RTN4R

Summary

RTN4R (reticulon 4 receptor, HGNC:18601) is a protein-coding gene on chromosome 22q11.21, encoding Reticulon-4 receptor (Q9BZR6). Receptor for RTN4, OMG and MAG.

This gene encodes the receptor for reticulon 4, oligodendrocyte myelin glycoprotein and myelin-associated glycoprotein. This receptor mediates axonal growth inhibition and may play a role in regulating axonal regeneration and plasticity in the adult central nervous system.

Source: NCBI Gene 65078 — RefSeq curated summary.

At a glance

• GWAS associations: 2
• Clinical variants (ClinVar): 100 total — 2 pathogenic
• Phenotypes (HPO): 7
• MANE Select transcript: NM_023004

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:18601
Approved symbol	RTN4R
Name	reticulon 4 receptor
Location	22q11.21
Locus type	gene with protein product
Status	Approved
Aliases	NgR1, NgR, NOGOR
Ensembl gene	ENSG00000040608
Ensembl biotype	protein_coding
OMIM	605566
Entrez	65078

Gene structure

Transcript identifiers

Ensembl transcripts: 6 — 3 protein_coding, 3 protein_coding_CDS_not_defined

ENST00000043402, ENST00000416372, ENST00000425986, ENST00000463936, ENST00000469601, ENST00000474642

RefSeq mRNA: 1 — MANE Select: NM_023004 NM_023004

CCDS: CCDS13777

Canonical transcript exons

ENST00000043402 — 2 exons

Exon	Start	End
ENSE00001358408	20268071	20268318
ENSE00001557601	20241415	20243110

Expression profiles

Bgee: expression breadth ubiquitous, 175 present calls, max score 95.60.

FANTOM5 (CAGE): breadth broad, TPM avg 0.9007 / max 18.9886, expressed in 502 samples.

FANTOM5 promoters (3 alternative TSS)

Promoter ID	TPM avg	Samples expressed
193190	0.6580	403
193189	0.2177	106
193188	0.0251	3

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
right hemisphere of cerebellum	UBERON:0014890	95.60	gold quality
cerebellar hemisphere	UBERON:0002245	95.00	gold quality
cerebellar cortex	UBERON:0002129	94.94	gold quality
cerebellum	UBERON:0002037	94.23	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	93.72	silver quality
right frontal lobe	UBERON:0002810	92.97	gold quality
Brodmann (1909) area 9	UBERON:0013540	91.26	gold quality
prefrontal cortex	UBERON:0000451	91.01	gold quality
dorsolateral prefrontal cortex	UBERON:0009834	89.75	gold quality
frontal cortex	UBERON:0001870	89.63	gold quality
anterior cingulate cortex	UBERON:0009835	89.25	gold quality
neocortex	UBERON:0001950	89.17	gold quality
cerebral cortex	UBERON:0000956	86.91	gold quality
cortical plate	UBERON:0005343	85.95	gold quality
cerebellar vermis	UBERON:0004720	85.89	gold quality
amygdala	UBERON:0001876	85.34	gold quality
primary visual cortex	UBERON:0002436	84.89	gold quality
embryo	UBERON:0000922	83.71	gold quality
ganglionic eminence	UBERON:0004023	83.71	gold quality
superior frontal gyrus	UBERON:0002661	83.54	gold quality
ventricular zone	UBERON:0003053	83.25	gold quality
temporal lobe	UBERON:0001871	82.79	gold quality
middle temporal gyrus	UBERON:0002771	82.49	gold quality
occipital lobe	UBERON:0002021	81.54	gold quality
oocyte	CL:0000023	81.52	gold quality
Ammon’s horn	UBERON:0001954	80.94	gold quality
brain	UBERON:0000955	80.80	gold quality
postcentral gyrus	UBERON:0002581	80.53	gold quality
forebrain	UBERON:0001890	80.19	gold quality
parietal lobe	UBERON:0001872	79.66	gold quality

Single-cell (SCXA)

Detected in 1 experiment(s), a significant marker in 0.

Experiment	Marker?	Max mean expression
E-ANND-3	no	1.71

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

23 targeting RTN4R, 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-30A-5P	100.00	76.31	3233
HSA-MIR-30B-5P	100.00	76.29	3248
HSA-MIR-30C-5P	100.00	76.29	3248
HSA-MIR-30D-5P	100.00	76.32	3233
HSA-MIR-30E-5P	100.00	76.32	3242
HSA-MIR-6745	99.74	65.33	1321
HSA-MIR-5700	99.64	69.88	2280
HSA-MIR-1276	99.36	68.18	1642
HSA-MIR-3675-3P	99.09	67.70	968
HSA-MIR-4651	99.06	67.57	2002
HSA-MIR-4801	98.96	69.42	2096
HSA-MIR-608	98.93	67.83	2013
HSA-MIR-10A-5P	98.89	69.85	712
HSA-MIR-10B-5P	98.89	69.86	711
HSA-MIR-4731-3P	98.56	68.60	1860
HSA-MIR-6776-5P	98.54	67.43	1304
HSA-MIR-4664-5P	98.17	65.07	1020
HSA-MIR-6812-5P	97.56	65.39	1059
HSA-MIR-342-5P	97.25	64.10	817
HSA-MIR-10400-5P	96.91	66.00	56
HSA-MIR-125B-2-3P	96.69	68.38	1210
HSA-MIR-4467	96.51	64.44	69
HSA-MIR-6747-5P	96.17	64.99	743

Literature-anchored findings (GeneRIF, showing 40)

• Oligodendrocyte-myelin glycoprotein is a Nogo receptor ligand that inhibits neurite outgrowth (PMID:12068310)
• Nogo-66-R mRNA expression in humans and mice was observed in neurons of the developing nervous system; expression was downregulated in the adult spinal cord of both species, and specific expression patterns were seen in the adult brain. (PMID:12378589)
• P75 interacts with the Nogo receptor as a co-receptor for Nogo, MAG (myelin-associated glycoprotein) and OMgp (PMID:12422217)
• Nogo-66 receptor (NgR) proteolysis occurs within the human nervous system indicating a potential cellular mechanism for the regulation of NgR function at the level of the receptor (PMID:15331667)
• the role of the RTN4R as a candidate gene for schizophrenia (PMID:15532024)
• Expression of the genes encoding Nogo and its receptor, NgR, between weeks eight and 23 of human embryonic development. (PMID:15749087)
• analysis revealed a novel disulfide structure in the C-terminal region (CT) of the NgR1, wherein the two Cys residues, Cys-335 and Cys-336, in the CT stalk are disulfide-linked to Cys-266 and Cys-309 in the LRRCT region (PMID:16342940)
• results suggest that there is no significant association between the genetic polymorphisms in the RTN4R gene and schizophrenia in the Han Chinese population (PMID:16897606)
• The molecular requirements for cerebral amyloid-beta peptide interaction with NgR are defined and correlated with the affinity of these polypeptides to improve spatial memory impairments in Alzheimer disease model mice. (PMID:17182778)
• results showed that NgR immunoreactivity was present in more than 50% of the pyramidal layer cells of the CA1 to CA4 subfields of the hippocampus; results suggest that NgR may be related to the formation of tangles in Alzheimer’s disease (PMID:17188332)
• Review highlights the function of Nogo-66 receptor-1 (NgR-1) during myelin inhibition. (PMID:17959786)
• RTN4R may modulate the genetic risk or clinical expression of schizophrenia in a subset of patients and identify additional studies that will be necessary to clarify the role of RTN4R in psychiatric phenotypes (PMID:18043741)
• For a restricted subset of individuals diagnosed with schizophrenia, the expression of dysfunctional NGR variants may contribute to increased disease risk. (PMID:19052207)
• We conclude that NgR1 alters the motility of immune cells exposed to myelin and may thus impact their behaviour within the CNS, particularly under conditions when immune cell activation is heightened. (PMID:19328785)
• This review summarizes recent research that generates interest in the Nogo-66 receptor (NgR1) as a focus of study in central nervous system injury and for its function in increasing susceptibility to developing schizophrenia. (PMID:19386899)
• Nogo-66 receptor (NgR)is identified as a high affinity receptor for BLyS; BLyS can function independently of myelin-associated inhibitors & likely serves as a redundant NgR ligand that negatively influences axonal outgrowth in the central nervous system (PMID:19439611)
• Hypermethylation of NOGOR gene is associated with adenocarcinoma. (PMID:20524398)
• Kiaa0319-like protein interacts with Nogo Receptor 1, supporting the idea that Kiaa0319-like protein participates in axon guidance. (PMID:20697954)
• In acute slices of adult mice, transgenic NGR suppresses long-term potentiation when locally applied to hippocampal CA1 synapses. (PMID:20844138)
• The results of this study suggested that Lack of association of the RTN4R genetic variations with risk of schizophrenia and SPEM abnormality in a Korean population. (PMID:21377214)
• A multi-domain fragment of Nogo-A protein is a potent inhibitor of cortical axon regeneration via Nogo receptor 1. (PMID:21454605)
• Expression of Nogo-66 receptor in human astrocytoma is correlated with tumor malignancy. (PMID:21681431)
• These results indicate that a lack of NgR1/2 expression promotes the adhesion of DCs to myelin. (PMID:21906273)
• Nogo receptor 3, a paralog of NgR1,functions as a NgR1 co-receptor for Nogo-66. (PMID:22133682)
• After optic nerve crush injury, transgenic NgR1-deficient neurons regenerate retinal ganglion axons as extensively as do zymosan-injected, macrophage-activated wild-type mice. (PMID:22728374)
• Strong overexpression of Nogo receptor 1 in forebrain neurons impairs aspects of cognitive function but does not alter plaque load in plaque-forming transgenic animals. (PMID:22903127)
• knockdown of NgR enhanced invasion and adhesion but increased cell apoptosis in C6 cells, suggesting that Nogo-66/NgR might have complex effects on glioma cells. (PMID:23982337)
• This study demonistrated that alterations in DTI metrics suggest white matter microstructural anomalies of the cerebral cortex in 22q11.2DS. Structural differences in ALIC appear to be associated with the Nogo-66 receptor gene. (PMID:24321711)
• NgR1 is a neural entry mediator for mammalian reovirus.NgR1 is required for efficient infection of primary cortical neurons by reovirus. (PMID:24922571)
• Authors highlight the structural and biochemical aspects of the interaction of Nogo receptors (R1 and R2) with myelin inhibitors such as MAG, Nogo A and OMgp.[Review] (PMID:24956133)
• Data indicate that leucine-rich repeat neuronal protein 1 (LINGO-1) is intracellular and competes with Nogo-66 receptor (NgR) for binding to p75 neurotrophin receptor (p75NTR). (PMID:25666623)
• Messenger RNA expression from RTN4R in human cortical brain tissue correlated significantly with the genotypes of rs701427. Observations suggest that a functional RTN4R gene variant is associated with sporadic ALS. (PMID:26083872)
• (188)Re-NGR-VEGI has the potential as a theranostic agent. (PMID:26768609)
• Panax notoginseng saponins provide neuroprotective effects in a rat model of cerebral ischemia and SH-SY5Y cells exposed to oxygen/glucose deprivation injury by inhibiting the overexpression of NgR1, RhoA, and ROCK2. (PMID:27288754)
• NgR1 ligand has a role in in oligodendrocyte progenitor cells fate in the context of a specific and common type of stroke (PMID:27956620)
• Allelic variation of the rs701428 SNP of RTN4R was significantly associated with volumetric differences in gray matter of the lingual gyrus and cuneus of the occipital lobe. Moreover, occipital gray matter volumes were robustly associated with ultra high risk symptoms of psychosis in the presence of the G allele of rs701428. (PMID:28139055)
• Results indicate an association between RTN4R genetic variation and phenotypes linked to prefrontal function. In an hierarchical approach, a SNP (rs696884) selected based on its association with RTN4R postmortem mRNA expression in the prefrontal cortex was shown to modulate prefrontal activity during working memory processing. (PMID:28755979)
• Nociceptin receptor ORL1 increases the cell surface expression of reticulon 4 receptor (NgR1) in HEK293T cells. (PMID:29615517)
• miR-10 can promote microglia cell proliferation and inhibit the inflammatory cytokine secretion via targeting the NgR gene to down-regulate its expression. (PMID:30312597)
• the treatment of glioblastoma multiforme cells with TGFb1 suppressed NgR maturation. We showed that NgR and vimentin interact, which could be a possible mechanism for the suppression of NgR maturation. (PMID:31649250)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	rtn4r	ENSDARG00000090035
mus_musculus	Rtn4r	ENSMUSG00000043811
rattus_norvegicus	Rtn4r	ENSRNOG00000030920

Paralogs (22): DCN (ENSG00000011465), ASPN (ENSG00000106819), FLRT3 (ENSG00000125848), FLRT1 (ENSG00000126500), LRRC4 (ENSG00000128594), LRRC4B (ENSG00000131409), PODNL1 (ENSG00000132000), LRTM1 (ENSG00000144771), LRRC4C (ENSG00000148948), LRRTM1 (ENSG00000162951), LRRC15 (ENSG00000172061), PODN (ENSG00000174348), LRRTM4 (ENSG00000176204), BGN (ENSG00000182492), LRRC19 (ENSG00000184434), FLRT2 (ENSG00000185070), GP1BA (ENSG00000185245), RTN4RL1 (ENSG00000185924), RTN4RL2 (ENSG00000186907), NYX (ENSG00000188937), LRRC66 (ENSG00000188993), LRRTM3 (ENSG00000198739)

Protein

Protein identifiers

Reticulon-4 receptor — Q9BZR6 (reviewed: Q9BZR6)

Alternative names: Nogo receptor, Nogo-66 receptor

All UniProt accessions (3): Q9BZR6, H7C0V4, H7C215

UniProt curated annotations — full annotation on UniProt →

Function. Receptor for RTN4, OMG and MAG. Functions as a receptor for the sialylated gangliosides GT1b and GM1. Besides, functions as a receptor for chondroitin sulfate proteoglycans. Can also bind heparin. Intracellular signaling cascades are triggered via the coreceptor NGFR. Signaling mediates activation of Rho and downstream reorganization of the actin cytoskeleton. Mediates axonal growth inhibition. Plays a role in regulating axon regeneration and neuronal plasticity in the adult central nervous system. Plays a role in postnatal brain development. Required for normal axon migration across the brain midline and normal formation of the corpus callosum. Protects motoneurons against apoptosis; protection against apoptosis is probably mediated via interaction with MAG. Acts in conjunction with RTN4 and LINGO1 in regulating neuronal precursor cell motility during cortical development. Like other family members, plays a role in restricting the number dendritic spines and the number of synapses that are formed during brain development. (Microbial infection) Acts as a receptor for Reovirus type 3.

Subunit / interactions. Homodimer. Interacts with MAG. Interacts with RTN4. Interacts with NGFR. Interacts with LINGO1. Interacts with KIAA0319L. Interacts with OLFM1; this inhibits interaction with LINGO1 and NGFR. Interacts with OMG. (Microbial infection) 2 molecules of RTN4R interact with Reovirus type 3 outer capsid protein sigma-3; this interaction allows the virus entry into the cell.

Subcellular location. Cell membrane. Membrane raft. Cell projection. Dendrite. Axon. Perikaryon.

Tissue specificity. Widespread in the brain but highest levels in the gray matter. Low levels in heart and kidney; not expressed in oligodendrocytes (white matter).

Post-translational modifications. N-glycosylated. O-glycosylated. Contains terminal sialic acid groups on its glycan chains.

Disease relevance. Schizophrenia (SCZD) [MIM:181500] A complex, multifactorial psychotic disorder or group of disorders characterized by disturbances in the form and content of thought (e.g. delusions, hallucinations), in mood (e.g. inappropriate affect), in sense of self and relationship to the external world (e.g. loss of ego boundaries, withdrawal), and in behavior (e.g bizarre or apparently purposeless behavior). Although it affects emotions, it is distinguished from mood disorders in which such disturbances are primary. Similarly, there may be mild impairment of cognitive function, and it is distinguished from the dementias in which disturbed cognitive function is considered primary. Some patients manifest schizophrenic as well as bipolar disorder symptoms and are often given the diagnosis of schizoaffective disorder. Disease susceptibility is associated with variants affecting the gene represented in this entry.

Similarity. Belongs to the Nogo receptor family.

RefSeq proteins (1): NP_075380* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000483	Cys-rich_flank_reg_C	Domain
IPR001611	Leu-rich_rpt	Repeat
IPR003591	Leu-rich_rpt_typical-subtyp	Repeat
IPR032675	LRR_dom_sf	Homologous_superfamily
IPR050541	LRR_TM_domain-containing	Family

Pfam: PF13855

UniProt features (83 total): sequence variant 16, mutagenesis site 15, strand 14, repeat 9, turn 7, helix 6, disulfide bond 5, domain 2, compositionally biased region 2, glycosylation site 2, signal peptide 1, chain 1, region of interest 1, lipid moiety-binding region 1, propeptide 1

Structure

Experimental structures (PDB)

2 structures.

PDB	Method	Resolution (Å)
1OZN	X-RAY DIFFRACTION	1.52
1P8T	X-RAY DIFFRACTION	3.2

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9BZR6-F1	76.47	0.61

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 (1): 447

Disulfide bonds (5): 27–33, 31–43, 264–287, 266–335, 309–336

Glycosylation sites (2): 82, 179

Mutagenesis-validated functional residues (15):

Position	Phenotype
151	impaired ganglioside binding.
160	complete loss of binding to reovirus type 3 outer capsid protein sigma-3. complete loss of infectivity.
162	complete loss of binding to reovirus type 3 outer capsid protein sigma-3. complete loss of infectivity.
184	complete loss of binding to reovirus type 3 outer capsid protein sigma-3. complete loss of infectivity.
189	complete loss of binding to reovirus type 3 outer capsid protein sigma-3. complete loss of infectivity.
199	impaired ganglioside binding.
206	complete loss of binding to reovirus type 3 outer capsid protein sigma-3. complete loss of infectivity.
208	complete loss of binding to reovirus type 3 outer capsid protein sigma-3. complete loss of infectivity.
235	complete loss of binding to reovirus type 3 outer capsid protein sigma-3. complete loss of infectivity.
256	complete loss of binding to reovirus type 3 outer capsid protein sigma-3. complete loss of infectivity.
277	no effect on interaction with mag.
277	decreases interaction with mag; when associated with d-279.
279	mildly decreases interaction with mag.
279	decreases interaction with mag; when associated with d-277.
279	impaired ganglioside binding.

Function

Pathways and Gene Ontology

Reactome pathways

5 pathways

ID	Pathway
R-HSA-193634	Axonal growth inhibition (RHOA activation)
R-HSA-162582	Signal Transduction
R-HSA-193697	p75NTR regulates axonogenesis
R-HSA-193704	p75 NTR receptor-mediated signalling
R-HSA-73887	Death Receptor Signaling

MSigDB gene sets: 219 (showing top): RNGTGGGC_UNKNOWN, GOBP_NEGATIVE_REGULATION_OF_CELL_DEVELOPMENT, GOBP_NEURON_PROJECTION_EXTENSION, GOBP_NEGATIVE_REGULATION_OF_AXON_EXTENSION, GOBP_SYNAPSE_ASSEMBLY, GOBP_REGULATION_OF_DEVELOPMENTAL_GROWTH, PEREZ_TP63_TARGETS, GOBP_NEGATIVE_REGULATION_OF_CELL_GROWTH, STARK_PREFRONTAL_CORTEX_22Q11_DELETION_DN, GOBP_POSITIVE_REGULATION_OF_RHO_PROTEIN_SIGNAL_TRANSDUCTION, GOBP_GROWTH, GOBP_REGULATION_OF_GTPASE_ACTIVITY, GOBP_REGULATION_OF_SMALL_GTPASE_MEDIATED_SIGNAL_TRANSDUCTION, GOCC_CELL_SURFACE, GOBP_REGENERATION

GO Biological Process (11): cell surface receptor signaling pathway (GO:0007166), axonogenesis (GO:0007409), negative regulation of neuron projection development (GO:0010977), corpus callosum development (GO:0022038), neuronal signal transduction (GO:0023041), negative regulation of axon extension (GO:0030517), positive regulation of Rho protein signal transduction (GO:0035025), positive regulation of GTPase activity (GO:0043547), negative regulation of axon regeneration (GO:0048681), regulation of postsynapse assembly (GO:0150052), regulation of synapse assembly (GO:0051963)

GO Molecular Function (8): heparin binding (GO:0008201), chondroitin sulfate binding (GO:0035374), signaling receptor activity (GO:0038023), neuregulin receptor activity (GO:0038131), ganglioside GM1 binding (GO:1905573), ganglioside GT1b binding (GO:1905576), protein binding (GO:0005515), lipid binding (GO:0008289)

GO Cellular Component (18): endoplasmic reticulum (GO:0005783), plasma membrane (GO:0005886), external side of plasma membrane (GO:0009897), cell surface (GO:0009986), neuron projection (GO:0043005), neuronal cell body (GO:0043025), dendritic shaft (GO:0043198), perikaryon (GO:0043204), axonal growth cone (GO:0044295), membrane raft (GO:0045121), extracellular exosome (GO:0070062), glutamatergic synapse (GO:0098978), membrane (GO:0016020), axon (GO:0030424), dendrite (GO:0030425), growth cone (GO:0030426), cell projection (GO:0042995), side of membrane (GO:0098552)

Reactome top-level categories

Rollup of top-4 pathways:

Category	Pathways
p75NTR regulates axonogenesis	1
p75 NTR receptor-mediated signalling	1
Death Receptor Signaling	1
Signal Transduction	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	6
signal transduction	2
glycosaminoglycan binding	2
sulfur compound binding	2
carboxylic acid binding	2
ganglioside binding	2
binding	2
membrane	2
neuron projection	2
cell morphogenesis involved in neuron differentiation	1
neuron projection morphogenesis	1
axon development	1
regulation of neuron projection development	1
neuron projection development	1
negative regulation of cell projection organization	1
telencephalon development	1
anatomical structure development	1
negative regulation of cell growth	1
regulation of axon extension	1
negative regulation of developmental growth	1
axon extension	1
negative regulation of axonogenesis	1
Rho protein signal transduction	1
regulation of Rho protein signal transduction	1
positive regulation of small GTPase mediated signal transduction	1
GTPase activity	1
regulation of GTPase activity	1
positive regulation of hydrolase activity	1
axon regeneration	1
negative regulation of response to external stimulus	1
regulation of axon regeneration	1
negative regulation of neuron projection regeneration	1
negative regulation of response to wounding	1
regulation of synapse assembly	1
postsynapse assembly	1
regulation of postsynapse organization	1
synapse assembly	1
regulation of synapse organization	1
regulation of cell junction assembly	1
molecular transducer activity	1

Protein interactions and networks

STRING

1734 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
RTN4R	MAG	P20916	999
RTN4R	RTN4	Q9NQC3	999
RTN4R	NGFR	P08138	996
RTN4R	ANPEP	P15144	996
RTN4R	TNFRSF19	Q9NS68	994
RTN4R	OMG	P23515	990
RTN4R	LINGO1	Q96FE5	989
RTN4R	KIAA0319L	Q8IZA0	816
RTN4R	EMG1	Q92979	812
RTN4R	MOG	Q16653	767
RTN4R	APP	P05067	757
RTN4R	BDNF	P23560	756
RTN4R	ZDHHC8	Q9ULC8	746
RTN4R	LINGO2	Q7L985	684
RTN4R	OLFM1	Q99784	682

IntAct

23 interactions, top by confidence:

A	B	Type	Score
LRRC32	SMPD2	psi-mi:“MI:0914”(association)	0.640
OTX1	RTN4R	psi-mi:“MI:0915”(physical association)	0.560
	RTN4R	psi-mi:“MI:0915”(physical association)	0.560
HOXA1	RTN4R	psi-mi:“MI:0915”(physical association)	0.560
RTN4R	KIAA0319L	psi-mi:“MI:0915”(physical association)	0.540
KIAA0319L	RTN4R	psi-mi:“MI:0915”(physical association)	0.540
KIAA0319L	RTN4R	psi-mi:“MI:0403”(colocalization)	0.540
FCGRT	GOLIM4	psi-mi:“MI:0914”(association)	0.530
RTN4R	SOAT1	psi-mi:“MI:0914”(association)	0.530
RTN4R	NGFR	psi-mi:“MI:0915”(physical association)	0.400
RTN4R	LINGO1	psi-mi:“MI:0915”(physical association)	0.400
S100A9	RTN4R	psi-mi:“MI:0915”(physical association)	0.370
RTN4R	CRLF1	psi-mi:“MI:0914”(association)	0.350
LRRC32	ORC4	psi-mi:“MI:0914”(association)	0.350
HOXA1	RTN4R	psi-mi:“MI:0915”(physical association)	0.000
OTX1	RTN4R	psi-mi:“MI:0915”(physical association)	0.000
	RTN4R	psi-mi:“MI:0915”(physical association)	0.000

BioGRID (39): RTN4R (Affinity Capture-MS), ARHGEF25 (Affinity Capture-MS), SOAT1 (Affinity Capture-MS), CKAP4 (Affinity Capture-MS), RTN4R (Affinity Capture-MS), LINGO1 (Affinity Capture-Western), RTN4R (Affinity Capture-Western), HOXA1 (Two-hybrid), OTX1 (Two-hybrid), MGAT5B (Two-hybrid), OMG (Reconstituted Complex), RTN4R (Affinity Capture-RNA), ARHGEF25 (Affinity Capture-MS), SPCS1 (Affinity Capture-MS), SOAT1 (Affinity Capture-MS)

ESM2 similar proteins: A1L515, A2A9Q0, D3YZZ2, D4A2Q0, E1BDF2, E7ERA6, F2Z333, H3BV60, O43508, O46547, O54907, P0C6B2, P0DH78, P41155, P51172, P70225, Q01113, Q13477, Q14626, Q29RT8, Q5RF19, Q5SZI1, Q5T7M4, Q5U4P2, Q63148, Q64385, Q6AZ51, Q6BAA4, Q6UWL6, Q6UXT9, Q6ZMC9, Q86UR1, Q86YD3, Q8BH06, Q8N1F8, Q8NFR9, Q96G42, Q99640, Q99M75, Q99MF4

Diamond homologs: A3KNN3, A4IIW9, A6H789, A6H793, A6NJW4, A8WHP9, C3YZ59, E5DHB5, G5EFX6, O02678, O14498, O35367, O42235, O46542, O60938, O62702, O75093, O75094, O88186, O88279, O88280, O94813, P02750, P07585, P14770, P21793, P24014, P28654, P28675, P35379, P59034, P59035, P70193, P79763, Q01129, Q28888, Q29393, Q3SXY7, Q3UY51, Q3ZBN5

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	2
Likely pathogenic	0
Uncertain significance	85
Likely benign	10
Benign	0

Top pathogenic / likely-pathogenic (2)

Variant ID	HGVS	Classification
145113	GRCh38/hg38 22q11.21(chr22:18907322-20250683)x1	Pathogenic
981206	GRCh37/hg19 22q11.1-12.1(chr22:16888899-26483608)x3	Pathogenic

SpliceAI

558 predictions. Top by Δscore:

Variant	Effect	Δscore
22:20243107:CTCC:C	acceptor_gain	1.0000
22:20243109:CC:C	acceptor_gain	1.0000
22:20243110:CC:C	acceptor_gain	1.0000
22:20243111:C:CC	acceptor_gain	1.0000
22:20243106:GCTCC:G	acceptor_gain	0.9900
22:20243107:CTCCC:C	acceptor_gain	0.9900
22:20243108:TCC:T	acceptor_gain	0.9900
22:20243108:TCCCT:T	acceptor_gain	0.9900
22:20243109:CCC:C	acceptor_gain	0.9900
22:20243109:CCCTG:C	acceptor_loss	0.9900
22:20243110:CCT:C	acceptor_loss	0.9900
22:20243111:CT:C	acceptor_loss	0.9900
22:20243112:T:C	acceptor_loss	0.9900
22:20268066:CTCA:C	donor_loss	0.9900
22:20268067:TCACC:T	donor_loss	0.9900
22:20268068:CA:C	donor_loss	0.9900
22:20268069:A:AC	donor_gain	0.9900
22:20268069:A:T	donor_loss	0.9900
22:20268069:ACCT:A	donor_gain	0.9900
22:20268070:C:CC	donor_gain	0.9900
22:20268070:CCT:C	donor_gain	0.9900
22:20268070:CCTC:C	donor_gain	0.9900
22:20246727:G:A	donor_gain	0.9500
22:20268069:ACCTC:A	donor_gain	0.9500
22:20268070:CCTCC:C	donor_gain	0.9500
22:20268069:AC:A	donor_gain	0.9400
22:20268070:CC:C	donor_gain	0.9400
22:20243118:C:CT	acceptor_gain	0.9100
22:20243119:A:T	acceptor_gain	0.9100
22:20243113:G:GC	acceptor_gain	0.8900

AlphaMissense

2997 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
22:20242431:A:C	F234L	0.999
22:20242431:A:T	F234L	0.999
22:20242433:A:G	F234L	0.999
22:20242945:A:C	F63C	0.999
22:20242347:C:A	W262C	0.998
22:20242347:C:G	W262C	0.998
22:20242349:A:G	W262R	0.998
22:20242349:A:T	W262R	0.998
22:20242372:T:C	Y254C	0.998
22:20242426:T:A	N236I	0.998
22:20242581:G:C	F184L	0.998
22:20242581:G:T	F184L	0.998
22:20242583:A:G	F184L	0.998
22:20242585:A:G	L183P	0.998
22:20242944:G:C	F63L	0.998
22:20242944:G:T	F63L	0.998
22:20242946:A:G	F63L	0.998
22:20242342:C:T	C264Y	0.997
22:20242353:G:C	N260K	0.997
22:20242353:G:T	N260K	0.997
22:20242435:A:G	L233P	0.997
22:20242497:G:C	N212K	0.997
22:20242497:G:T	N212K	0.997
22:20242513:A:G	L207P	0.997
22:20242513:A:T	L207H	0.997
22:20242804:A:G	L110P	0.997
22:20242355:T:A	N260Y	0.996
22:20242363:A:T	L257H	0.996
22:20242366:C:A	R256M	0.996
22:20242366:C:G	R256T	0.996

dbSNP variants (sampled 300 via entrez): RS1000005339 (22:20248509 C>T), RS1000197364 (22:20262268 T>G), RS1000416789 (22:20258512 A>G), RS1000539355 (22:20268498 G>C), RS1000634238 (22:20268309 G>A,C), RS1000844086 (22:20253694 G>A), RS1000930312 (22:20263616 C>G), RS1000986653 (22:20259065 A>C), RS1000997939 (22:20258851 G>A), RS1001047274 (22:20258615 G>T), RS1001190688 (22:20241035 C>T), RS1001692945 (22:20257315 G>A), RS1001745674 (22:20250943 C>A,T), RS1001770815 (22:20245999 C>G), RS1001788360 (22:20249802 G>A,T)

Disease associations

OMIM: gene MIM:605566 | disease phenotypes: MIM:181500, MIM:115470, MIM:608363

GenCC curated gene-disease

Mondo (4): schizophrenia (MONDO:0005090), schizophrenia, susceptibility to (MONDO:0100182), cat-eye syndrome (MONDO:0007276), chromosome 22q11.2 microduplication syndrome (MONDO:0012020)

Orphanet (3): 22q11.2 duplication syndrome (Orphanet:1727), Cat-eye syndrome (Orphanet:195), NON RARE IN EUROPE: Schizophrenia (Orphanet:3140)

HPO phenotypes

7 total (7 of 7 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000738	Hallucinations
HP:0000746	Delusion
HP:0002353	EEG abnormality
HP:0007086	Social and occupational deterioration
HP:0100753	Schizophrenia
HP:0410291	Negativism

GWAS associations

2 associations (top):

Study	Trait	p-value
GCST001762_10	Obesity-related traits	2.000000e-06
GCST006585_920	Blood protein levels	8.000000e-25

MeSH disease descriptors (2)

Descriptor	Name	Tree numbers
C567224	Chromosome 22q11.2 Microduplication Syndrome (supp.)
C535918	Schmid-Fraccaro syndrome (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

41 total (human), top 30 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Arsenic	affects methylation, affects cotreatment, decreases expression, increases abundance	2
Lead	affects expression	2
Phenylmercuric Acetate	decreases expression, affects cotreatment	2
urushiol	decreases expression	1
triphenyl phosphate	affects expression	1
hydroxyhydroquinone	decreases expression, decreases reaction	1
tris(2-butoxyethyl) phosphate	affects expression	1
sodium arsenite	affects cotreatment, decreases expression, increases abundance	1
butyraldehyde	increases expression	1
manganese chloride	affects cotreatment, decreases expression, increases abundance	1
aflatoxin B2	decreases methylation	1
4-aminobenzhydrazide	decreases expression, decreases reaction	1
S-(1,2-dichlorovinyl)cysteine	affects response to substance, increases expression, affects cotreatment, decreases expression	1
di-n-butylphosphoric acid	affects expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, decreases expression	1
abrine	decreases expression	1
dorsomorphin	affects cotreatment, decreases expression	1
jinfukang	increases expression	1
Resveratrol	decreases expression, affects cotreatment	1
Fulvestrant	increases methylation	1
Acetaminophen	increases expression	1
Benzo(a)pyrene	affects methylation	1
Calcitriol	increases expression	1
Cisplatin	decreases expression	1
Hydrogen Peroxide	affects expression	1
Lipopolysaccharides	decreases expression, affects response to substance, increases expression, affects cotreatment	1
Manganese	affects cotreatment, decreases expression, increases abundance	1
Niclosamide	increases expression	1
Plant Extracts	affects cotreatment, decreases expression	1
Silicon Dioxide	increases expression	1

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT00000374	PHASE4	COMPLETED	Treatment for First-Episode Schizophrenia
NCT00001656	PHASE4	COMPLETED	Comparison of Clozapine vs Olanzapine in Childhood-Onset Psychotic Disorders
NCT00007774	PHASE4	COMPLETED	To Determine if Olanzapine is More Cost Effective Than Haloperidol for the Treatment of Schizophrenia
NCT00014001	PHASE4	COMPLETED	CATIE- Schizophrenia Trial
NCT00018668	PHASE4	COMPLETED	Antipsychotic Response in Schizophrenia
NCT00034801	PHASE4	COMPLETED	Olanzapine Versus Active Comparator in the Treatment of Depression in Patients With Schizophrenia
NCT00034905	PHASE4	COMPLETED	A Comparison of Seroquel vs. Risperidone in Schizophrenia
NCT00036088	PHASE4	COMPLETED	Olanzapine Versus An Active Comparator in the Treatment of Schizophrenia
NCT00044187	PHASE4	COMPLETED	The Assessment of a Weight-Gain Agent for the Treatment of Olanzapine-Associated Anti-Obesity Agent in Patients With Schizophrenia, Schizophreniform Disorder, Schizoaffective Disorder, and Bipolar I Disorder
NCT00044655	PHASE4	COMPLETED	Switching Medication to Treat Schizophrenia
NCT00048828	PHASE4	COMPLETED	Treating Drug-Resistant Childhood Schizophrenia
NCT00053703	PHASE4	COMPLETED	Treatment of Early Onset Schizophrenia Spectrum Disorders (TEOSS)
NCT00056498	PHASE4	COMPLETED	Risperidone Treatment in Schizophrenia Patients Who Are Currently Taking Clozapine
NCT00061802	PHASE4	COMPLETED	Efficacy and Safety of Two Atypical Antipsychotics vs. Placebo in Patients With an Acute Exacerbation of Either Schizophrenia or Schizoaffective Disorder
NCT00080327	PHASE4	COMPLETED	Study of Three Doses of Aripiprazole in Patients With Acute Schizophrenia
NCT00088049	PHASE4	COMPLETED	Study of Olanzapine vs. Aripiprazole in the Treatment of Schizophrenia
NCT00090012	PHASE4	COMPLETED	Comparison of Continuing Olanzapine to Switching to Quetiapine in Overweight or Obese Patients With Schizophrenia and Schizoaffective Disorder
NCT00100776	PHASE4	COMPLETED	Efficacy of High Dose Olanzapine for the Treatment of Schizophrenia and Schizoaffective Disorder
NCT00103571	PHASE4	COMPLETED	Olanzapine Versus Aripiprazole in the Treatment of Acutely Ill Patients With Schizophrenia
NCT00108368	PHASE4	COMPLETED	The Effects of Risperidone and Olanzapine on Thinking
NCT00114595	PHASE4	COMPLETED	Ethyl-Eicosapentaenoic Acid and Tardive Dyskinesia
NCT00130923	PHASE4	COMPLETED	Risperidone Long-acting Versus Oral Risperidone in Patients With Schizophrenia and Alcohol Use Disorder
NCT00137020	PHASE4	COMPLETED	Clinical Effect Of Cross Titration Of Antipsychotics With Ziprasidone In Schizophrenia Or Schizoaffective Disorder
NCT00140166	PHASE4	COMPLETED	Treatment of Acute Schizophrenia With Vitamin Therapy
NCT00145847	PHASE4	COMPLETED	Naltrexone Treatment of Alcohol Abuse in Schizophrenia
NCT00148564	PHASE4	COMPLETED	Energy Homeostasis Under Treatment With Atypical Antipsychotics
NCT00156715	PHASE4	COMPLETED	Efficacy of Quetiapine in the Treatment of Patients With Schizophrenia and a Comorbid Substance Use Disorder
NCT00158223	PHASE4	COMPLETED	Effectiveness of Pimozide in Augmenting the Effects of Clozapine in the Treatment of Schizophrenia
NCT00159081	PHASE4	COMPLETED	One Year Drug Treatment in First-Episode Schizophrenia
NCT00159120	PHASE4	COMPLETED	Maintenance Treatment vs. Stepwise Drug Discontinuation in First-Episode Schizophrenia
NCT00159133	PHASE4	COMPLETED	Prodrome-Based Early Intervention With Antipsychotics vs. Benzodiazepines in First-Episode Schizophrenia
NCT00159757	PHASE4	TERMINATED	12 Week Open, Non-Comparative Switch Study Of Oral Ziprazidone In Previously Treated Schizophrenic Patients
NCT00167817	PHASE4	COMPLETED	Effect of Switch to Aripiprazole on Health and Smoking Parameters in Patients With Schizophrenia: A Pilot Study
NCT00169026	PHASE4	TERMINATED	Alcoholism and Schizophrenia: Effects of Clozapine
NCT00169039	PHASE4	TERMINATED	Clozapine Versus Chlorpromazine for Treatment-Unresponsive Schizophrenia
NCT00169065	PHASE4	COMPLETED	Effectiveness of Clozapine Versus Olanzapine for Treatment-resistant Schizophrenia
NCT00169091	PHASE4	TERMINATED	Clozapine Versus Haloperidol for Treating the First Episode of Schizophrenia
NCT00176423	PHASE4	COMPLETED	Efficacy Study of Galantamine for Cognitive Impairments in Schizophrenia
NCT00176436	PHASE4	COMPLETED	Atomoxetine for Treatment of Weight Gain in Olanzapine or Clozapine Patients
NCT00177008	PHASE4	COMPLETED	Aripiprazole for the Treatment of Schizophrenia With Co-Morbid Social Anxiety