MADCAM1

Summary

MADCAM1 (mucosal vascular addressin cell adhesion molecule 1, HGNC:6765) is a protein-coding gene on chromosome 19p13.3, encoding Mucosal addressin cell adhesion molecule 1 (Q13477). Cell adhesion leukocyte receptor expressed by mucosal venules, helps to direct lymphocyte traffic into mucosal tissues including the Peyer patches and the intestinal lamina propria.

The protein encoded by this gene is an endothelial cell adhesion molecule that interacts preferentially with the leukocyte beta7 integrin LPAM-1 (alpha4beta7), L-selectin, and VLA-4 (alpha4beta1) on myeloid cells to direct leukocytes into mucosal and inflamed tissues. It is a member of the immunoglobulin family and is similar to ICAM1 and VCAM1. At least seven alternatively spliced transcripts encoding different protein isoforms have been found for this gene, but the full-length nature of some variants has not been determined.

Source: NCBI Gene 8174 — RefSeq curated summary.

At a glance

• Clinical variants (ClinVar): 76 total
• Druggable target: yes
• MANE Select transcript: NM_130760

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:6765
Approved symbol	MADCAM1
Name	mucosal vascular addressin cell adhesion molecule 1
Location	19p13.3
Locus type	gene with protein product
Status	Approved
Aliases	MACAM1
Ensembl gene	ENSG00000099866
Ensembl biotype	protein_coding
OMIM	102670
Entrez	8174

Gene structure

Transcript identifiers

Ensembl transcripts: 8 — 7 protein_coding, 1 retained_intron

ENST00000215637, ENST00000346144, ENST00000382683, ENST00000587541, ENST00000622449, ENST00000868303, ENST00000949591, ENST00000949592

RefSeq mRNA: 2 — MANE Select: NM_130760 NM_130760, NM_130762

CCDS: CCDS12028, CCDS12029

Canonical transcript exons

ENST00000215637 — 5 exons

Exon	Start	End
ENSE00000655528	498496	498825
ENSE00000892393	497833	498117
ENSE00003701228	501669	501929
ENSE00003842760	504745	505343
ENSE00003848167	496486	496551

Expression profiles

Bgee: expression breadth ubiquitous, 170 present calls, max score 85.36.

FANTOM5 (CAGE): breadth broad, TPM avg 1.2061 / max 73.4960, expressed in 626 samples.

FANTOM5 promoters (3 alternative TSS)

Promoter ID	TPM avg	Samples expressed
172678	0.9682	573
172679	0.2042	35
172680	0.0336	17

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	85.36	gold quality
vermiform appendix	UBERON:0001154	83.78	gold quality
mucosa of transverse colon	UBERON:0004991	83.66	gold quality
caecum	UBERON:0001153	82.13	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	79.33	gold quality
pancreatic ductal cell	CL:0002079	79.22	silver quality
mucosa of sigmoid colon	UBERON:0004993	78.94	silver quality
ileal mucosa	UBERON:0000331	78.38	gold quality
colonic epithelium	UBERON:0000397	77.53	gold quality
colonic mucosa	UBERON:0000317	77.52	gold quality
sperm	CL:0000019	76.25	gold quality
small intestine Peyer’s patch	UBERON:0003454	75.41	gold quality
male germ cell	CL:0000015	75.24	gold quality
right hemisphere of cerebellum	UBERON:0014890	74.17	gold quality
small intestine	UBERON:0002108	73.86	gold quality
cerebellar hemisphere	UBERON:0002245	73.75	gold quality
cerebellar cortex	UBERON:0002129	73.68	gold quality
transverse colon	UBERON:0001157	73.52	gold quality
right frontal lobe	UBERON:0002810	73.16	gold quality
cerebellum	UBERON:0002037	73.10	gold quality
spleen	UBERON:0002106	73.06	gold quality
hair follicle	UBERON:0002073	72.36	gold quality
cingulate cortex	UBERON:0003027	72.08	gold quality
endometrium epithelium	UBERON:0004811	71.96	gold quality
anterior cingulate cortex	UBERON:0009835	71.89	gold quality
epithelial cell of pancreas	CL:0000083	71.87	gold quality
skeletal muscle tissue of rectus abdominis	UBERON:0004511	71.67	gold quality
Brodmann (1909) area 9	UBERON:0013540	71.42	gold quality
dorsolateral prefrontal cortex	UBERON:0009834	71.32	gold quality
epithelium of nasopharynx	UBERON:0001951	70.87	gold quality

Single-cell (SCXA)

Detected in 2 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-HCAD-11	yes	1989.56
E-ANND-3	no	1.25

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): BCLAF1, BTF3, NFKB1, NKX2-3, RELA

miRNA regulators (miRDB)

22 targeting MADCAM1, 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-6798-5P	100.00	65.77	699
HSA-MIR-6744-5P	99.93	66.82	748
HSA-MIR-515-5P	99.92	69.82	2343
HSA-MIR-519E-5P	99.92	69.62	2358
HSA-MIR-153-5P	99.89	73.86	6317
HSA-MIR-4728-5P	99.85	69.39	4718
HSA-MIR-4495	99.82	72.08	3080
HSA-MIR-6785-5P	99.82	68.68	4428
HSA-MIR-6764-5P	99.75	67.89	2304
HSA-MIR-149-3P	99.72	68.22	3963
HSA-MIR-4524A-3P	99.72	66.85	2406
HSA-MIR-6779-5P	99.70	65.76	2363
HSA-MIR-6883-5P	99.69	68.05	3785
HSA-MIR-7106-5P	99.53	67.47	3574
HSA-MIR-297	99.40	69.58	1418
HSA-MIR-6760-5P	98.87	66.73	1515
HSA-MIR-11399	98.71	65.69	869
HSA-MIR-4266	98.53	67.29	1035
HSA-MIR-615-5P	98.10	63.76	591
HSA-MIR-6869-5P	97.17	67.06	634
HSA-MIR-3162-5P	95.67	67.53	794
HSA-MIR-874-3P	95.02	65.66	806

Literature-anchored findings (GeneRIF, showing 18)

• Ca2+ is essential for cell tethering in flow and rolling interactions through alpha 4 integrins with MAdCAM-1 as substrate; Mg2+ promotes firm adhesion of cells on MAdCAM-1 but with much lower tethering efficiency in shear flow. (PMID:11705388)
• A crystal structure for the two extracellular amino-terminal domains of human MAdCAM-1 (PMID:11807247)
• more extensive expression of MAdCAM-1 in Crohn’s disease (CrD), than in ulcerative colitis, which could contribute not only to mucosal inflammation, but also to transmural inflammation in CrD. (PMID:12100519)
• MAdCAM-1/integrin alpha4beta7 homing system may participate in gastric inflammation in response to H pylori-infection and contributes to MALT formation, typically leading to the development of nodular gastritis. (PMID:14669317)
• a marker of graft rejection in small intestine transplantation (PMID:15050155)
• PI3-K/Akt is involved in the gut-specific differentiation of human intestinal microvascular endothelial cells, which results in expression of the mucosal addressin MAdCAM-1 (PMID:15483224)
• Immobilized CCL25 and CCL28 are both able to trigger integrin alpha(4)beta(7)-dependent lymphocyte arrest on MAdCAM-1 under shear flow. (PMID:18308860)
• mucosal addressin cell adhesion molecule 1 may represent an important determinant for the generation of mucosal damage in celiac disease (PMID:19157500)
• MADCAM1 gene polymorphisms may be associated with the risk of chronic GVHD and may, also, affect mortality related to aHSCT. (PMID:19286444)
• Findings suggest that the inactive alpha4beta7 and alpha4beta7 activated by different stimuli have distinct conformations with different structural requirements for MAdCAM-1 binding. (PMID:21296888)
• Domain 1 of mucosal addressin cell adhesion molecule has an I1-set fold and a flexible integrin-binding loop. (PMID:23297416)
• MADCAM1 is up-regulated in liver cirrhosis with expression on peribiliary vascular plexus and lymphoid aggregates (PMID:23839340)
• Both the ACT-1 assay and the MAdCAM-1 assay demonstrated acceptable reproducibility and repeatability. The assays were sufficiently stable to allow for clinical use. During clinical testing the assays demonstrated that vedolizumab was able to saturate peripheral cells at all doses tested. (PMID:25908521)
• Doxo-induced apoptosis has a role in inhibiting hepatocellular carcinoma by targeting Madcam1 and AKT and blocking protein translation initiation (PMID:26124182)
• n the present study, mucosal addressin cell adhesion molecule-1 was selectively expressed on alpha-smooth muscle actin-positive reticular framework. The reticular framework may function in lymphocyte homing and segregation into the periarteriolar lymphoid sheath, lymph follicle and marginal zone. (PMID:31866620)
• Baseline levels of dynamic CD4(+) T cell adhesion to MAdCAM-1 correlate with clinical response to vedolizumab treatment in ulcerative colitis: a cohort study. (PMID:32293299)
• Frequency of Effector Memory Cells Expressing Integrin alpha4beta7 Is Associated With TGF-beta1 Levels in Therapy Naive HIV Infected Women With Low CD4(+) T Cell Count. (PMID:33828560)
• sMAdCAM: IL-6 Ratio Influences Disease Progression and Anti-Viral Responses in SARS-CoV-2 Infection. (PMID:34194420)

Cross-species orthologs

2 orthologs

Organism	Symbol	Gene ID
mus_musculus	Madcam1	ENSMUSG00000020310
rattus_norvegicus	Madcam1	ENSRNOG00000008217

Protein

Protein identifiers

Mucosal addressin cell adhesion molecule 1 — Q13477 (reviewed: Q13477)

All UniProt accessions (2): Q13477, U3KQ59

UniProt curated annotations — full annotation on UniProt →

Function. Cell adhesion leukocyte receptor expressed by mucosal venules, helps to direct lymphocyte traffic into mucosal tissues including the Peyer patches and the intestinal lamina propria. It can bind both integrin alpha-4/beta-7 and L-selectin, regulating both the passage and retention of leukocytes. Isoform 2, lacking the mucin-like domain, may be specialized in supporting integrin alpha-4/beta-7-dependent adhesion strengthening, independent of L-selectin binding.

Subunit / interactions. Homodimer.

Subcellular location. Membrane.

Tissue specificity. Highly expressed on high endothelial venules (HEV) and lamina propia venules found in the small intestine, and to a lesser extent in the colon and spleen. Very low levels of expression found in pancreas and brain. Not expressed in the thymus, prostate, ovaries, testis, heart, placenta, lung, liver, skeletal muscle, kidney or peripheral blood leukocytes.

Post-translational modifications. The Ser/Thr-rich mucin-like domain may provide possible sites for O-glycosylation.

Polymorphism. The number of repeats in the mucin domain varies between 5 and 8 repeats.

Isoforms (4)

UniProt ID	Names	Canonical?
Q13477-1	1	yes
Q13477-2	2
Q13477-3	3
Q13477-4	4

RefSeq proteins (2): NP_570116, NP_570118 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR003599	Ig_sub	Domain
IPR007110	Ig-like_dom	Domain
IPR013783	Ig-like_fold	Homologous_superfamily
IPR015169	Adhes-Ig-like	Domain
IPR036179	Ig-like_dom_sf	Homologous_superfamily
IPR037413	MADCAM1	Family

Pfam: PF09085

UniProt features (49 total): strand 16, repeat 6, region of interest 3, disulfide bond 3, splice variant 3, sequence conflict 3, compositionally biased region 2, topological domain 2, sequence variant 2, turn 2, domain 2, signal peptide 1, chain 1, glycosylation site 1, transmembrane region 1, helix 1

Structure

Experimental structures (PDB)

7 structures.

PDB	Method	Resolution (Å)
4HBQ	X-RAY DIFFRACTION	1.4
4HD9	X-RAY DIFFRACTION	1.7
1GSM	X-RAY DIFFRACTION	1.9
1BQS	X-RAY DIFFRACTION	2.2
4HCR	X-RAY DIFFRACTION	2.3
4HC1	X-RAY DIFFRACTION	2.87
9P95	ELECTRON MICROSCOPY	3.05

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q13477-F1	74.94	0.45

Antibody-complex structures (SAbDab): 2 — 4HC1, 4HCR

Functional residue map

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

Disulfide bonds (3): 47–94, 51–98, 134–204

Glycosylation sites (1): 83

Function

Pathways and Gene Ontology

Reactome pathways

2 pathways

ID	Pathway
R-HSA-198933	Immunoregulatory interactions between a Lymphoid and a non-Lymphoid cell
R-HSA-216083	Integrin cell surface interactions

MSigDB gene sets: 145 (showing top): CREL_01, BENPORATH_ES_WITH_H3K27ME3, REACTOME_ADAPTIVE_IMMUNE_SYSTEM, GOBP_POSITIVE_REGULATION_OF_LYMPHOCYTE_MIGRATION, GOBP_REGULATION_OF_LEUKOCYTE_MIGRATION, GOBP_REGULATION_OF_MONONUCLEAR_CELL_MIGRATION, GOBP_CELL_CELL_ADHESION, GOBP_CELLULAR_EXTRAVASATION, GOBP_LEUKOCYTE_MIGRATION, GOBP_POSITIVE_REGULATION_OF_LEUKOCYTE_MIGRATION, BLALOCK_ALZHEIMERS_DISEASE_UP, GGGNNTTTCC_NFKB_Q6_01, GOBP_LEUKOCYTE_ADHESION_TO_VASCULAR_ENDOTHELIAL_CELL, NUMATA_CSF3_SIGNALING_VIA_STAT3, GOBP_LEUKOCYTE_CELL_CELL_ADHESION

GO Biological Process (10): positive regulation of leukocyte migration (GO:0002687), immune response (GO:0006955), cell adhesion (GO:0007155), cell-matrix adhesion (GO:0007160), signal transduction (GO:0007165), integrin-mediated signaling pathway (GO:0007229), heterotypic cell-cell adhesion (GO:0034113), receptor clustering (GO:0043113), leukocyte tethering or rolling (GO:0050901), positive regulation of lymphocyte migration (GO:2000403)

GO Molecular Function (1): integrin binding involved in cell-matrix adhesion (GO:0098640)

GO Cellular Component (2): plasma membrane (GO:0005886), membrane (GO:0016020)

Reactome top-level categories

Rollup of top-2 pathways:

Category	Pathways
Adaptive Immune System	1
Extracellular matrix organization	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular process	2
positive regulation of immune system process	1
regulation of leukocyte migration	1
positive regulation of cell migration	1
leukocyte migration	1
immune system process	1
response to stimulus	1
cell-substrate adhesion	1
cell communication	1
signaling	1
regulation of cellular process	1
cellular response to stimulus	1
cell surface receptor signaling pathway	1
cell-cell adhesion	1
plasma membrane	1
protein localization to membrane	1
cellular extravasation	1
leukocyte adhesion to vascular endothelial cell	1
positive regulation of mononuclear cell migration	1
lymphocyte migration	1
regulation of lymphocyte migration	1
integrin binding	1
cell-matrix adhesion	1
cell-matrix adhesion mediator activity	1
membrane	1
cell periphery	1
cellular anatomical structure	1

Protein interactions and networks

STRING

700 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
MADCAM1	ACKR2	O00590	996
MADCAM1	CCR9	P51686	994
MADCAM1	SELL	P14151	993
MADCAM1	ITGA4	P13612	980
MADCAM1	ITGB7	P26010	942
MADCAM1	CCL25	O15444	928
MADCAM1	NTAN1	Q96AB6	859
MADCAM1	VCAM1	P19320	855
MADCAM1	ICAM1	P05362	843
MADCAM1	IGBP1	P78318	828
MADCAM1	SELE	P16111	826
MADCAM1	CD8A	P01732	807
MADCAM1	CD4	P01730	801
MADCAM1	ITGB2	P05107	779
MADCAM1	ACKR4	Q9NPB9	777

IntAct

5 interactions, top by confidence:

A	B	Type	Score
ITGA4	ITGB7	psi-mi:“MI:0407”(direct interaction)	0.740
MADCAM1	TCAF2	psi-mi:“MI:0914”(association)	0.530
	ITGA4	psi-mi:“MI:0407”(direct interaction)	0.360

BioGRID (6): FAM115C (Affinity Capture-MS), TMEM97 (Affinity Capture-MS), ARFGEF2 (Affinity Capture-MS), ITGB7 (Reconstituted Complex), TMEM97 (Affinity Capture-MS), FAM115C (Affinity Capture-MS)

ESM2 similar proteins: A0A1B0GW64, A0A5F4BST2, A0PJX4, A8MVS5, A8MWV9, B0FP48, E5RIL1, E9PGG2, O14836, O60320, O95998, P09564, Q01113, Q01114, Q13477, Q2KI80, Q2T9R2, Q3TS39, Q3UPR0, Q3URD2, Q4V9L6, Q5FVJ4, Q5M869, Q6A044, Q6UWJ8, Q75VT8, Q864V4, Q8BRJ3, Q8BX43, Q8C503, Q8IVY1, Q8K5A9, Q8N112, Q8NC24, Q8NDY8, Q8QZT4, Q8R138, Q969Z4, Q9BUF7, Q9CQM1

Diamond homologs: O70540, Q13477, Q61826

SIGNOR signaling

2 interactions.

A	Effect	B	Mechanism
BTF3	“down-regulates quantity by repression”	MADCAM1	“transcriptional regulation”
NKX2-3	“up-regulates quantity by expression”	MADCAM1	“transcriptional regulation”

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	67
Likely benign	5
Benign	0

Top pathogenic / likely-pathogenic (0)

SpliceAI

1155 predictions. Top by Δscore:

Variant	Effect	Δscore
19:501926:GGCT:G	donor_gain	1.0000
19:501927:GCTG:G	donor_gain	1.0000
19:504743:A:AG	acceptor_gain	1.0000
19:504744:G:GA	acceptor_gain	1.0000
19:504744:GC:G	acceptor_gain	1.0000
19:496550:CGGTG:C	donor_loss	0.9900
19:496552:G:GA	donor_loss	0.9900
19:496552:G:GG	donor_gain	0.9900
19:496553:T:A	donor_loss	0.9900
19:496561:G:T	donor_gain	0.9900
19:498115:ACGGT:A	donor_loss	0.9900
19:498116:CGG:C	donor_loss	0.9900
19:498118:GTGA:G	donor_loss	0.9900
19:498119:T:A	donor_loss	0.9900
19:498823:CCGGT:C	donor_loss	0.9900
19:498824:CGG:C	donor_loss	0.9900
19:498825:GGTG:G	donor_loss	0.9900
19:498827:TGAG:T	donor_loss	0.9900
19:498828:G:GG	donor_loss	0.9900
19:501667:A:AG	acceptor_gain	0.9900
19:501668:G:GG	acceptor_gain	0.9900
19:501668:GTC:G	acceptor_gain	0.9900
19:501668:GTCC:G	acceptor_gain	0.9900
19:501668:GTCCT:G	acceptor_gain	0.9900
19:501908:G:GT	donor_gain	0.9900
19:501925:AGGCT:A	donor_gain	0.9900
19:501926:GGCTG:G	donor_gain	0.9900
19:501927:GCT:G	donor_gain	0.9900
19:501930:G:GG	donor_gain	0.9900
19:504741:CCA:C	acceptor_loss	0.9900

AlphaMissense

2400 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
19:497960:G:C	W60C	1.000
19:497960:G:T	W60C	1.000
19:497958:T:A	W60R	0.998
19:497958:T:C	W60R	0.998
19:498725:G:C	W189C	0.997
19:498725:G:T	W189C	0.997
19:498499:T:G	F114C	0.996
19:498060:T:A	C94S	0.995
19:498061:G:A	C94Y	0.995
19:498061:G:C	C94S	0.995
19:498060:T:C	C94R	0.994
19:498062:C:G	C94W	0.993
19:498558:T:A	C134S	0.993
19:498559:G:C	C134S	0.993
19:497959:G:C	W60S	0.992
19:498558:T:C	C134R	0.992
19:498559:G:A	C134Y	0.991
19:498768:T:A	C204S	0.991
19:498769:G:C	C204S	0.991
19:498498:T:C	F114L	0.990
19:498500:C:A	F114L	0.990
19:498500:C:G	F114L	0.990
19:498769:G:A	C204Y	0.990
19:498770:C:G	C204W	0.990
19:497919:T:C	C47R	0.989
19:497921:C:G	C47W	0.989
19:498009:A:C	S77R	0.989
19:498011:C:A	S77R	0.989
19:498011:C:G	S77R	0.989
19:498499:T:C	F114S	0.989

dbSNP variants (sampled 300 via entrez): RS1000104932 (19:499991 G>C), RS1000238804 (19:497817 G>C,T), RS1000541929 (19:503516 G>A), RS1001469734 (19:501550 C>A,T), RS1001672527 (19:497367 A>C,G,T), RS1001779694 (19:499415 TACAA>T), RS1002211216 (19:503196 G>A), RS1002230431 (19:499121 C>G,T), RS1002267008 (19:502880 C>G), RS1002314940 (19:496191 T>G), RS1002518234 (19:498133 G>A), RS1002548103 (19:502072 C>A), RS1002600698 (19:501830 G>A), RS1002789761 (19:504521 G>A), RS1003017659 (19:499491 C>A,G,T)

Disease associations

OMIM: gene MIM:102670 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

0 associations (top):

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL4467 (SINGLE PROTEIN)

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

CTD chemical–gene interactions

19 total (human), top 19 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
entinostat	increases expression, affects cotreatment, affects expression	2
triphenyl phosphate	affects expression	1
tris(1,3-dichloro-2-propyl)phosphate	decreases expression	1
butyraldehyde	decreases expression	1
pentanal	decreases expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, affects expression	1
dorsomorphin	affects cotreatment, affects expression	1
Resveratrol	affects cotreatment, decreases expression	1
Acetaminophen	increases expression	1
Amphotericin B	increases expression	1
Benzo(a)pyrene	affects methylation	1
Dichlorodiphenyl Dichloroethylene	decreases expression	1
Plant Extracts	affects cotreatment, decreases expression	1
Silicon Dioxide	decreases expression	1
Smoke	increases expression	1
Tobacco Smoke Pollution	decreases expression	1
Valproic Acid	increases methylation	1
Cyclosporine	decreases methylation	1
Okadaic Acid	decreases expression	1

ChEMBL screening assays

1 unique, capped per target: 1 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL708522	Binding	The concentration of compound required to prevent 50 percent of cells from adhering to MAdCAM-1	Sulfonopeptide inhibitors of leukocyte adhesion — Bioorg Med Chem Lett

Clinical trials (associated diseases)

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