RGMB

Summary

RGMB (repulsive guidance molecule BMP co-receptor b, HGNC:26896) is a protein-coding gene on chromosome 5q15, encoding Repulsive guidance molecule B (Q6NW40). Member of the repulsive guidance molecule (RGM) family that contributes to the patterning of the developing nervous system.

RGMB is a glycosylphosphatidylinositol (GPI)-anchored member of the repulsive guidance molecule family (see RGMA, MIM 607362) and contributes to the patterning of the developing nervous system (Samad et al., 2005 [PubMed 15671031]).

Source: NCBI Gene 285704 — RefSeq curated summary.

At a glance

• GWAS associations: 4
• Clinical variants (ClinVar): 61 total
• MANE Select transcript: NM_001366508

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:26896
Approved symbol	RGMB
Name	repulsive guidance molecule BMP co-receptor b
Location	5q15
Locus type	gene with protein product
Status	Approved
Aliases	FLJ90406, DRAGON
Ensembl gene	ENSG00000174136
Ensembl biotype	protein_coding
OMIM	612687
Entrez	285704

Gene structure

Transcript identifiers

Ensembl transcripts: 23 — 18 protein_coding, 4 protein_coding_CDS_not_defined, 1 retained_intron

ENST00000308234, ENST00000434027, ENST00000504776, ENST00000505265, ENST00000507054, ENST00000508978, ENST00000513185, ENST00000894564, ENST00000894565, ENST00000894566, ENST00000894567, ENST00000894568, ENST00000894569, ENST00000894570, ENST00000894571, ENST00000894572, ENST00000929800, ENST00000929801, ENST00000929802, ENST00000929803, ENST00000947709, ENST00000947710, ENST00000947711

RefSeq mRNA: 5 — MANE Select: NM_001366508 NM_001012761, NM_001366508, NM_001366509, NM_001366510, NM_001366511

CCDS: CCDS47251, CCDS93751

Canonical transcript exons

ENST00000513185 — 3 exons

Exon	Start	End
ENSE00001325695	98779580	98780088
ENSE00001482681	98793085	98796494
ENSE00002033563	98773663	98774206

Expression profiles

Bgee: expression breadth ubiquitous, 254 present calls, max score 97.48.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 31.6103 / max 1118.2747, expressed in 1563 samples.

FANTOM5 promoters (21 alternative TSS)

Promoter ID	TPM avg	Samples expressed
57759	12.9246	1533
57761	2.8500	891
57751	2.7627	765
57758	1.8297	1069
57756	1.7698	759
57745	1.7462	833
57750	1.2130	647
57749	1.2037	458
57760	1.1588	597
57754	0.9128	279

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
ileal mucosa	UBERON:0000331	97.48	gold quality
pylorus	UBERON:0001166	97.28	gold quality
upper arm skin	UBERON:0004263	96.08	gold quality
upper leg skin	UBERON:0004262	95.64	gold quality
tibialis anterior	UBERON:0001385	94.97	silver quality
lower esophagus muscularis layer	UBERON:0035833	94.58	gold quality
lower esophagus	UBERON:0013473	94.53	gold quality
cardia of stomach	UBERON:0001162	94.11	gold quality
cardiac muscle of right atrium	UBERON:0003379	92.94	gold quality
esophagogastric junction muscularis propria	UBERON:0035841	92.81	gold quality
rectum	UBERON:0001052	92.36	gold quality
deltoid	UBERON:0001476	92.33	gold quality
dorsal root ganglion	UBERON:0000044	92.19	gold quality
body of stomach	UBERON:0001161	92.13	gold quality
stomach	UBERON:0000945	92.07	gold quality
fundus of stomach	UBERON:0001160	91.98	gold quality
parotid gland	UBERON:0001831	91.33	gold quality
cortical plate	UBERON:0005343	91.05	gold quality
quadriceps femoris	UBERON:0001377	90.67	gold quality
stromal cell of endometrium	CL:0002255	90.38	gold quality
vastus lateralis	UBERON:0001379	90.30	gold quality
nipple	UBERON:0002030	90.12	gold quality
mucosa of stomach	UBERON:0001199	89.60	gold quality
left ventricle myocardium	UBERON:0006566	89.13	gold quality
skeletal muscle tissue of biceps brachii	UBERON:0004502	88.87	gold quality
superior vestibular nucleus	UBERON:0007227	88.68	gold quality
oviduct epithelium	UBERON:0004804	88.53	gold quality
skeletal muscle tissue	UBERON:0001134	88.49	gold quality
Brodmann (1909) area 46	UBERON:0006483	88.48	gold quality
muscle tissue	UBERON:0002385	88.43	gold quality

Single-cell (SCXA)

Detected in 2 experiment(s), a significant marker in 2.

Experiment	Marker?	Max mean expression
E-GEOD-125970	yes	235.55
E-ANND-3	yes	10.03

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): DRGX

Literature-anchored findings (GeneRIF, showing 11)

• Reduced expression of RGMB in breast cancer was associated with breast cancer. (PMID:21617229)
• The expression of RGMA, RGMB and RGMC was evident in most examined prostate cancer cell lines, and also in the prostate cancer tissues (PMID:22076499)
• current data firstly revealed that RGMB may act as a negative regulator in breast cancer through BMP signaling (PMID:22415859)
• two RGMB ectodomains conformationally stabilize the juxtamembrane regions of two NEO1 receptors in a pH-dependent manner. (PMID:23744777)
• Study highlights the potential importance of RGMb in propagating pro-angiogenic effects of HGF and BMP-7. (PMID:24970050)
• Data show that Dragon expression was increased in colon cancer tissues compared to control tissues in CAC mouse model and in human patients. (PMID:26029998)
• RGMB was down-regulation in non-small cell lung cancer. (PMID:26055877)
• Our results demonstrate that RGMB is an important inhibitor of non-small cell lung cancer metastasis and that low RGMB expression is a novel predictor or a poor prognosis. (PMID:26910889)
• RGMB enhances the suppressive activity of the monomeric secreted form of CTLA-4. (PMID:31061392)
• Repulsive guidance molecules lock growth differentiation factor 5 in an inhibitory complex. (PMID:32576689)
• RNF4RGMbBMP6 axis required for osteogenic differentiation and cancer cell survival. (PMID:36153321)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
danio_rerio	rgmb	ENSDARG00000079323
mus_musculus	Rgmb	ENSMUSG00000048027
rattus_norvegicus	Rgmb	ENSRNOG00000064721
caenorhabditis_elegans	drag-1	WBGENE00022154

Paralogs (2): HJV (ENSG00000168509), RGMA (ENSG00000182175)

Protein

Protein identifiers

Repulsive guidance molecule B — Q6NW40 (reviewed: Q6NW40)

Alternative names: DRG11-responsive axonal guidance and outgrowth of neurite

All UniProt accessions (2): Q6NW40, J3KNF6

UniProt curated annotations — full annotation on UniProt →

Function. Member of the repulsive guidance molecule (RGM) family that contributes to the patterning of the developing nervous system. Acts as a bone morphogenetic protein (BMP) coreceptor that potentiates BMP signaling. Promotes neuronal adhesion. May inhibit neurite outgrowth.

Subunit / interactions. Homooligomer. Interacts with DRGX. Interacts with BMP2 and BMP4. Interacts with the BMP type I receptors ACVR1, BMPR1A and BMPR1B and with the BMP type II receptor ACVR2B. The functional complex with its receptor NEO1/neogenin appears to be a heterotetramer with a 2:2 stoichiometry, RGM molecules acting as staples that bring two NEO1 receptors together without interacting themselves, this arrangement leads to activation of downstream signaling via RhoA.

Subcellular location. Cell membrane. Membrane raft.

Post-translational modifications. GPI-anchored. Autocatalytically cleaved at low pH; the two chains remain linked via two disulfide bonds.

Similarity. Belongs to the repulsive guidance molecule (RGM) family.

RefSeq proteins (5): NP_001012779, NP_001353437, NP_001353438, NP_001353439, NP_001353440 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR009496	RGM_C	Domain
IPR010536	RGM_N	Domain
IPR040287	RGM	Family

Pfam: PF06534, PF06535

UniProt features (37 total): strand 11, helix 9, disulfide bond 2, mutagenesis site 2, sequence conflict 2, turn 2, glycosylation site 2, signal peptide 1, chain 1, propeptide 1, region of interest 1, compositionally biased region 1, site 1, lipid moiety-binding region 1

Structure

Experimental structures (PDB)

11 structures.

PDB	Method	Resolution (Å)
6Z3J	X-RAY DIFFRACTION	1.65
4BQ6	X-RAY DIFFRACTION	2.3
4BQ8	X-RAY DIFFRACTION	2.8
4UI0	X-RAY DIFFRACTION	2.8
4UHZ	X-RAY DIFFRACTION	2.85
4UI2	X-RAY DIFFRACTION	3.15
6Z3H	X-RAY DIFFRACTION	3.16
7NE0	X-RAY DIFFRACTION	3.25
6Z3M	X-RAY DIFFRACTION	5.5
7NDG	ELECTRON MICROSCOPY	5.98
4BQ7	X-RAY DIFFRACTION	6.6

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q6NW40-F1	80.41	0.57

Functional residue map

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

Catalytic / active sites (1): 168–169 (cleavage; by autolysis)

Post-translational modifications (1): 413

Disulfide bonds (2): 163–312, 139–226

Glycosylation sites (2): 120, 383

Mutagenesis-validated functional residues (2):

Position	Phenotype
186	severely impairs interaction with neo1.
206	introduces a n-linked glycan; changes interaction with neo1 from a 2:2 to a 1:1 stoichiometry.

Function

Pathways and Gene Ontology

Reactome pathways

1 pathways

ID	Pathway
R-HSA-373752	Netrin-1 signaling

MSigDB gene sets: 179 (showing top): GSE45365_CD8A_DC_VS_CD11B_DC_IFNAR_KO_MCMV_INFECTION_UP, GARGALOVIC_RESPONSE_TO_OXIDIZED_PHOSPHOLIPIDS_BLUE_UP, GOBP_RESPONSE_TO_BMP, GOBP_RESPONSE_TO_GROWTH_FACTOR, SENESE_HDAC1_TARGETS_UP, VECCHI_GASTRIC_CANCER_EARLY_DN, GRYDER_PAX3FOXO1_ENHANCERS_IN_TADS, MILI_PSEUDOPODIA_CHEMOTAXIS_DN, chr5q15, GOCC_SIDE_OF_MEMBRANE, GOCC_ENDOPLASMIC_RETICULUM_GOLGI_INTERMEDIATE_COMPARTMENT, PID_BMP_PATHWAY, GOMF_CORECEPTOR_ACTIVITY, CHICAS_RB1_TARGETS_CONFLUENT, GARGALOVIC_RESPONSE_TO_OXIDIZED_PHOSPHOLIPIDS_BLACK_UP

GO Biological Process (6): cell adhesion (GO:0007155), signal transduction (GO:0007165), BMP signaling pathway (GO:0030509), positive regulation of DNA-templated transcription (GO:0045893), positive regulation of macromolecule metabolic process (GO:0010604), regulation of primary metabolic process (GO:0080090)

GO Molecular Function (3): coreceptor activity (GO:0015026), identical protein binding (GO:0042802), protein binding (GO:0005515)

GO Cellular Component (5): endoplasmic reticulum-Golgi intermediate compartment (GO:0005793), plasma membrane (GO:0005886), membrane raft (GO:0045121), side of membrane (GO:0098552), membrane (GO:0016020)

Reactome top-level categories

Rollup of top-1 pathways:

Category	Pathways
Axon guidance	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular process	2
membrane	2
cellular anatomical structure	2
cell communication	1
signaling	1
regulation of cellular process	1
cellular response to stimulus	1
cellular response to BMP stimulus	1
transforming growth factor beta receptor superfamily signaling pathway	1
DNA-templated transcription	1
regulation of DNA-templated transcription	1
positive regulation of RNA biosynthetic process	1
positive regulation of metabolic process	1
macromolecule metabolic process	1
regulation of macromolecule metabolic process	1
regulation of metabolic process	1
primary metabolic process	1
signaling receptor activity	1
protein binding	1
binding	1
cytoplasm	1
intracellular membrane-bounded organelle	1
cell periphery	1
membrane microdomain	1
leaflet of membrane bilayer	1

Protein interactions and networks

STRING

508 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
RGMB	PDCD1LG2	Q9BQ51	974
RGMB	NEO1	Q92859	909
RGMB	DRGX	A6NNA5	878
RGMB	BMP2	P12643	786
RGMB	BMP4	P12644	750
RGMB	CD274	Q9NZQ7	650
RGMB	NOG	Q13253	563
RGMB	FAM174A	Q8TBP5	438
RGMB	HAMP	P81172	402
RGMB	BMP6	P22004	383
RGMB	UNC5C	O95185	383
RGMB	RIOK2	Q9BVS4	371
RGMB	SLCO6A1	Q86UG4	371
RGMB	SMOC2	Q9H3U7	368
RGMB	BMP5	P22003	364

IntAct

10 interactions, top by confidence:

A	B	Type	Score
BMP2	RGMB	psi-mi:“MI:0407”(direct interaction)	0.690
BMP2	Neo1	psi-mi:“MI:0915”(physical association)	0.600
BMP2	Neo1	psi-mi:“MI:0407”(direct interaction)	0.600
RGMB	Neo1	psi-mi:“MI:0407”(direct interaction)	0.560

BioGRID (13): BMP2 (Reconstituted Complex), BMP4 (Reconstituted Complex), ACVR1 (Affinity Capture-Western), BMPR1A (Affinity Capture-Western), BMPR1B (Affinity Capture-Western), ACVR2A (Affinity Capture-Western), ACVR2B (Affinity Capture-Western), RGMB (Proximity Label-MS), RGMB (Proximity Label-MS), RGMB (Proximity Label-MS), RGMB (Proximity Label-MS), RGMB (Affinity Capture-MS), RGMB (Affinity Capture-RNA)

ESM2 similar proteins: A0A1D5PUP4, A5YT95, O35757, O62650, O75882, O95980, P07225, P09858, P10669, P17247, P19883, P21214, P21674, P26012, P26013, P27090, P30371, P31514, P31515, P47931, P49767, P50291, P61811, P61812, P97299, P97953, Q07257, Q0VBD0, Q17QD6, Q38L25, Q5RA73, Q6NW40, Q6V9H4, Q6ZQ11, Q863H1, Q86X52, Q8BFR2, Q8CI19, Q8JG54, Q8N475

Diamond homologs: G5EDE5, Q6NW40, Q7TQ33, Q6PCX7, Q6ZVN8, Q7TQ32, Q8JG54, Q8N7M5, Q96B86, Q9N0A6

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	51
Likely benign	5
Benign	0

Top pathogenic / likely-pathogenic (0)

SpliceAI

999 predictions. Top by Δscore:

Variant	Effect	Δscore
5:98779578:A:AG	acceptor_gain	1.0000
5:98779578:AG:A	acceptor_gain	1.0000
5:98779578:AGGT:A	acceptor_gain	1.0000
5:98779579:G:GA	acceptor_gain	1.0000
5:98779579:GG:G	acceptor_gain	1.0000
5:98779579:GGT:G	acceptor_gain	1.0000
5:98779579:GGTG:G	acceptor_gain	1.0000
5:98779579:GGTGA:G	acceptor_gain	1.0000
5:98769623:GTG:G	donor_gain	0.9900
5:98769625:GGT:G	donor_loss	0.9900
5:98769626:G:GG	donor_gain	0.9900
5:98769627:T:G	donor_loss	0.9900
5:98770671:GAT:G	donor_gain	0.9900
5:98779576:A:AG	acceptor_gain	0.9900
5:98779576:ATAG:A	acceptor_gain	0.9900
5:98779577:T:G	acceptor_gain	0.9900
5:98780087:AGGCA:A	donor_loss	0.9900
5:98780090:CAAGT:C	donor_loss	0.9900
5:98780091:AA:A	donor_loss	0.9900
5:98769615:G:T	donor_gain	0.9800
5:98769621:CTGTG:C	donor_gain	0.9800
5:98769624:TG:T	donor_gain	0.9800
5:98769625:GG:G	donor_gain	0.9800
5:98770661:GGT:G	donor_gain	0.9800
5:98770674:G:GG	donor_gain	0.9800
5:98773191:G:GT	donor_gain	0.9800
5:98779577:TAG:T	acceptor_gain	0.9800
5:98779578:AGG:A	acceptor_gain	0.9800
5:98780092:AGTAT:A	donor_loss	0.9800
5:98770669:ATGAT:A	donor_gain	0.9700

AlphaMissense

2872 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
5:98779631:T:G	F63C	1.000
5:98779931:G:A	C163Y	1.000
5:98779985:G:A	C181Y	1.000
5:98779986:C:G	C181W	1.000
5:98779618:T:A	C59S	0.999
5:98779618:T:C	C59R	0.999
5:98779619:G:C	C59S	0.999
5:98779687:T:A	C82S	0.999
5:98779688:G:A	C82Y	0.999
5:98779688:G:C	C82S	0.999
5:98779688:G:T	C82F	0.999
5:98779689:C:G	C82W	0.999
5:98779738:T:A	C99S	0.999
5:98779738:T:C	C99R	0.999
5:98779739:G:A	C99Y	0.999
5:98779739:G:C	C99S	0.999
5:98779740:C:G	C99W	0.999
5:98779756:T:G	Y105D	0.999
5:98779759:C:G	H106D	0.999
5:98779787:T:C	L115P	0.999
5:98779804:T:A	C121S	0.999
5:98779804:T:C	C121R	0.999
5:98779805:G:C	C121S	0.999
5:98779930:T:A	C163S	0.999
5:98779930:T:C	C163R	0.999
5:98779931:G:C	C163S	0.999
5:98779931:G:T	C163F	0.999
5:98779932:T:G	C163W	0.999
5:98779939:T:C	F166L	0.999
5:98779941:T:A	F166L	0.999

dbSNP variants (sampled 300 via entrez): RS1000068120 (5:98774802 A>G), RS1000120841 (5:98796645 G>T), RS1000264907 (5:98776683 A>C,G), RS1000303188 (5:98787158 G>A), RS1000369323 (5:98769700 A>G), RS1000574180 (5:98779842 A>G), RS1000595639 (5:98788378 C>T), RS1000683129 (5:98785770 T>A), RS1000757098 (5:98791804 G>A,C), RS1000855362 (5:98775408 T>C), RS1000975799 (5:98770090 T>C), RS1001028114 (5:98770423 C>G,T), RS1001028515 (5:98779514 T>A), RS1001294044 (5:98791541 C>G,T), RS1001323493 (5:98775689 G>A)

Disease associations

OMIM: gene MIM:612687 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

4 associations (top):

Study	Trait	p-value
GCST000904_1	Asperger disorder	1.000000e-06
GCST002263_9	Acute urticaria and angioedema (non-steroidal anti-inflammatory drug-induced)	3.000000e-06
GCST003773_14	Loneliness (multivariate analysis)	3.000000e-06
GCST006628_5	Systolic blood pressure	2.000000e-09

EFO canonical traits (3, from GWAS)

EFO ID	Trait name
EFO:0005533	response to non-steroidal anti-inflammatory
EFO:0007865	loneliness measurement
EFO:0006335	systolic blood pressure

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Benzo(a)pyrene	affects cotreatment, increases expression, increases methylation	6
Valproic Acid	decreases expression, increases expression	4
Tetrachlorodibenzodioxin	increases expression	3
perfluorooctane sulfonic acid	increases expression	2
Arsenic	affects methylation, affects cotreatment, increases abundance, increases expression	2
Phenylmercuric Acetate	affects cotreatment, decreases expression	2
p-Chloromercuribenzoic Acid	decreases expression, affects cotreatment	2
sotorasib	affects cotreatment, decreases expression	1
triphenyl phosphate	affects expression	1
bisphenol A	decreases expression	1
trichostatin A	decreases expression	1
methylparaben	decreases expression	1
4-(N-methyl-N-nitrosamino)-1-(3-pyridyl)-1-butanone	increases expression, affects cotreatment	1
sodium arsenite	affects cotreatment, increases abundance, increases expression	1
9,10-dihydro-9,10-dihydroxybenzo(a)pyrene	increases expression	1
perfluorooctanoic acid	increases expression	1
manganese chloride	increases abundance, increases expression, affects cotreatment	1
potassium chromate(VI)	decreases expression	1
diallyl trisulfide	increases expression	1
mercuric bromide	decreases expression, affects cotreatment	1
CGP 52608	increases reaction, affects binding	1
2-palmitoylglycerol	increases expression	1
entinostat	decreases 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	decreases expression	1
trametinib	decreases expression, affects cotreatment	1
NVP-BKM120	affects cotreatment, decreases expression	1
Dasatinib	decreases expression	1

Cellosaurus cell lines

1 cell lines: 1 transformed cell line

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

Cellosaurus	Name	Category	Sex
CVCL_D9QF	Ubigene HEK293 RGMB KO	Transformed cell line	Female

Clinical trials (associated diseases)

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