915”(physical association)	0.370
NR3C1	NR2E3	psi-mi:“MI:0915”(physical association)	0.370
HOXC13	NR2E3	psi-mi:“MI:0915”(physical association)	0.370
PPARG	NR2E3	psi-mi:“MI:0915”(physical association)	0.370
POLR3D	NR2E3	psi-mi:“MI:0915”(physical association)	0.370
SNAPC1	NR2E3	psi-mi:“MI:0915”(physical association)	0.370
ZNF232	NR2E3	psi-mi:“MI:0915”(physical association)	0.370
NR2E3	IRF9	psi-mi:“MI:0915”(physical association)	0.370
NR2E3	DEDD2	psi-mi:“MI:0915”(physical association)	0.370
NR2E3	RBFOX2	psi-mi:“MI:0915”(physical association)	0.370
WDR5	NR2E3	psi-mi:“MI:0915”(physical association)	0.000

BioGRID (26): NR2E3 (FRET), NR1D1 (FRET), CRX (FRET), NRL (FRET), NR2E3 (FRET), NR2E3 (FRET), NR2E3 (FRET), NR2E3 (Two-hybrid), DDI1 (Affinity Capture-MS), RARA (Reconstituted Complex), RXRA (Reconstituted Complex), NR2E3 (Two-hybrid), NR2E3 (Two-hybrid), NR2E3 (Two-hybrid), NR2E3 (Two-hybrid)

ESM2 similar proteins: A2T7D9, A3RGC1, O35627, O42295, O42450, O54915, O57606, O75469, P04625, P11473, P15204, P18113, P18115, P18117, P18119, P37242, P48281, P55055, P62044, P62045, P68305, P68306, Q02777, Q02965, Q13133, Q14994, Q1L673, Q28037, Q28570, Q28571, Q5E9B6, Q60644, Q62685, Q62755, Q8MIM3, Q8SQ01, Q90382, Q91241, Q91279, Q91424

Diamond homologs: A2T928, A2T929, G5ECR9, O00482, O08580, O09017, O09018, O42101, O44960, O45666, O76202, O95718, P10276, P10588, P10589, P10826, P11416, P11474, P11475, P13631, P16375, P16376, P18514, P18516, P18911, P19793, P20153, P22448, P22449, P22605, P24468, P28699, P28700, P28701, P28702, P28704, P28705, P41235, P43135, P43136

SIGNOR signaling

3 interactions.

A	Effect	B	Mechanism
NR1D1	up-regulates	NR2E3
NR2E3	up-regulates	NR1D1	binding
NR2E3	“up-regulates quantity by expression”	ESR1	“transcriptional regulation”

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	61
Likely pathogenic	58
Uncertain significance	319
Likely benign	319
Benign	14

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1045258	NM_014249.4(NR2E3):c.1217A>G (p.Asp406Gly)	Pathogenic
1059167	NM_014249.4(NR2E3):c.1096_1100+19del	Pathogenic
1069860	NC_000015.9:g.(?72103074)(72110035_?)del	Pathogenic
1072367	NM_014249.4(NR2E3):c.189_198del (p.Cys64fs)	Pathogenic
1074070	NM_014249.4(NR2E3):c.457del (p.Ala153fs)	Pathogenic
1351606	NM_014249.4(NR2E3):c.417_418del (p.Glu140fs)	Pathogenic
1361677	NM_014249.4(NR2E3):c.119-2A>G	Pathogenic
1391690	NM_014249.4(NR2E3):c.444_477del (p.Pro150fs)	Pathogenic
1432619	NM_014249.4(NR2E3):c.36del (p.Val13fs)	Pathogenic
1438705	NM_014249.4(NR2E3):c.946G>A (p.Asp316Asn)	Pathogenic
1445894	NM_014249.4(NR2E3):c.731del (p.Leu244fs)	Pathogenic
1451083	NM_014249.4(NR2E3):c.133_151dup (p.Gly51fs)	Pathogenic
1453596	NM_014249.4(NR2E3):c.50_51insAG (p.Pro18fs)	Pathogenic
1455685	NM_014249.4(NR2E3):c.639_640insT (p.Pro214fs)	Pathogenic
1456422	NM_014249.4(NR2E3):c.131C>A (p.Ser44Ter)	Pathogenic
1458873	NM_014249.4(NR2E3):c.1048C>T (p.Gln350Ter)	Pathogenic
1458927	NM_014249.4(NR2E3):c.324C>A (p.Cys108Ter)	Pathogenic
183143	NM_014249.4(NR2E3):c.143_144delinsAGTGTGCCTCCAGTGCCTCGCTCCA (p.Arg48fs)	Pathogenic
1995976	NM_014249.4(NR2E3):c.872del (p.Gly291fs)	Pathogenic
2000387	NC_000015.10:g.71811483del	Pathogenic
2002490	NM_014249.4(NR2E3):c.367C>T (p.Gln123Ter)	Pathogenic
2015692	NM_014249.4(NR2E3):c.199dup (p.Cys67fs)	Pathogenic
2029290	NM_014249.4(NR2E3):c.143_147dup (p.Cys50fs)	Pathogenic
2077159	NC_000015.10:g.71811958_71811977dup	Pathogenic
2095888	NM_014249.4(NR2E3):c.839del (p.Pro280fs)	Pathogenic
2425924	NC_000015.9:g.(?72109883)(72110035_?)del	Pathogenic
2425925	NC_000015.9:g.(?72104430)(72106256_?)del	Pathogenic
2677356	NM_014249.4(NR2E3):c.583del (p.Ile195fs)	Pathogenic
2694697	NM_014249.4(NR2E3):c.844G>T (p.Glu282Ter)	Pathogenic
2709776	NM_014249.4(NR2E3):c.1155dup (p.Ile386fs)	Pathogenic

SpliceAI

1391 predictions. Top by Δscore:

Variant	Effect	Δscore
15:71811605:TACAG:T	donor_gain	1.0000
15:71811606:ACAG:A	donor_gain	1.0000
15:71811607:CAG:C	donor_gain	1.0000
15:71811608:AG:A	donor_gain	1.0000
15:71811609:GG:G	donor_gain	1.0000
15:71811610:G:GG	donor_gain	1.0000
15:71811610:GTGA:G	donor_loss	1.0000
15:71811764:A:AG	acceptor_gain	1.0000
15:71811765:G:GA	acceptor_gain	1.0000
15:71811765:G:T	acceptor_loss	1.0000
15:71811865:GGACG:G	donor_gain	1.0000
15:71811866:GACGG:G	donor_gain	1.0000
15:71811867:A:T	donor_gain	1.0000
15:71811953:A:AG	acceptor_gain	1.0000
15:71811954:G:GG	acceptor_gain	1.0000
15:71811954:GCC:G	acceptor_gain	1.0000
15:71812334:A:AG	acceptor_gain	1.0000
15:71812335:G:GG	acceptor_gain	1.0000
15:71812335:GCT:G	acceptor_gain	1.0000
15:71812409:C:CA	acceptor_gain	1.0000
15:71812507:ATCAG:A	donor_loss	1.0000
15:71812508:TCAG:T	donor_loss	1.0000
15:71812509:CAGGT:C	donor_loss	1.0000
15:71812510:AG:A	donor_loss	1.0000
15:71812511:GG:G	donor_loss	1.0000
15:71812513:T:A	donor_loss	1.0000
15:71814109:GCCC:G	donor_gain	1.0000
15:71810818:G:GT	donor_gain	0.9900
15:71811482:GGC:G	acceptor_gain	0.9900
15:71811610:G:T	donor_gain	0.9900

AlphaMissense

2692 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
15:71811554:T:C	C64R	1.000
15:71811555:G:A	C64Y	1.000
15:71811556:C:G	C64W	1.000
15:71811572:T:C	F70L	1.000
15:71811573:T:C	F70S	1.000
15:71811573:T:G	F70C	1.000
15:71811574:C:A	F70L	1.000
15:71811574:C:G	F70L	1.000
15:71811575:T:C	F71L	1.000
15:71811576:T:C	F71S	1.000
15:71811577:C:A	F71L	1.000
15:71811577:C:G	F71L	1.000
15:71811580:G:C	K72N	1.000
15:71811580:G:T	K72N	1.000
15:71811582:G:T	R73M	1.000
15:71811767:T:C	C83R	1.000
15:71811788:T:A	C90S	1.000
15:71811788:T:C	C90R	1.000
15:71811789:G:C	C90S	1.000
15:71811809:C:A	R97S	1.000
15:71811818:T:A	C100S	1.000
15:71811818:T:C	C100R	1.000
15:71811819:G:C	C100S	1.000
15:71811820:C:G	C100W	1.000
15:71811827:T:A	C103S	1.000
15:71811827:T:C	C103R	1.000
15:71811828:G:A	C103Y	1.000
15:71811828:G:C	C103S	1.000
15:71811834:T:C	L105P	1.000
15:71811858:T:C	M113T	1.000

dbSNP variants (sampled 300 via entrez): RS1000423948 (15:71809927 C>A), RS1001021644 (15:71814941 T>C), RS1001122113 (15:71812162 T>C), RS1001567179 (15:71809409 A>G), RS1001583767 (15:71815239 T>C), RS1001631367 (15:71813999 T>A), RS1001731100 (15:71814617 C>T), RS1001865080 (15:71816942 A>G,T), RS1002037377 (15:71809579 G>A), RS1002205881 (15:71810278 C>T), RS1002369299 (15:71816663 C>T), RS1002578434 (15:71813855 C>T), RS1002804081 (15:71809049 CG>C), RS1003162883 (15:71809388 T>C,G), RS1003419602 (15:71813067 G>A)

Disease associations

OMIM: gene MIM:604485 | disease phenotypes: MIM:611131, MIM:268100, MIM:268000, MIM:120970, MIM:204000

GenCC curated gene-disease

Disease	Classification	Inheritance
enhanced S-cone syndrome	Definitive	Autosomal recessive
retinitis pigmentosa 37	Definitive	Autosomal dominant
Goldmann-Favre syndrome	Strong	Autosomal dominant
retinitis pigmentosa	Supportive	Autosomal dominant

ClinGen Gene-Disease Validity (2)

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

Disease	Classification	Inheritance
inherited retinal dystrophy	Definitive	AD
enhanced S-cone syndrome	Definitive	AR

Mondo (10): retinitis pigmentosa 37 (MONDO:0012625), enhanced S-cone syndrome (MONDO:0100288), inherited retinal dystrophy (MONDO:0019118), retinitis pigmentosa (MONDO:0019200), Goldmann-Favre syndrome (MONDO:0100289), cone-rod dystrophy (MONDO:0015993), ocular albinism (MONDO:0017304), optic atrophy (MONDO:0003608), retinal disorder (MONDO:0005283), Leber congenital amaurosis (MONDO:0018998)

Orphanet (6): Goldmann-Favre syndrome (Orphanet:53540), Retinitis pigmentosa (Orphanet:791), OBSOLETE: Inherited retinal disorder (Orphanet:71862), Cone rod dystrophy (Orphanet:1872), Ocular albinism (Orphanet:284804), Leber congenital amaurosis (Orphanet:65)

HPO phenotypes

50 total (30 of 50 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000007	Autosomal recessive inheritance
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:0000543	Optic disc pallor
HP:0000546	Retinal degeneration
HP:0000550	Undetectable electroretinogram
HP:0000551	Color vision defect
HP:0000552	Tritanomaly
HP:0000563	Keratoconus
HP:0000580	Pigmentary retinopathy
HP:0000602	Ophthalmoplegia
HP:0000613	Photophobia
HP:0000618	Blindness
HP:0000639	Nystagmus
HP:0000642	Red-green dyschromatopsia
HP:0000648	Optic atrophy
HP:0000662	Nyctalopia
HP:0000842	Hyperinsulinemia
HP:0000969	Edema
HP:0001105	Retinal atrophy
HP:0001133	Constriction of peripheral visual field
HP:0003621	Juvenile onset
HP:0007663	Reduced visual acuity
HP:0007675	Progressive night blindness

GWAS associations

5 associations (top):

Study	Trait	p-value
GCST001823_21	Metabolite levels (HVA/MHPG ratio)	2.000000e-06
GCST006976_99	Macular thickness	1.000000e-08
GCST90002383_228	Hematocrit	6.000000e-16
GCST90002384_391	Hemoglobin	1.000000e-16
GCST90002403_492	Red blood cell count	2.000000e-20

EFO canonical traits (5, from GWAS)

EFO ID	Trait name
EFO:0005131	HVA measurement
EFO:0005133	MHPG measurement
EFO:0004348	hematocrit
EFO:0004509	hemoglobin measurement
EFO:0004305	erythrocyte count

MeSH disease descriptors (9)

Descriptor	Name	Tree numbers
D016117	Albinism, Ocular	C11.270.040.090; C16.320.290.040.090; C16.320.565.100.102.090; C16.320.850.080.090; C17.800.621.440.102.090; C17.800.827.080.090; C18.452.648.100.102.090
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
D009896	Optic Atrophy	C10.292.700.225; C11.640.451
D012164	Retinal Diseases	C11.768
D058499	Retinal Dystrophies	C11.768.585.658
D012174	Retinitis Pigmentosa	C11.270.684; C11.768.585.658.500; C16.320.290.684
C564835	Enhanced S-Cone Syndrome (supp.)
C567005	Retinitis Pigmentosa 37 (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL4374 (SINGLE PROTEIN)

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

GtoPdb / IUPHAR curated pharmacology

(IUPHAR/BPS Guide to Pharmacology — expert-curated)

Target class: nhr — 2E. Tailless-like receptors

Binding affinities (BindingDB)

175 measured of 210 human assays (239 total across all organisms); most potent 50 below. Values come from heterogeneous assays and are not directly comparable.

Ligand	Measure	Value
6-bromanyl-2-(furan-2-yl)quinoline-4-carboxylic acid	IC50	23 nM
7-(4-methoxyphenyl)-5-phenyl-pyrido[2,3-d]pyrimidin-4-amine	IC50	237 nM
7-(4-fluorophenyl)-5-(4-methylphenyl)-4-pyrido[2,3-d]pyrimidinamine	IC50	336 nM
6-bromo-2-thiophen-2-ylquinoline-4-carboxylic acid	IC50	395 nM
5-(3a-hydroxy-2-oxo-3,4,6,6a-tetrahydro-1H-thieno[3,4-d]imidazol-4-yl)pentanoic acid methyl ester	IC50	577 nM
4-(4-butoxyphenyl)-5-cyano-2-methyl-N-phenyl-6-sulfanylidene-1H-pyridine-3-carboxamide	IC50	778 nM
1-[2-(N-methylsulfonyl-4-phenoxyanilino)-1-oxoethyl]-4-piperidinecarboxamide	IC50	792 nM
MLS000548752	EC50	907 nM
4-(3-bromophenyl)-2-(4-bromophenyl)-7-methyl-2H-pyrazolo[3,4-d]pyridazine	IC50	915 nM
MLS001173402	IC50	934 nM
SMR000620955	IC50	941 nM
SMR000306271	IC50	1090 nM
2-(4-benzofuro[3,2-d]pyrimidinylthio)-N-[2-(trifluoromethyl)phenyl]acetamide	IC50	1110 nM
3-(1-benzofuran-2-ylcarbonyl)-2-(3-chlorophenyl)-1-(5-methyl-1,2-oxazol-3-yl)-4-oxidanyl-2H-pyrrol-5-one	IC50	1190 nM
cid_3245690	IC50	1230 nM
SMR000516584	IC50	1270 nM
d-Desthiobiotin	IC50	1380 nM
MLS000690352	IC50	1390 nM
1-[2-(4-methoxyphenyl)-3,4-dimethylpyrazolo[3,4-d]pyridazin-7-yl]-N-[(2-methylphenyl)methyl]piperidine-4-carboxamide	IC50	1440 nM
2-[2,4-bis(chloranyl)phenoxy]-N-[4-(6-morpholin-4-ylpyridazin-3-yl)phenyl]ethanamide	IC50	1500 nM
MLS000585653	IC50	1560 nM
6-bromo-2-(2-furyl)-4-quinolinecarboxylic acid	IC50	1580 nM
N-(4,6-dimethyl-2-pyridinyl)-N’-(3-methoxyphenyl)thiourea	IC50	1610 nM
1,3,6-Trimethyl-1H-pyrimido[5,4-e][1,2,4]triazine-5,7-dione	EC50	1610 nM
SMR000079256	IC50	1670 nM
4-hydroxy-3-[(7-methoxy-2-benzofuranyl)-oxomethyl]-1-(5-methyl-3-isoxazolyl)-2-thiophen-2-yl-2H-pyrrol-5-one	IC50	1730 nM
2-(1,3-benzodioxol-5-yl)-6-bromoquinoline-4-carboxylic acid	IC50	1760 nM
6-chloro-N-[3-([1,3]thiazolo[5,4-b]pyridin-2-yl)phenyl]pyridine-3-carboxamide	IC50	1800 nM
3-(1-benzofuran-2-carbonyl)-2-(4-chlorophenyl)-4-hydroxy-1-(5-methyl-1,2-oxazol-3-yl)-2H-pyrrol-5-one	IC50	1840 nM
cid_3240852	IC50	1920 nM
N-Benzhydryl-2-(8,8-dimethyl-1-oxo-8,9-dihydro-1H,6H-7-oxa-11-thia-2,4,10-triaza-benzo[b]fluoren-2-yl )-acetamide	IC50	1940 nM
3-(1-benzofuran-2-ylcarbonyl)-2-(3-bromophenyl)-1-(5-methyl-1,2-oxazol-3-yl)-4-oxidanyl-2H-pyrrol-5-one	IC50	1970 nM
MLS000050497	IC50	2000 nM
2-(8-chloro-4-oxo-2-sulfanylidene-1H-benzofuro[3,2-d]pyrimidin-3-yl)acetic acid ethyl ester	IC50	2020 nM
MLS000548751	IC50	2070 nM
cid_2946893	IC50	2140 nM
N-(4-methoxyphenyl)-2-[(4-phenyl-5-thiophen-2-yl-1,2,4-triazol-3-yl)sulfanyl]acetamide	IC50	2160 nM
SMR000322789	IC50	2220 nM
3-[2-benzofuranyl(oxo)methyl]-2-(3-bromophenyl)-1-[2-(dimethylamino)ethyl]-4-hydroxy-2H-pyrrol-5-one	IC50	2250 nM
SMR000414964	IC50	2300 nM
1-(6-bromo-4-phenylquinazolin-2-yl)piperidine-4-carboxylic acid	IC50	2320 nM
3-(1-benzofuran-2-carbonyl)-2-(3-bromophenyl)-4-hydroxy-1-(2-morpholin-4-ylethyl)-2H-pyrrol-5-one	IC50	2360 nM
6,8-dibromo-4-(1-piperidinyl)quinazoline	IC50	2360 nM
SMR000550011	IC50	2380 nM
SMR000646795	IC50	2390 nM
4-(5-methyl-2-furanyl)-2-sulfanylidene-5,6,7,8-tetrahydro-1H-quinoline-3-carbonitrile	IC50	2400 nM
cid_2505717	IC50	2430 nM
SMR000269454	IC50	2480 nM
2-(2,4-dimethyl-5-oxidanylidene-thieno[3,4]pyrrolo[1,3-d]pyridazin-6-yl)-N-(2-phenylethyl)ethanamide	IC50	2660 nM
(1S)-1,5-anhydro-1-(1,3,6,7-tetrahydroxy-9-oxo-9H-xanthen-2-yl)-D-glucitol	IC50	2710 nM

ChEMBL bioactivities

143 potent at pChembl≥5 of 157 total, top 50 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
7.46	EC50	35	nM	CHEMBL386138
6.86	IC50	139.1	nM	CHEMBL1391310
6.85	EC50	141	nM	CHEMBL386138
6.83	EC50	147	nM	CHEMBL213426
6.83	IC50	149.1	nM	CHEMBL1232381
6.78	IC50	167.3	nM	CHEMBL1602811
6.77	EC50	170	nM	CHEMBL384623
6.75	IC50	177.9	nM	CHEMBL1575389
6.75	IC50	177.9	nM	CHEMBL1384281
6.73	IC50	185.5	nM	CHEMBL1326814
6.66	IC50	220.2	nM	CHEMBL1324779
6.58	EC50	260	nM	CHEMBL212336
6.58	EC50	260	nM	CHEMBL213665
6.57	EC50	270	nM	CHEMBL215539
6.57	EC50	270	nM	CHEMBL384623
6.52	IC50	303.4	nM	CHEMBL1544403
6.50	EC50	316	nM	CHEMBL213426
6.48	EC50	330	nM	CHEMBL213665
6.48	IC50	330.1	nM	CHEMBL1433074
6.43	EC50	370	nM	CHEMBL214562
6.41	IC50	389.4	nM	CHEMBL1454198
6.32	IC50	473.9	nM	CHEMBL1565040
6.21	EC50	610	nM	CHEMBL215539
6.14	EC50	720	nM	CHEMBL212336
6.13	IC50	748.2	nM	CHEMBL312032
6.11	IC50	774.2	nM	CHEMBL1482670
6.09	IC50	812.5	nM	CHEMBL1417231
6.07	IC50	862	nM	CHEMBL1392806
6.01	EC50	986	nM	CHEMBL214445
6.00	IC50	1001	nM	CHEMBL1407788
5.98	IC50	1055	nM	CHEMBL1601194
5.98	IC50	1056	nM	CHEMBL1391385
5.96	IC50	1090	nM	CHEMBL1566010
5.93	IC50	1173	nM	CHEMBL1405306
5.88	EC50	1320	nM	CHEMBL424715
5.88	EC50	1328	nM	CHEMBL214445
5.86	IC50	1378	nM	CHEMBL1499411
5.85	IC50	1426	nM	CHEMBL1358081
5.85	IC50	1421	nM	CHEMBL1543331
5.84	IC50	1457	nM	CHEMBL1302552
5.83	IC50	1492	nM	CHEMBL1536779
5.79	IC50	1613	nM	CHEMBL1368667
5.79	IC50	1636	nM	CHEMBL1373811
5.72	IC50	1903	nM	CHEMBL1580962
5.70	IC50	2011	nM	CHEMBL1407986
5.69	IC50	2039	nM	CHEMBL1379684
5.68	EC50	2100	nM	CHEMBL214457
5.68	IC50	2093	nM	CHEMBL1304585
5.68	IC50	2092	nM	CHEMBL1336910
5.66	EC50	2200	nM	CHEMBL384232

PubChem BioAssay actives

31 with measured affinity, of 38 total; 18 most potent distinct compounds. Largely complementary to BindingDB; screening values are coarse (µM, 4 dp), so sub-nM hits tie at the floor.

Compound	Assay	Type	Value	Unit
2-chloro-N-[4-[6-(cyclopropanecarbonylamino)-1H-benzimidazol-2-yl]phenyl]benzamide	271159: Agonist activity at NR2E3 by luciferase NCOR release assay in CHO cells	ec50	0.0350	uM
2-chloro-N-[4-[6-(2-methylpropanoylamino)-1H-benzimidazol-2-yl]phenyl]benzamide	271159: Agonist activity at NR2E3 by luciferase NCOR release assay in CHO cells	ec50	0.1470	uM
N-[4-[6-[(2-chlorobenzoyl)amino]-1H-benzimidazol-2-yl]phenyl]-2-fluorobenzamide	271159: Agonist activity at NR2E3 by luciferase NCOR release assay in CHO cells	ec50	0.1700	uM
2-chloro-N-[4-[6-[[(1S,2R)-2-fluorocyclopropanecarbonyl]amino]-1H-benzimidazol-2-yl]phenyl]benzamide	271159: Agonist activity at NR2E3 by luciferase NCOR release assay in CHO cells	ec50	0.2600	uM
N-[4-[6-[(2-chlorobenzoyl)amino]-1H-benzimidazol-2-yl]phenyl]-2-methylbenzamide	271158: Agonist activity at NR2E3 by beta lactamase transactivation assay	ec50	0.2600	uM
N-[2-(4-benzamidophenyl)-3H-benzimidazol-5-yl]-2-chlorobenzamide	271158: Agonist activity at NR2E3 by beta lactamase transactivation assay	ec50	0.2700	uM
2-chloro-N-[4-[6-[(1-phenylcyclopropanecarbonyl)amino]-1H-benzimidazol-2-yl]phenyl]benzamide	271159: Agonist activity at NR2E3 by luciferase NCOR release assay in CHO cells	ec50	0.3700	uM
2-chloro-N-[4-[6-(cyclobutanecarbonylamino)-1H-benzimidazol-2-yl]phenyl]benzamide	271159: Agonist activity at NR2E3 by luciferase NCOR release assay in CHO cells	ec50	0.9860	uM
2-chloro-N-[4-[6-(cyclopentanecarbonylamino)-1H-benzimidazol-2-yl]phenyl]benzamide	271159: Agonist activity at NR2E3 by luciferase NCOR release assay in CHO cells	ec50	1.3200	uM
2-chloro-N-[4-[6-[(2,2-difluorocyclopropanecarbonyl)amino]-1H-benzimidazol-2-yl]phenyl]benzamide	271158: Agonist activity at NR2E3 by beta lactamase transactivation assay	ec50	2.1000	uM
2-chloro-N-[4-[6-[(2-chlorobenzoyl)amino]-1H-benzimidazol-2-yl]phenyl]pyridine-3-carboxamide	271159: Agonist activity at NR2E3 by luciferase NCOR release assay in CHO cells	ec50	2.2000	uM
2-chloro-N-[4-[6-[(1-methylcyclopropanecarbonyl)amino]-1H-benzimidazol-2-yl]phenyl]benzamide	271158: Agonist activity at NR2E3 by beta lactamase transactivation assay	ec50	2.5000	uM
2-chloro-N-[4-[6-(2,2-dimethylpropanoylamino)-1H-benzimidazol-2-yl]phenyl]benzamide	271159: Agonist activity at NR2E3 by luciferase NCOR release assay in CHO cells	ec50	2.6100	uM
2-chloro-N-[2-[1-(4-fluorophenyl)pyrazol-4-yl]-3H-benzimidazol-5-yl]benzamide	271159: Agonist activity at NR2E3 by luciferase NCOR release assay in CHO cells	ec50	4.1000	uM
2-chloro-N-[2-[3-[(2-chlorobenzoyl)amino]phenyl]-3H-benzimidazol-5-yl]benzamide	271159: Agonist activity at NR2E3 by luciferase NCOR release assay in CHO cells	ec50	4.1000	uM
2-chloro-N-[2-(3,5-dichloro-2-hydroxyphenyl)-3H-benzimidazol-5-yl]benzamide	271159: Agonist activity at NR2E3 by luciferase NCOR release assay in CHO cells	ec50	4.2000	uM
N-[2-(1,3-benzodioxol-5-yl)-3H-benzimidazol-5-yl]-2-chlorobenzamide	271159: Agonist activity at NR2E3 by luciferase NCOR release assay in CHO cells	ec50	7.2000	uM
2-chloro-N-[4-[6-[(1-cyanocyclopropanecarbonyl)amino]-1H-benzimidazol-2-yl]phenyl]benzamide	271159: Agonist activity at NR2E3 by luciferase NCOR release assay in CHO cells	ec50	10.0000	uM

CTD chemical–gene interactions

13 total (human), top 13 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Benzo(a)pyrene	decreases expression, decreases reaction, affects methylation, affects binding	2
bisphenol A	decreases methylation	1
terbufos	increases methylation	1
butyraldehyde	decreases expression	1
benzo(e)pyrene	increases methylation	1
S-ethyl glutathione	decreases expression, decreases reaction	1
Acetylcysteine	decreases expression, decreases reaction	1
Fonofos	increases methylation	1
Methapyrilene	increases methylation	1
Parathion	increases methylation	1
Valproic Acid	increases methylation	1
Cadmium Chloride	increases expression	1
Copper Sulfate	decreases expression	1

ChEMBL screening assays

6 unique, capped per target: 5 functional, 1 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL1613893	Functional	PUBCHEM_BIOASSAY: TR-FRET-based biochemical high throughput dose response assay for agonists of nuclear receptor subfamily 2, group E, member 3 (NR2E3). (Class of assay: confirmatory) [Related pubchem assays: 2379 (Screening (NR2E3 agonists	PubChem BioAssay data set
CHEMBL1961851	Binding	Effect on PNR(NR2E3) dependent reporter activity in HEK293 cells at 20 uM	Regulation of circadian behaviour and metabolism by synthetic REV-ERB agonists. — Nature

Cellosaurus cell lines

4 cell lines: 3 embryonic stem cell, 1 induced pluripotent stem cell

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

Cellosaurus	Name	Category	Sex
CVCL_A4V1	SEES3-1V human NR2E3, clone1	Embryonic stem cell	Male
CVCL_A4V2	SEES3-1V human NR2E3, clone2	Embryonic stem cell	Male
CVCL_A4V3	SEES3-1V human NR2E3, clone3	Embryonic stem cell	Male
CVCL_QX82	IDVi001-A	Induced pluripotent stem cell	Female

Clinical trials (associated diseases)

259 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
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
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
NCT06628947	PHASE2	RECRUITING	A Phase II Study of Intravitreal KIO-301 in Patients With Late-stage Retinitis Pigmentosa
NCT06912633	PHASE2	RECRUITING	Safety of a Single, Intravitreal Injection of 6.0M jCell (Famzeretcel) in Retinitis Pigmentosa (RP)
NCT03763227	PHASE2	COMPLETED	Intravitreal Ranibizumab (Lucentis®) in the Treatment of Non-leaking Macular Cysts in Retinal Dystrophy
NCT00063765	PHASE1	COMPLETED	Evaluation of Safety of Ciliary Neurotrophic Factor Implants in the Eye
NCT00065455	PHASE1	COMPLETED	Investigating the Effect of Vitamin A Supplementation on Retinitis Pigmentosa
NCT00458575	PHASE1	TERMINATED	A Study to Evaluate the Safety of CNTO 2476 in Patients With Advanced Retinitis Pigmentosa