RTN4

Summary

RTN4 (reticulon 4, HGNC:14085) is a protein-coding gene on chromosome 2p16.1, encoding Reticulon-4 (Q9NQC3). Required to induce the formation and stabilization of endoplasmic reticulum (ER) tubules.

This gene belongs to the family of reticulon encoding genes. Reticulons are associated with the endoplasmic reticulum, and are involved in neuroendocrine secretion or in membrane trafficking in neuroendocrine cells. The product of this gene is a potent neurite outgrowth inhibitor which may also help block the regeneration of the central nervous system in higher vertebrates. Alternatively spliced transcript variants derived both from differential splicing and differential promoter usage and encoding different isoforms have been identified.

Source: NCBI Gene 57142 — RefSeq curated summary.

At a glance

• GWAS associations: 7
• Clinical variants (ClinVar): 241 total
• Druggable target: yes
• MANE Select transcript: NM_020532

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:14085
Approved symbol	RTN4
Name	reticulon 4
Location	2p16.1
Locus type	gene with protein product
Status	Approved
Aliases	NSP-CL, KIAA0886, NOGO, ASY, NOGOA, NOGOB, NOGOC
Ensembl gene	ENSG00000115310
Ensembl biotype	protein_coding
OMIM	604475
Entrez	57142

Gene structure

Transcript identifiers

Ensembl transcripts: 18 — 15 protein_coding, 2 retained_intron, 1 protein_coding_CDS_not_defined

ENST00000317610, ENST00000337526, ENST00000357376, ENST00000357732, ENST00000394609, ENST00000394611, ENST00000404909, ENST00000405240, ENST00000427710, ENST00000438462, ENST00000461004, ENST00000485749, ENST00000486085, ENST00000491592, ENST00000852508, ENST00000852509, ENST00000938587, ENST00000951906

RefSeq mRNA: 11 — MANE Select: NM_020532 NM_001321859, NM_001321860, NM_001321861, NM_001321862, NM_001321863, NM_001321904, NM_007008, NM_020532, NM_153828, NM_207520, NM_207521

CCDS: CCDS1851, CCDS1852, CCDS42683, CCDS42684, CCDS42685

Canonical transcript exons

ENST00000337526 — 9 exons

Exon	Start	End
ENSE00000809956	54973821	54973867
ENSE00000809957	54974695	54974764
ENSE00001330486	54987491	54987698
ENSE00001555275	54972189	54973198
ENSE00003515856	55028164	55028220
ENSE00003529090	55025086	55027485
ENSE00003581476	54973563	54973621
ENSE00003671987	54982515	54982653
ENSE00003850245	55049745	55050451

Expression profiles

Bgee: expression breadth ubiquitous, 295 present calls, max score 99.98.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 235.8943 / max 12789.0703, expressed in 1828 samples.

FANTOM5 promoters (32 alternative TSS)

Promoter ID	TPM avg	Samples expressed
28433	107.2877	1828
28435	49.9942	1822
28407	26.1841	617
28431	17.6125	1781
28432	8.8447	1698
28430	8.6106	1724
28436	5.1098	1529
28402	1.7476	905
28408	1.5234	202
28404	1.1974	743

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
pons	UBERON:0000988	99.98	gold quality
parietal lobe	UBERON:0001872	99.95	gold quality
postcentral gyrus	UBERON:0002581	99.95	gold quality
subthalamic nucleus	UBERON:0001906	99.94	gold quality
superior vestibular nucleus	UBERON:0007227	99.94	gold quality
dorsal plus ventral thalamus	UBERON:0001897	99.93	gold quality
substantia nigra pars compacta	UBERON:0001965	99.93	gold quality
substantia nigra pars reticulata	UBERON:0001966	99.93	gold quality
lateral nuclear group of thalamus	UBERON:0002736	99.93	gold quality
orbitofrontal cortex	UBERON:0004167	99.93	gold quality
medulla oblongata	UBERON:0001896	99.92	gold quality
superior frontal gyrus	UBERON:0002661	99.92	gold quality
inferior vagus X ganglion	UBERON:0005363	99.92	gold quality
lateral globus pallidus	UBERON:0002476	99.91	gold quality
ventral tegmental area	UBERON:0002691	99.91	gold quality
Brodmann (1909) area 23	UBERON:0013554	99.91	gold quality
dorsal root ganglion	UBERON:0000044	99.90	gold quality
entorhinal cortex	UBERON:0002728	99.90	gold quality
middle temporal gyrus	UBERON:0002771	99.90	gold quality
dorsal motor nucleus of vagus nerve	UBERON:0002870	99.90	gold quality
endothelial cell	CL:0000115	99.89	gold quality
renal medulla	UBERON:0000362	99.88	gold quality
CA1 field of hippocampus	UBERON:0003881	99.88	gold quality
choroid plexus epithelium	UBERON:0003911	99.88	gold quality
skeletal muscle tissue of rectus abdominis	UBERON:0004511	99.88	gold quality
cerebellar vermis	UBERON:0004720	99.88	gold quality
lower lobe of lung	UBERON:0008949	99.88	gold quality
biceps brachii	UBERON:0001507	99.86	gold quality
trigeminal ganglion	UBERON:0001675	99.86	gold quality
frontal pole	UBERON:0002795	99.86	gold quality

Single-cell (SCXA)

Detected in 16 experiment(s), a significant marker in 9.

Experiment	Marker?	Max mean expression
E-GEOD-137537	yes	6523.45
E-MTAB-11121	yes	4980.77
E-MTAB-8142	yes	101.00
E-HCAD-35	yes	45.51
E-MTAB-7316	yes	34.84
E-HCAD-1	yes	19.03
E-HCAD-10	yes	17.38
E-CURD-46	yes	10.44
E-MTAB-6379	no	1976.55
E-CURD-135	no	1274.68
E-MTAB-8495	no	1182.17
E-MTAB-7052	no	558.01
E-GEOD-81383	no	528.69
E-HCAD-5	no	16.68
E-ENAD-27	no	3.98

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): CEBPG, E2F1

miRNA regulators (miRDB)

115 targeting RTN4, 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-6867-5P	100.00	82.21	3464
HSA-MIR-34A-5P	99.99	71.21	1784
HSA-MIR-449A	99.99	71.05	1776
HSA-MIR-548C-3P	99.99	74.01	7587
HSA-MIR-196A-1-3P	99.99	72.15	2772
HSA-MIR-3692-3P	99.98	70.27	2139
HSA-MIR-5696	99.98	72.36	4487
HSA-LET-7F-2-3P	99.98	70.98	2588
HSA-MIR-1185-1-3P	99.98	71.04	2593
HSA-MIR-1185-2-3P	99.98	71.04	2593
HSA-MIR-3148	99.97	75.06	6478
HSA-MIR-34C-5P	99.97	70.45	1577
HSA-MIR-449B-5P	99.97	70.26	1580
HSA-MIR-570-3P	99.96	72.41	4910
HSA-MIR-1250-3P	99.96	70.04	4038
HSA-MIR-495-3P	99.96	72.81	4197
HSA-MIR-5688	99.96	73.23	4504
HSA-MIR-338-5P	99.92	72.34	2951
HSA-MIR-497-5P	99.92	71.83	2674
HSA-MIR-6508-5P	99.92	70.67	2465
HSA-MIR-450B-5P	99.92	71.48	3175
HSA-MIR-15A-5P	99.90	72.80	2787
HSA-MIR-15B-5P	99.90	72.78	2798
HSA-MIR-16-5P	99.90	72.80	2780
HSA-MIR-195-5P	99.90	72.81	2805
HSA-MIR-153-5P	99.89	73.86	6317
HSA-MIR-424-5P	99.89	71.90	2641
HSA-MIR-6838-5P	99.89	71.94	2690
HSA-MIR-4496	99.88	68.89	2236
HSA-MIR-182-5P	99.87	74.03	2589

Literature-anchored findings (GeneRIF, showing 40)

• The alteration in Nogo gene expression in muscle biopsy represents a potential diagnostic tool for the early stages of amyotrophic lateral sclerosis. (PMID:12270696)
• Elevated expression of Nogo mRNA in schizophrenia was confirmed by RT-PCR. Nogo mRNA was found to contain a CAA insert polymorphism in the 3’-untranslated region. (PMID:12425946)
• results describe the regulation of nogo expression through its promoter region (PMID:12488097)
• ASY may be multi-functional, regulating apoptosis, tumor development, and neuronal regeneration [review] (PMID:12510146)
• ER stress of highly overexpressed Nogo-B may lead to aversive cellular reactions under particular conditions. Our data do not support a function of Nogo-B as a physiological pro-apoptotic protein in certain types of cancer. (PMID:12618765)
• ASYIP(ASY-interacting) protein co-localized with ASY in endoplasmic reticulum. Characterization of ASYIP gene may help clarify mechanism of ASY-induced apoptosis or Nogo-involved inhibition of neuronal regeneration in central nervous system. (PMID:12811824)
• this study found a similar frequency of the CAA insertion for patients and controls in both populations, but a large difference in CAA insertion frequency between the European American and the African American. (PMID:14741411)
• Nogo-B is a regulator of vascular homeostasis and remodeling broadens the functional scope of this family of proteins (PMID:15034570)
• The steady-state level of reticulon 4-B mRNA was shown to be up-regulated by pressure, but not by mechanical stretch; close association with endoplasmic reticulum (PMID:15147731)
• In temporal lobe epilepsy Nogo-A mRNA and immunoreactivity were markedly up-regulated in most neurons and their processes throughout the hippocampal formation. (PMID:15245492)
• Expression of the genes encoding Nogo and its receptor, NgR, between weeks eight and 23 of human embryonic development (PMID:15749087)
• Nogo CAA 3’UTR insertion polymorphism is not associated with schizophrenia or bipolar disorder (PMID:15820318)
• There was a statistically significant difference at the allelic level for both the CAA (chi2 = 4.378, df = 1, P value = 0.036) and TATC (chi2 = 5.807, df = 1, P = 0.016) polymorphisms in the female subgroup. (PMID:15953657)
• results identify Nogo-B as a new physiological substrate of MAPKAP-K2 (PMID:16095439)
• Nogo-A is possibly the best characterized of a variety of neurite growth inhibitors present in CNS myelin–REVIEW (PMID:16629624)
• ASY/Nogo gene may act as a suppressor against adult T-cell leukemia/lymphoma progression, independent of Tax expression (PMID:16646068)
• Reticulon proteins such as Nogo-A participate in the neuronal responses stemming from hippocampal formation during senescence, and particularly in Alzheimer disease . (PMID:16772867)
• identify a previously uncharacterized Nogo-B receptor specific for the amino terminus of Nogo-B. (PMID:16835300)
• Expressed in HEK293 cells, Nogo-C confers apoptosis by inducing caspase-3 and p53 activation through the c-jun N-terminal kinase-c-Jun-dependent pathway. (PMID:16905119)
• Results describe the mapping of interaction domains mediating binding between BACE1 and RTN3/Nogo proteins. (PMID:16979658)
• Nogo C to be overexpressed by 26% in the schizophrenia tissues And Nogo B was reduced by 17% in the frontal cortices who had severe depression. (PMID:17022955)
• There is a direct correlation between the expression of Nogo A and C and the presence of alleles with a CAA insert in 3’ UTR. New sample group shows Nogo C upregulation in schizophrenia and Nogo B downregulation in depression. (PMID:17022955)
• Data show that the C-terminal of Nogo protein interacts with CX26. (PMID:17029193)
• Soluble Nogo-A may be specific for the cerebrofinal fluid of patients with multiple sclerosis and may predict failure of axonal regeneration in the central nervous system. (PMID:17242333)
• systematic substitution analysis of all 6 Cys residues of Nogo-A indicated that this domain forms 2 structural disulfide bonds among Cys residues 424, 464, 559 & 597, whereas the Cys residues at positions 699 & 912 seem to be dispensable for folding. (PMID:17437522)
• The detection of Nogo-A in muscle biopsy samples from LMNS patients correctly identified patients who further progressed to ALS with 91% accuracy, 94% sensitivity, and 88% specificity. (PMID:17455292)
• Nogo-A expression was negatively correlated with the malignancy grade of oligodendroglial tumors. (PMID:17592524)
• The presence of Nogo-A in diseased human muscle biopsies is not limited to amyotrophic lateral sclerosis. (PMID:17626519)
• Reduction of Nogo-B protein expression in thoracic aortic aneurysms is closely correlated to the formation of aneurysm and that Nogo-B may play a protective role in the pathological process of aneurysms. (PMID:17645629)
• Accordingly, two novel mechanisms, A beta PP overexpression and ER stress, are involved in Nogo-B and Nogo-A expression in human muscle. (PMID:17764014)
• Data is the first report to demonstrate the relationship between Nogo expression and heart failure, including cell-type specificity, in human HF and phenotypic rescue. (PMID:17971502)
• found A172G (Thr58Ala), A340G (Arg114Gly), A571G (Ile191Val) mutations of Nogo-C in hepatocellular carcinoma patients from Qidong in China (PMID:18080785)
• Inhibition of integrin signaling by Amino-Nogo (nucleotide fragment 540-2592) contributes to the failure of central nervous system axon regeneration. (PMID:18234903)
• A 25 kD band is detectable on Western blots stained with Nogo-A antibody in almost all CSF specimens, but is not likely to be a useful biomarker for multiple sclerosis. (PMID:18495952)
• Nogo-a expression in glial CNS tumors may be a marker to differentiate between oligodendrogliomas and other gliomas. (PMID:18685489)
• RTN4 allele (TATC)(2) and (TATC)(2)/(TATC)(2) genotype are associated with DCM. (PMID:18948092)
• analysis of the interaction between ubiquitin ligase WWP1 and Nogo-A (PMID:19035836)
• Using shotgun mass spectrometry, we found this protein differentially expressed in the dorsolateral prefrontal cortex from patients with schizophrenia. (PMID:19165527)
• Phosphorylation of Nogo receptors by casein kinase II (CK2) inhibits binding of the myelin-associated proteins. (PMID:19336839)
• An RTN4-C mutant lacking the C-terminal domain bound to BACE1 comparably to wild-type RTN4-C & reduced Abeta40 & Abeta42 secretion by cells expressing Swedish mutant APP. (PMID:19405102)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	rtn4a	ENSDARG00000044601
mus_musculus	Rtn4	ENSMUSG00000020458
rattus_norvegicus	Rtn4	ENSRNOG00000004621
drosophila_melanogaster	Rtnl2	FBGN0015831
drosophila_melanogaster	Rtnl1	FBGN0053113

Paralogs (4): RTN2 (ENSG00000125744), RTN3 (ENSG00000133318), RTN1 (ENSG00000139970), PRR18 (ENSG00000176381)

Protein

Protein identifiers

Reticulon-4 — Q9NQC3 (reviewed: Q9NQC3)

Alternative names: Foocen, Neurite outgrowth inhibitor, Neuroendocrine-specific protein, Neuroendocrine-specific protein C homolog, RTN-x, Reticulon-5

All UniProt accessions (4): A0A0U1RQR6, C9J685, Q9NQC3, H7C106

UniProt curated annotations — full annotation on UniProt →

Function. Required to induce the formation and stabilization of endoplasmic reticulum (ER) tubules. They regulate membrane morphogenesis in the ER by promoting tubular ER production. They influence nuclear envelope expansion, nuclear pore complex formation and proper localization of inner nuclear membrane proteins. However each isoform have specific functions mainly depending on their tissue expression specificities. Developmental neurite growth regulatory factor with a role as a negative regulator of axon-axon adhesion and growth, and as a facilitator of neurite branching. Regulates neurite fasciculation, branching and extension in the developing nervous system. Involved in down-regulation of growth, stabilization of wiring and restriction of plasticity in the adult CNS. Regulates the radial migration of cortical neurons via an RTN4R-LINGO1 containing receptor complex. Acts as a negative regulator of central nervous system angiogenesis. Inhibits spreading, migration and sprouting of primary brain microvascular endothelial cells (MVECs). Also induces the retraction of MVECs lamellipodia and filopodia in a ROCK pathway-dependent manner. Mainly function in endothelial cells and vascular smooth muscle cells, is also involved in immune system regulation. Modulator of vascular remodeling, promotes the migration of endothelial cells but inhibits the migration of vascular smooth muscle cells. Regulates endothelial sphingolipid biosynthesis with direct effects on vascular function and blood pressure. Inhibits serine palmitoyltransferase, SPTLC1, the rate-limiting enzyme of the novo sphingolipid biosynthetic pathway, thereby controlling production of endothelial sphingosine-1-phosphate (S1P). Required to promote macrophage homing and functions such as cytokine/chemokine gene expression involved in angiogenesis, arteriogenesis and tissue repair. Mediates ICAM1 induced transendothelial migration of leukocytes such as monocytes and neutrophils and acute inflammation. Necessary for immune responses triggered by nucleic acid sensing TLRs, such as TLR9, is required for proper TLR9 location to endolysosomes. Also involved in immune response to LPS. Plays a role in liver regeneration through the modulation of hepatocytes proliferation. Reduces the anti-apoptotic activity of Bcl-xl and Bcl-2. This is likely consecutive to their change in subcellular location, from the mitochondria to the endoplasmic reticulum, after binding and sequestration. With isoform C, inhibits BACE1 activity and amyloid precursor protein processing. Regulates cardiomyocyte apoptosis upon hypoxic conditions. With isoform B, inhibits BACE1 activity and amyloid precursor protein processing.

Subunit / interactions. Binds to RTN4R. Interacts with ATL1. Interacts with TMEM170A. Interacts with RTN4IP1. Interacts in trans with CNTNAP1. Interacts with REEP5. Interacts with synaptic plasticity regulator PANTS; the interaction results in enhanced RTN4-mediated inhibition of AMPA receptor clustering. Interacts with GPR50. Homodimer. Interacts with BAD/Bcl-xl and BCL2. Interact with RTN3. Interacts with NGBR. Interacts with SPTLC1. Interacts with GRAMD4. Interacts with CDH5. Interacts with BACE1 and BACE2. Interacts with REEP5. Interacts with RETREG3. Interacts with BACE1 and BACE2. Interacts with TMEM33.

Subcellular location. Endoplasmic reticulum membrane. Cell membrane. Synapse Endoplasmic reticulum membrane. Cell junction Endoplasmic reticulum membrane.

Tissue specificity. Isoform A: is specifically expressed in brain and testis and weakly in heart and skeletal muscle. Isoform B: widely expressed except for the liver. Highly expressed in endothelial cells and vascular smooth muscle cells, including blood vessels and mesenteric arteries. Isoform C: is expressed in brain, skeletal muscle and adipocytes. Isoform D is testis-specific.

Domain organisation. Three regions, residues 59-172, 544-725 and the loop 66 amino acids, between the two transmembrane domains, known as Nogo-66 loop, appear to be responsible for the inhibitory effect on neurite outgrowth and the spreading of neurons. This Nogo-66 loop also mediates the binding of RTN4 to its receptor. N-terminal part, called Am-Nogo-B(1-200), is the functional domain for RTN4B-mediated signaling in endothelial and vascular smooth muscle cells.

Isoforms (6)

UniProt ID	Names	Canonical?
Q9NQC3-1	A, RTN4A, Nogo-A, RTN-xL	yes
Q9NQC3-2	B, RTN4B, ASY, Nogo-B, RTN-xS, Foocen-M, RTN4B1, Nogo-B1
Q9NQC3-3	C, RTN4C, Nogo-C, Foocen-S
Q9NQC3-4	6
Q9NQC3-5	B2, RTN4B2, Nogo-B2
Q9NQC3-6	D, Rtn-T, RTN4Aa, RTN4Ab, RTN4D, RTN4E, RTN4F, RTN4G

RefSeq proteins (11): NP_001308788, NP_001308789, NP_001308790, NP_001308791, NP_001308792, NP_001308833, NP_008939, NP_065393, NP_722550, NP_997403, NP_997404 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR003388	Reticulon	Domain
IPR046964	RTN1-4	Family

Pfam: PF02453

UniProt features (54 total): modified residue 17, compositionally biased region 8, splice variant 6, sequence variant 4, sequence conflict 4, helix 4, topological domain 3, region of interest 3, transmembrane region 2, chain 1, turn 1, domain 1

Structure

Experimental structures (PDB)

2 structures.

PDB	Method	Resolution (Å)
2G31	SOLUTION NMR
2JV5	SOLUTION NMR

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9NQC3-F1	40.92	0.00

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 (17): 1, 7, 15, 107, 152, 181, 182, 184, 361, 446, 450, 511, 749, 858, 881, 991, 1104

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: 572 (showing top): GOBP_REGULATION_OF_HEPATOCYTE_PROLIFERATION, GCM_MAP4K4, GOBP_REGULATION_OF_VASCULOGENESIS, GOBP_HEPATICOBILIARY_SYSTEM_DEVELOPMENT, GOBP_EMBRYO_DEVELOPMENT_ENDING_IN_BIRTH_OR_EGG_HATCHING, GOBP_EPITHELIUM_DEVELOPMENT, GOBP_NEGATIVE_REGULATION_OF_CELL_DEVELOPMENT, GOBP_NEURON_RECOGNITION, GOBP_GLAND_MORPHOGENESIS, GOBP_REGULATION_OF_MAMMARY_GLAND_EPITHELIAL_CELL_PROLIFERATION, GOBP_REGULATION_OF_MORPHOGENESIS_OF_A_BRANCHING_STRUCTURE, GOBP_REGULATION_OF_ERBB_SIGNALING_PATHWAY, GOBP_MYELOID_LEUKOCYTE_MIGRATION, GOBP_NEURON_PROJECTION_EXTENSION, GOBP_NEGATIVE_REGULATION_OF_AXON_EXTENSION

GO Biological Process (44): blastocyst formation (GO:0001825), leukocyte migration involved in inflammatory response (GO:0002523), apoptotic process (GO:0006915), endoplasmic reticulum organization (GO:0007029), axonal fasciculation (GO:0007413), brain development (GO:0007420), positive regulation of epithelial cell migration (GO:0010634), cerebral cortex radial glia-guided migration (GO:0021801), central nervous system vasculogenesis (GO:0022009), neuron differentiation (GO:0030182), negative regulation of cell growth (GO:0030308), regulation of cell migration (GO:0030334), negative regulation of axon extension (GO:0030517), positive regulation of mammary gland epithelial cell proliferation (GO:0033601), positive regulation of toll-like receptor 9 signaling pathway (GO:0034165), positive regulation of Rac protein signal transduction (GO:0035022), cell migration involved in vasculogenesis (GO:0035441), regulation of apoptotic process (GO:0042981), positive regulation of angiogenesis (GO:0045766), modulation of chemical synaptic transmission (GO:0050804), protein stabilization (GO:0050821), nuclear pore complex assembly (GO:0051292), positive regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction (GO:0051897), cardiac epithelial to mesenchymal transition (GO:0060317), positive regulation of macrophage cytokine production (GO:0060907), protein localization to lysosome (GO:0061462), cellular response to hypoxia (GO:0071456), endoplasmic reticulum tubular network organization (GO:0071786), endoplasmic reticulum tubular network formation (GO:0071787), intracellular sphingolipid homeostasis (GO:0090156), cell adhesion involved in sprouting angiogenesis (GO:0120078), regulation of postsynapse assembly (GO:0150052), negative regulation of amyloid-beta formation (GO:1902430), positive regulation of neutrophil migration (GO:1902624), positive regulation of macrophage migration (GO:1905523), positive regulation of protein localization to endoplasmic reticulum (GO:1905552), positive regulation of ERBB3 signaling pathway (GO:1905580), positive regulation of artery morphogenesis (GO:1905653), endoplasmic reticulum tubular network membrane organization (GO:1990809), regulation of branching morphogenesis of a nerve (GO:2000172)

GO Molecular Function (6): RNA binding (GO:0003723), ubiquitin protein ligase binding (GO:0031625), protein homodimerization activity (GO:0042803), cadherin binding (GO:0045296), metal ion binding (GO:0046872), protein binding (GO:0005515)

GO Cellular Component (16): nuclear envelope (GO:0005635), endoplasmic reticulum (GO:0005783), endoplasmic reticulum membrane (GO:0005789), plasma membrane (GO:0005886), postsynaptic density (GO:0014069), cell junction (GO:0030054), neuron projection (GO:0043005), neuronal cell body (GO:0043025), synapse (GO:0045202), anchoring junction (GO:0070161), endoplasmic reticulum tubular network (GO:0071782), endoplasmic reticulum tubular network membrane (GO:0098826), glutamatergic synapse (GO:0098978), membrane (GO:0016020), cell projection (GO:0042995), postsynapse (GO:0098794)

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	4
vasculogenesis	2
cell migration	2
endomembrane system	2
endoplasmic reticulum subcompartment	2
cell junction	2
synapse	2
blastocyst development	1
anatomical structure formation involved in morphogenesis	1
inflammatory response	1
leukocyte migration	1
programmed cell death	1
apoptotic signaling pathway	1
execution phase of apoptosis	1
organelle organization	1
endomembrane system organization	1
neuron recognition	1
axon development	1
neuron projection fasciculation	1
central nervous system development	1
animal organ development	1
head development	1
epithelial cell migration	1
regulation of epithelial cell migration	1
positive regulation of cell migration	1
cerebral cortex radially oriented cell migration	1
telencephalon glial cell migration	1
cell differentiation	1
generation of neurons	1
regulation of cell growth	1
cell growth	1
negative regulation of growth	1
negative regulation of cellular process	1
regulation of cell motility	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
mammary gland epithelial cell proliferation	1

Protein interactions and networks

STRING

2306 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
RTN4	RTN4R	Q9BZR6	999
RTN4	RTN4IP1	Q8WWV3	985
RTN4	LINGO1	Q96FE5	982
RTN4	OMG	P23515	981
RTN4	MAG	P20916	980
RTN4	NGFR	P08138	957
RTN4	RTN4RL1	Q86UN2	950
RTN4	NUS1	Q96E22	920
RTN4	BACE1	P56817	916
RTN4	REEP5	Q00765	901
RTN4	RTN4RL2	Q86UN3	873
RTN4	TNFRSF19	Q9NS68	751
RTN4	APP	P05067	725
RTN4	EMG1	Q92979	718
RTN4	PTPRS	Q13332	708

IntAct

217 interactions, top by confidence:

A	B	Type	Score
RTN3	RTN4	psi-mi:“MI:0915”(physical association)	0.750
RTN4	SYT16	psi-mi:“MI:0915”(physical association)	0.740
SYT16	RTN4	psi-mi:“MI:0915”(physical association)	0.740
CFTR	ESYT2	psi-mi:“MI:2364”(proximity)	0.710
RTN4	ARL6IP1	psi-mi:“MI:0915”(physical association)	0.670
SNX15	RTN4	psi-mi:“MI:0915”(physical association)	0.670
ARL6IP1	RTN4	psi-mi:“MI:0915”(physical association)	0.670
RTN4	SNX15	psi-mi:“MI:0915”(physical association)	0.670
RTN4	CERT1	psi-mi:“MI:0915”(physical association)	0.670
	PMPCB	psi-mi:“MI:0914”(association)	0.640
RTN2	RTN4	psi-mi:“MI:0915”(physical association)	0.620
RTN4	SNX1	psi-mi:“MI:0915”(physical association)	0.560
ZFYVE21	RTN4	psi-mi:“MI:0915”(physical association)	0.560
SNX1	RTN4	psi-mi:“MI:0915”(physical association)	0.560
RTN4	ZFYVE21	psi-mi:“MI:0915”(physical association)	0.560
DERL2	RTN4	psi-mi:“MI:0915”(physical association)	0.560
ITGA6	ITGB1	psi-mi:“MI:0914”(association)	0.560
RTN4	HTR2C	psi-mi:“MI:0915”(physical association)	0.550
RTN4	SPG21	psi-mi:“MI:0915”(physical association)	0.550

BioGRID (516): RTN4 (Affinity Capture-MS), RTN4 (Two-hybrid), RTN4 (Two-hybrid), RTN4 (Two-hybrid), RTN4 (Two-hybrid), ZFYVE21 (Two-hybrid), SYT16 (Two-hybrid), RTN4 (Affinity Capture-MS), RTN4 (Affinity Capture-MS), RTN4 (Affinity Capture-MS), RTN4 (Affinity Capture-MS), GOLT1B (Affinity Capture-MS), KTN1 (Affinity Capture-MS), DERL2 (Affinity Capture-MS), TMEM70 (Affinity Capture-MS)

ESM2 similar proteins: A0A1S4GMU2, A0JM08, A1CME3, A1Z7A8, A1ZBW7, A3LZ57, F1QIC4, G5ECQ3, O13735, O14100, O42854, O43083, O74500, P34549, P38904, P39705, P41993, P47068, P48415, Q0KIC3, Q0P5H2, Q0WQ57, Q24211, Q2U968, Q498L0, Q4KMC9, Q4WD95, Q5AYL5, Q6BXI1, Q6CM10, Q6FWU4, Q7JKP6, Q86TC9, Q8INM3, Q8R2M2, Q9BX66, Q9H792, Q9HDX7, Q9JK11, Q9N5K3

Diamond homologs: A7MC64, O70622, O75298, O95197, Q08D83, Q16799, Q28D16, Q4FZ58, Q4FZ76, Q5IS59, Q5J6M8, Q5MY90, Q5RBL9, Q64548, Q68EW1, Q6IFY7, Q6RJR6, Q6WN19, Q8K0T0, Q99P72, Q9ES97, Q9JK11, Q9NQC3, Q6NPD8, Q9SH59

SIGNOR signaling

2 interactions.

A	Effect	B	Mechanism
RTN4	up-regulates	LINGO1	binding
MAPKAPK2	unknown	RTN4	phosphorylation

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 207 IntAct physical interaction partners (hypergeometric vs the genome-wide background, BH-FDR, gene-set size 15–500, ranked by fold). A functional readout of the neighbourhood — distinct from this gene’s own memberships above, and biased toward well-studied / hub proteins, so read it as themes rather than proof.

Reactome pathways:

Pathway	Partners	Fold	FDR
Signaling by phosphorylated juxtamembrane, extracellular and kinase domain KIT mutants	5	19.2×	2e-03
SHC1 events in ERBB2 signaling	5	17.6×	2e-03
Signaling by ERBB2 TMD/JMD mutants	5	17.6×	2e-03
Basigin interactions	5	16.3×	2e-03
Signaling by ERBB2 KD Mutants	5	15.7×	2e-03
Signaling by ERBB2	5	12.8×	4e-03
R-HSA-425366	6	8.1×	7e-03
Signaling by BRAF and RAF1 fusions	6	7.6×	9e-03

GO biological processes:

GO term	Partners	Fold	FDR
membrane organization	5	14.3×	6e-03
epidermal growth factor receptor signaling pathway	7	9.7×	3e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	201
Likely benign	12
Benign	6

Top pathogenic / likely-pathogenic (0)

SpliceAI

1344 predictions. Top by Δscore:

Variant	Effect	Δscore
2:54973561:A:AC	donor_gain	1.0000
2:54973562:C:CG	donor_gain	1.0000
2:54973562:CTTAG:C	donor_gain	1.0000
2:54973565:AG:A	donor_gain	1.0000
2:54973566:G:C	donor_gain	1.0000
2:54982510:CTTA:C	donor_loss	1.0000
2:54982511:TTA:T	donor_loss	1.0000
2:54982512:TACC:T	donor_loss	1.0000
2:54982513:A:AC	donor_gain	1.0000
2:54982513:AC:A	donor_gain	1.0000
2:54982513:ACCTT:A	donor_gain	1.0000
2:54982514:C:CA	donor_gain	1.0000
2:54982514:CC:C	donor_gain	1.0000
2:54982514:CCT:C	donor_gain	1.0000
2:54982514:CCTT:C	donor_gain	1.0000
2:54982514:CCTTC:C	donor_gain	1.0000
2:54982649:ATGCC:A	acceptor_gain	1.0000
2:54982650:TGCC:T	acceptor_gain	1.0000
2:54982651:GCC:G	acceptor_gain	1.0000
2:54982652:CC:C	acceptor_gain	1.0000
2:54982652:CCC:C	acceptor_gain	1.0000
2:54982653:CC:C	acceptor_gain	1.0000
2:54982653:CCT:C	acceptor_loss	1.0000
2:54982654:C:CA	acceptor_loss	1.0000
2:54982654:C:CC	acceptor_gain	1.0000
2:54982654:C:T	acceptor_gain	1.0000
2:54982662:C:CT	acceptor_gain	1.0000
2:54987487:TCACC:T	donor_loss	1.0000
2:54987488:CA:C	donor_loss	1.0000
2:54987489:A:C	donor_loss	1.0000

AlphaMissense

7775 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
2:54974731:C:G	G1132R	1.000
2:54974749:A:G	W1126R	1.000
2:54974749:A:T	W1126R	1.000
2:54987598:G:C	S1038R	1.000
2:54987598:G:T	S1038R	1.000
2:54987600:T:G	S1038R	1.000
2:54987607:G:C	S1035R	1.000
2:54987607:G:T	S1035R	1.000
2:54987609:T:G	S1035R	1.000
2:54973848:A:C	S1150R	0.999
2:54973848:A:T	S1150R	0.999
2:54973850:T:G	S1150R	0.999
2:54974715:C:T	G1137D	0.999
2:54974716:C:G	G1137R	0.999
2:54974730:C:T	G1132D	0.999
2:54987553:G:C	S1053R	0.999
2:54987553:G:T	S1053R	0.999
2:54987555:T:G	S1053R	0.999
2:54987590:G:T	A1041D	0.999
2:54987640:G:C	S1024R	0.999
2:54987640:G:T	S1024R	0.999
2:54987642:T:G	S1024R	0.999
2:54974706:A:G	L1140P	0.998
2:54974712:A:G	L1138P	0.998
2:54974717:A:C	N1136K	0.998
2:54974717:A:T	N1136K	0.998
2:54974731:C:A	G1132C	0.998
2:54974733:A:T	V1131D	0.998
2:54982519:A:G	L1119P	0.998
2:54982558:A:G	L1106P	0.998

dbSNP variants (sampled 300 via entrez): RS1000037017 (2:54975267 A>C), RS1000041744 (2:55118021 G>A), RS1000052566 (2:55081909 C>T), RS1000064918 (2:55035168 A>G), RS1000093237 (2:55088207 G>C,T), RS1000097672 (2:55012037 T>C), RS1000101002 (2:55093711 G>GAA), RS1000123172 (2:55079500 G>A,C), RS1000123847 (2:55040937 C>G), RS1000131921 (2:55117479 T>C), RS1000143583 (2:55068079 T>G), RS1000153359 (2:55037400 T>C), RS1000191366 (2:55034455 T>A,C), RS1000203732 (2:55112609 C>T), RS1000206741 (2:54981812 T>C)

Disease associations

OMIM: gene MIM:604475 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

0 total (0 of 0 shown, HPO-id order):

GWAS associations

7 associations (top):

Study	Trait	p-value
GCST000426_3	Obesity (extreme)	1.000000e-06
GCST006624_82	Systolic blood pressure	1.000000e-09
GCST010988_177	Adult body size	4.000000e-12
GCST011687_1	Systolic blood pressure	1.000000e-08
GCST012047_14	Fasting glucose	8.000000e-07
GCST90002388_70	Lymphocyte count	5.000000e-13
GCST90002402_235	Platelet count	3.000000e-09

EFO canonical traits (3, from GWAS)

EFO ID	Trait name
EFO:0006335	systolic blood pressure
EFO:0004587	lymphocyte count
EFO:0004309	platelet count

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL3712895 (SINGLE PROTEIN)

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

GtoPdb / IUPHAR curated pharmacology

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

Target class: other protein — Reticulons and associated proteins

Most potent curated ligand interactions (1 total), top 1:

Ligand	Action	Affinity	Parameter
ozanezumab	Binding	9.19	pKd

ChEMBL bioactivities

4 potent at pChembl≥5 of 5 total, top 4 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
8.28	Kd	5.308	nM	CHEMBL3752910
8.28	ED50	5.308	nM	CHEMBL3752910
5.45	Kd	3550	nM	CHEMBL5653589
5.45	ED50	3550	nM	CHEMBL5653589

PubChem BioAssay actives

2 with measured affinity, of 13 total; 2 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
4-methyl-3-[(1-methyl-6-pyridin-3-ylpyrazolo[3,4-d]pyrimidin-4-yl)amino]-N-[3-(trifluoromethyl)phenyl]benzamide	2149328: Binding affinity to human RTN4 incubated for 45 mins by Kinobead based pull down assay	kd	0.0053	uM
4-methyl-3-[(2-methyl-6-pyridin-3-ylpyrazolo[3,4-d]pyrimidin-4-yl)amino]-N-[3-(trifluoromethyl)phenyl]benzamide	2149328: Binding affinity to human RTN4 incubated for 45 mins by Kinobead based pull down assay	kd	3.5495	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Particulate Matter	increases reaction, increases expression, decreases expression, increases abundance, affects expression	4
bisphenol A	increases expression	2
sodium arsenite	decreases expression, increases abundance, increases expression	2
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	increases expression, affects cotreatment	2
Vehicle Emissions	affects expression, increases reaction, increases abundance, increases expression	2
Benzo(a)pyrene	decreases expression, increases methylation	2
Lead	affects splicing, decreases expression	2
Phenylmercuric Acetate	affects cotreatment, increases expression	2
Valproic Acid	affects expression, increases expression	2
aristolochic acid I	decreases expression	1
FR900359	affects phosphorylation	1
TAK-243	decreases sumoylation	1
methylmercuric chloride	increases expression	1
triphenyl phosphate	affects expression	1
deoxynivalenol	increases expression	1
lead acetate	increases expression	1
pyrogallol 1,3-dimethyl ether	increases expression, affects cotreatment, affects localization	1
testosterone undecanoate	decreases expression	1
trichostatin A	increases expression	1
arsenite	affects binding, decreases reaction	1
perfluorooctanoic acid	decreases expression	1
manganese chloride	decreases expression, increases abundance	1
cupric chloride	increases expression	1
CGP 52608	affects binding, increases reaction	1
chloropicrin	decreases expression	1
corosolic acid	decreases expression	1
oxidized-L-alpha-1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphorylcholine	affects expression, increases reaction	1
ICG 001	decreases expression	1
ON 01910	affects expression	1
2-amino-14,16-dimethyloctadecan-3-ol	decreases expression	1

ChEMBL screening assays

7 unique, capped per target: 7 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL4118765	Binding	Binding affinity to RTN4 in human NCI-H23 cells at 1 uM by mass spectrometry based pull down assay	Studies of TAK1-centered polypharmacology with novel covalent TAK1 inhibitors. — Bioorg Med Chem

Cellosaurus cell lines

7 cell lines: 6 cancer cell line, 1 transformed cell line

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

Cellosaurus	Name	Category	Sex
CVCL_D7ZT	Ubigene A-549 RTN4 KO	Cancer cell line	Male
CVCL_D9R3	Ubigene HEK293 RTN4 KO	Transformed cell line	Female
CVCL_TJ81	HAP1 RTN4 (-) 1	Cancer cell line	Male
CVCL_TJ82	HAP1 RTN4 (-) 2	Cancer cell line	Male
CVCL_TJ83	HAP1 RTN4 (-) 3	Cancer cell line	Male
CVCL_TJ84	HAP1 RTN4 (-) 4	Cancer cell line	Male
CVCL_ZF86	CLC26	Cancer cell line	Male

Clinical trials (associated diseases)

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