RTN4RL2

Summary

RTN4RL2 (reticulon 4 receptor like 2, HGNC:23053) is a protein-coding gene on chromosome 11q12.1, encoding Reticulon-4 receptor-like 2 (Q86UN3). Cell surface receptor that plays a functionally redundant role in the inhibition of neurite outgrowth mediated by MAG.

Enables signaling receptor activity. Predicted to be involved in cell surface receptor signaling pathway; corpus callosum development; and negative regulation of neuron projection development. Located in cell surface and plasma membrane.

Source: NCBI Gene 349667 — RefSeq curated summary.

At a glance

• GWAS associations: 3
• Clinical variants (ClinVar): 46 total
• MANE Select transcript: NM_178570

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:23053
Approved symbol	RTN4RL2
Name	reticulon 4 receptor like 2
Location	11q12.1
Locus type	gene with protein product
Status	Approved
Aliases	NgR2, NGRH1
Ensembl gene	ENSG00000186907
Ensembl biotype	protein_coding
OMIM	610462
Entrez	349667

Gene structure

Transcript identifiers

Ensembl transcripts: 3 — 3 protein_coding

ENST00000335099, ENST00000395120, ENST00000533205

RefSeq mRNA: 1 — MANE Select: NM_178570 NM_178570

CCDS: CCDS7957

Canonical transcript exons

ENST00000335099 — 3 exons

Exon	Start	End
ENSE00001331852	57467609	57468090
ENSE00001331854	57476162	57477534
ENSE00002175494	57460528	57460896

Expression profiles

Bgee: expression breadth ubiquitous, 156 present calls, max score 90.23.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 8.6709 / max 295.6349, expressed in 1278 samples.

FANTOM5 promoters (3 alternative TSS)

Promoter ID	TPM avg	Samples expressed
114274	7.9713	1245
114275	0.4362	169
114273	0.2634	121

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
right lobe of liver	UBERON:0001114	90.23	gold quality
left lobe of thyroid gland	UBERON:0001120	88.52	gold quality
right frontal lobe	UBERON:0002810	88.41	gold quality
cortical plate	UBERON:0005343	88.40	gold quality
prefrontal cortex	UBERON:0000451	88.04	gold quality
anterior cingulate cortex	UBERON:0009835	87.93	gold quality
right lobe of thyroid gland	UBERON:0001119	87.84	gold quality
Brodmann (1909) area 9	UBERON:0013540	86.77	gold quality
thyroid gland	UBERON:0002046	86.44	gold quality
dorsolateral prefrontal cortex	UBERON:0009834	83.95	gold quality
frontal cortex	UBERON:0001870	83.62	gold quality
neocortex	UBERON:0001950	83.29	gold quality
amygdala	UBERON:0001876	80.00	gold quality
cerebral cortex	UBERON:0000956	79.51	gold quality
ganglionic eminence	UBERON:0004023	79.39	gold quality
apex of heart	UBERON:0002098	77.58	gold quality
Ammon’s horn	UBERON:0001954	74.13	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	72.88	gold quality
liver	UBERON:0002107	71.64	gold quality
temporal lobe	UBERON:0001871	71.37	gold quality
superior frontal gyrus	UBERON:0002661	70.90	gold quality
omental fat pad	UBERON:0010414	70.88	gold quality
forebrain	UBERON:0001890	70.86	gold quality
peritoneum	UBERON:0002358	70.80	gold quality
gall bladder	UBERON:0002110	69.83	gold quality
postcentral gyrus	UBERON:0002581	69.60	silver quality
adipose tissue of abdominal region	UBERON:0007808	69.23	gold quality
minor salivary gland	UBERON:0001830	69.22	gold quality
adenohypophysis	UBERON:0002196	68.86	gold quality
brain	UBERON:0000955	68.60	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)

36 targeting RTN4RL2, 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-12136	99.98	72.81	5713
HSA-MIR-4725-3P	99.96	69.53	2520
HSA-MIR-6780B-5P	99.96	69.60	2562
HSA-MIR-4271	99.88	68.32	2244
HSA-MIR-3151-5P	99.86	63.83	1069
HSA-MIR-4728-5P	99.85	69.39	4718
HSA-MIR-6785-5P	99.82	68.68	4428
HSA-MIR-577	99.78	69.13	2479
HSA-MIR-149-3P	99.72	68.22	3963
HSA-MIR-6883-5P	99.69	68.05	3785
HSA-MIR-6722-3P	99.45	67.62	1919
HSA-MIR-3692-5P	99.29	67.04	1421
HSA-MIR-6510-5P	99.14	66.59	1081
HSA-MIR-1909-3P	99.03	66.56	1662
HSA-MIR-412-3P	98.86	66.89	712
HSA-MIR-6754-3P	98.84	66.60	889
HSA-MIR-3194-3P	98.83	66.22	1167
HSA-MIR-5000-3P	98.79	65.63	1251
HSA-MIR-138-5P	98.43	70.49	1292
HSA-MIR-197-3P	98.09	69.23	1004
HSA-MIR-18B-3P	98.05	65.55	595
HSA-MIR-4436A	98.05	64.83	1140
HSA-MIR-3132	97.96	67.91	711
HSA-MIR-6728-5P	97.79	66.33	891
HSA-MIR-379-5P	97.52	67.81	485
HSA-MIR-3529-5P	97.12	67.06	440
HSA-MIR-6773-5P	97.04	64.30	595
HSA-MIR-6845-5P	96.55	64.65	969
HSA-MIR-4652-5P	96.46	64.22	553

Literature-anchored findings (GeneRIF, showing 6)

• predominantly expressed in the neurons of the embryonic and adult nervous systems (PMID:14664809)
• The release of N-terminal fragment-NgRH1 was blocked by a hydroxamate-based zinc metalloproteinase inhibitor and tissue inhibitor of metalloproteinases-2 and -3 (PMID:15629437)
• Nogo-66 receptor homolog 1 signaling regulates activity-dependent synaptic strength and neuronal plasticity. (PMID:18337405)
• These results indicate that a lack of NgR1/2 expression promotes the adhesion of DCs to myelin. (PMID:21906273)
• 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)
• The NOGO receptor NgR2, a novel alphaVbeta3 integrin effector, induces neuroendocrine differentiation in prostate cancer. (PMID:36344556)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
danio_rerio	rtn4rl2b	ENSDARG00000037495
danio_rerio	rtn4rl2a	ENSDARG00000052012
mus_musculus	Rtn4rl2	ENSMUSG00000050896
rattus_norvegicus	Rtn4rl2	ENSRNOG00000021513

Paralogs (22): DCN (ENSG00000011465), RTN4R (ENSG00000040608), 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), NYX (ENSG00000188937), LRRC66 (ENSG00000188993), LRRTM3 (ENSG00000198739)

Protein

Protein identifiers

Reticulon-4 receptor-like 2 — Q86UN3 (reviewed: Q86UN3)

Alternative names: Nogo receptor-like 3, Nogo-66 receptor homolog 1, Nogo-66 receptor-related protein 2

All UniProt accessions (2): Q86UN3, G3V1D7

UniProt curated annotations — full annotation on UniProt →

Function. Cell surface receptor that plays a functionally redundant role in the inhibition of neurite outgrowth mediated by MAG. Plays a functionally redundant role in postnatal brain development. Contributes to normal axon migration across the brain midline and normal formation of the corpus callosum. Does not seem to play a significant role in regulating axon regeneration in the adult central nervous system. Protects motoneurons against apoptosis; protection against apoptosis is probably mediated by MAG. Like other family members, plays a role in restricting the number dendritic spines and the number of synapses that are formed during brain development. Signaling mediates activation of Rho and downstream reorganization of the actin cytoskeleton.

Subunit / interactions. Interaction with MAG is controversial, and may be indirect. Does not interact with MAG, OMG and RTN4. Interacts with MAG.

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

Tissue specificity. Highly expressed in brain and liver. Expressed at lower levels in kidney, mammary gland, placenta, skeletal muscle, spleen and thyroid.

Post-translational modifications. Undergoes zinc metalloproteinase-mediated ectodomain shedding in neuroblastoma cells; is released both as a full-length ectodomain and an N-terminal fragment containing the leucine-rich repeat (LRR) region of the protein. N-glycosylated.

Similarity. Belongs to the Nogo receptor family.

Isoforms (2)

UniProt ID	Names	Canonical?
Q86UN3-1	1	yes
Q86UN3-2	2

RefSeq proteins (1): NP_848665* (*=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 (27 total): repeat 8, disulfide bond 4, glycosylation site 3, domain 2, region of interest 2, splice variant 2, signal peptide 1, chain 1, compositionally biased region 1, lipid moiety-binding region 1, propeptide 1, sequence conflict 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q86UN3-F1	80.27	0.69

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): 390

Disulfide bonds (4): 31–37, 35–46, 265–288, 267–310

Glycosylation sites (3): 50, 93, 236

Function

Pathways and Gene Ontology

Reactome pathways

1 pathways

ID	Pathway
R-HSA-163125	Post-translational modification: synthesis of GPI-anchored proteins

MSigDB gene sets: 103 (showing top): BENPORATH_ES_WITH_H3K27ME3, GOBP_SYNAPSE_ASSEMBLY, MAZ_Q6, GOBP_POSITIVE_REGULATION_OF_SYNAPSE_ASSEMBLY, GOCC_CELL_SURFACE, GOBP_REGENERATION, GOBP_NEUROGENESIS, GOBP_REGULATION_OF_CELL_JUNCTION_ASSEMBLY, GOBP_RESPONSE_TO_AXON_INJURY, GOBP_REGULATION_OF_NERVOUS_SYSTEM_DEVELOPMENT, GOBP_REGULATION_OF_CELLULAR_COMPONENT_BIOGENESIS, GGGTGGRR_PAX4_03, GOBP_POSITIVE_REGULATION_OF_NERVOUS_SYSTEM_DEVELOPMENT, GOBP_FOREBRAIN_DEVELOPMENT, GOBP_NEGATIVE_REGULATION_OF_CELLULAR_COMPONENT_ORGANIZATION

GO Biological Process (5): cell surface receptor signaling pathway (GO:0007166), negative regulation of neuron projection development (GO:0010977), corpus callosum development (GO:0022038), axon regeneration (GO:0031103), positive regulation of synapse assembly (GO:0051965)

GO Molecular Function (2): signaling receptor activity (GO:0038023), protein binding (GO:0005515)

GO Cellular Component (13): extracellular region (GO:0005576), plasma membrane (GO:0005886), external side of plasma membrane (GO:0009897), cell surface (GO:0009986), axon (GO:0030424), dendrite (GO:0030425), neuron projection (GO:0043005), perikaryon (GO:0043204), membrane raft (GO:0045121), extracellular exosome (GO:0070062), membrane (GO:0016020), cell projection (GO:0042995), side of membrane (GO:0098552)

Reactome top-level categories

Rollup of top-1 pathways:

Category	Pathways
Post-translational protein modification	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	6
membrane	2
neuron projection	2
signal transduction	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
neuron projection regeneration	1
response to axon injury	1
axon development	1
synapse assembly	1
positive regulation of nervous system development	1
regulation of synapse assembly	1
positive regulation of cell junction assembly	1
molecular transducer activity	1
binding	1
cell periphery	1
plasma membrane	1
cell surface	1
side of membrane	1
dendritic tree	1
plasma membrane bounded cell projection	1
neuronal cell body	1
membrane microdomain	1
extracellular vesicle	1
leaflet of membrane bilayer	1

Protein interactions and networks

STRING

866 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
RTN4RL2	MAG	P20916	917
RTN4RL2	RTN4	Q9NQC3	873
RTN4RL2	TNFRSF19	Q9NS68	721
RTN4RL2	ERBB3	P21860	628
RTN4RL2	OMG	P23515	593
RTN4RL2	PTPRS	Q13332	514
RTN4RL2	VCAN	P13611	480
RTN4RL2	ANKRD13B	Q86YJ7	468
RTN4RL2	TMEM91	Q6ZNR0	460
RTN4RL2	TMEM25	Q86YD3	456
RTN4RL2	ERBB4	Q15303	449
RTN4RL2	EMG1	Q92979	447
RTN4RL2	S1PR2	O95136	446
RTN4RL2	SLC25A31	Q9H0C2	413
RTN4RL2	PPP1R3A	Q16821	371

IntAct

14 interactions, top by confidence:

A	B	Type	Score
NRROS	NDUFA3	psi-mi:“MI:0914”(association)	0.530
LGALS3	PODXL	psi-mi:“MI:0914”(association)	0.530
Cbx1	FLOT1	psi-mi:“MI:0915”(physical association)	0.400
Trim69		psi-mi:“MI:0915”(physical association)	0.400
RTN4RL2	NUDCD2	psi-mi:“MI:0915”(physical association)	0.400
LGALS3	PODXL	psi-mi:“MI:0914”(association)	0.350
ANK2	IGKV2-40	psi-mi:“MI:0914”(association)	0.350
CLEC12B	GXYLT2	psi-mi:“MI:0914”(association)	0.350
LCN6	COCH	psi-mi:“MI:0914”(association)	0.350
NRROS	HS6ST1	psi-mi:“MI:0914”(association)	0.350
IL20	HRAS	psi-mi:“MI:0914”(association)	0.350
TMEM106A	TMEM131L	psi-mi:“MI:0914”(association)	0.350

BioGRID (20): RTN4RL2 (Affinity Capture-MS), RTN4RL2 (Affinity Capture-MS), RTN4RL2 (Affinity Capture-MS), RTN4RL2 (Proximity Label-MS), RTN4RL2 (Affinity Capture-MS), RTN4RL2 (Affinity Capture-MS), RTN4RL2 (Affinity Capture-MS), RTN4RL2 (Affinity Capture-MS), RTN4RL2 (Affinity Capture-MS), RTN4RL2 (Affinity Capture-MS), RTN4RL2 (Affinity Capture-MS), RTN4RL2 (Affinity Capture-MS), RTN4RL2 (Affinity Capture-MS), RTN4RL2 (Affinity Capture-MS), RTN4RL2 (Affinity Capture-MS)

ESM2 similar proteins: A1A4H9, A2ARI4, A2VDH3, A6H793, D4A6D8, E9Q7T7, F1MLX5, F1MT22, O75325, P59034, P59035, Q13641, Q149C3, Q3URE9, Q3UVD5, Q3UY51, Q4KLL3, Q4R8Y9, Q50LG9, Q5M8M9, Q5PQV5, Q5R6B1, Q5RDJ4, Q5VT99, Q6GQU6, Q6UY18, Q6ZSA7, Q7M6Z0, Q7TQ62, Q80WD1, Q86UE6, Q86UN2, Q86UN3, Q86WK6, Q8BHA1, Q8K0S5, Q8K377, Q8N7C0, Q91ZV8, Q96FE5

Diamond homologs: A3KNN3, A4IIW9, A6NJW4, A8WHP9, E9Q7T7, O02833, O15335, O55226, O70210, O75093, O75094, O88279, O88280, O94769, O94813, P0C6S8, P24014, P35858, P35859, P56400, P58727, P70389, Q27972, Q5FW85, Q5RDJ4, Q62192, Q66HV9, Q6NUI6, Q6R5N8, Q7M6Z0, Q80TR4, Q80WD0, Q80WD1, Q86UN2, Q86UN3, Q96FE5, Q99467, Q99M75, Q99PI8, Q9BY71

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	45
Likely benign	0
Benign	0

Top pathogenic / likely-pathogenic (0)

SpliceAI

454 predictions. Top by Δscore:

Variant	Effect	Δscore
11:57460896:GGTAA:G	donor_loss	1.0000
11:57460897:GTAAG:G	donor_loss	1.0000
11:57468091:GT:G	donor_loss	1.0000
11:57476147:C:G	acceptor_gain	1.0000
11:57476152:C:G	acceptor_gain	1.0000
11:57460892:GCAAG:G	donor_gain	0.9900
11:57460895:AG:A	donor_gain	0.9900
11:57460896:GG:G	donor_gain	0.9900
11:57460897:G:GG	donor_gain	0.9900
11:57460898:T:A	donor_loss	0.9900
11:57467603:CCACA:C	acceptor_loss	0.9900
11:57467604:CACAG:C	acceptor_loss	0.9900
11:57467605:ACAGC:A	acceptor_loss	0.9900
11:57467606:CAGC:C	acceptor_loss	0.9900
11:57467607:A:AG	acceptor_gain	0.9900
11:57467607:A:T	acceptor_loss	0.9900
11:57467608:G:GC	acceptor_gain	0.9900
11:57467608:G:GT	acceptor_loss	0.9900
11:57467608:GCT:G	acceptor_gain	0.9900
11:57467608:GCTC:G	acceptor_gain	0.9900
11:57468092:T:A	donor_loss	0.9900
11:57476146:A:AG	acceptor_gain	0.9900
11:57476151:A:AG	acceptor_gain	0.9900
11:57476156:A:AG	acceptor_gain	0.9900
11:57476157:C:G	acceptor_gain	0.9900
11:57476157:CCCA:C	acceptor_loss	0.9900
11:57476158:CCA:C	acceptor_loss	0.9900
11:57476159:CAGGA:C	acceptor_loss	0.9900
11:57476160:A:AG	acceptor_gain	0.9900
11:57476160:A:C	acceptor_loss	0.9900

AlphaMissense

2664 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
11:57467681:G:A	C35Y	1.000
11:57467713:T:A	C46S	1.000
11:57467713:T:C	C46R	1.000
11:57467714:G:A	C46Y	1.000
11:57467714:G:C	C46S	1.000
11:57467715:C:G	C46W	1.000
11:57467773:T:C	F66L	1.000
11:57467774:T:G	F66C	1.000
11:57467775:C:A	F66L	1.000
11:57467775:C:G	F66L	1.000
11:57467777:T:C	L67P	1.000
11:57467785:A:T	N70Y	1.000
11:57467786:A:T	N70I	1.000
11:57467787:C:A	N70K	1.000
11:57467787:C:G	N70K	1.000
11:57467843:T:C	L89P	1.000
11:57467852:A:T	N92I	1.000
11:57467853:C:A	N92K	1.000
11:57467853:C:G	N92K	1.000
11:57467882:T:C	F102S	1.000
11:57467882:T:G	F102C	1.000
11:57467909:T:C	L111P	1.000
11:57467915:T:A	L113H	1.000
11:57467915:T:C	L113P	1.000
11:57467918:G:T	G114V	1.000
11:57467925:C:A	N116K	1.000
11:57467925:C:G	N116K	1.000
11:57467957:T:C	F127S	1.000
11:57467957:T:G	F127C	1.000
11:57467975:T:C	L133P	1.000

dbSNP variants (sampled 300 via entrez): RS1000069728 (11:57465051 G>A,C,T), RS1000248304 (11:57458857 G>A), RS1000382832 (11:57476810 G>A,T), RS1000508752 (11:57465269 C>T), RS1000648685 (11:57460381 A>C,G,T), RS1000656676 (11:57468693 A>G), RS1000820224 (11:57462738 C>T), RS1000961586 (11:57471389 G>T), RS1001257983 (11:57472783 C>T), RS1001290464 (11:57472302 T>C), RS1001308927 (11:57471034 G>A,C), RS1001352842 (11:57470317 G>A), RS1001571241 (11:57464462 G>C,T), RS1001665599 (11:57458799 T>A,G), RS1001891601 (11:57465309 C>T)

Disease associations

OMIM: gene MIM:610462 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

3 associations (top):

Study	Trait	p-value
GCST004748_22	Lung cancer	5.000000e-07
GCST007325_67	General risk tolerance (MTAG)	4.000000e-10
GCST012335_8	Hodgkin’s lymphoma	8.000000e-12

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0008579	risk-taking behaviour

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
bisphenol A	increases expression, increases methylation	2
dicrotophos	increases expression	1
abrine	decreases expression	1
jinfukang	affects cotreatment, decreases expression	1
(+)-JQ1 compound	decreases expression	1
Resveratrol	decreases expression, affects cotreatment	1
Cisplatin	affects cotreatment, decreases expression	1
Diazinon	increases methylation	1
Lead	affects expression	1
Plant Extracts	affects cotreatment, decreases expression	1
Ribonucleotides	affects binding	1
Urethane	decreases expression	1
Butyric Acid	increases expression	1

Cellosaurus cell lines

1 cell lines: 1 cancer cell line

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

Cellosaurus	Name	Category	Sex
CVCL_B2EC	Abcam HeLa RTN4RL2 KO	Cancer cell line	Female

Clinical trials (associated diseases)

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