JAM3

Summary

JAM3 (junctional adhesion molecule 3, HGNC:15532) is a protein-coding gene on chromosome 11q25, encoding Junctional adhesion molecule C (Q9BX67). Junctional adhesion protein that mediates heterotypic cell-cell interactions with its cognate receptor JAM2 to regulate different cellular processes.

Tight junctions represent one mode of cell-to-cell adhesion in epithelial or endothelial cell sheets, forming continuous seals around cells and serving as a physical barrier to prevent solutes and water from passing freely through the paracellular space. The protein encoded by this immunoglobulin superfamily gene member is localized in the tight junctions between high endothelial cells. Unlike other proteins in this family, the this protein is unable to adhere to leukocyte cell lines and only forms weak homotypic interactions. The encoded protein is a member of the junctional adhesion molecule protein family and acts as a receptor for another member of this family. A mutation in an intron of this gene is associated with hemorrhagic destruction of the brain, subependymal calcification, and congenital cataracts. Alternative splicing results in multiple transcript variants.

Source: NCBI Gene 83700 — RefSeq curated summary.

At a glance

• Gene–disease (curated): porencephaly-microcephaly-bilateral congenital cataract syndrome (Strong, GenCC)
• GWAS associations: 2
• Clinical variants (ClinVar): 239 total — 11 pathogenic, 5 likely-pathogenic
• Phenotypes (HPO): 19
• Dosage sensitivity (ClinGen): haploinsufficiency autosomal recessive, triplosensitivity no evidence
• MANE Select transcript: NM_032801

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:15532
Approved symbol	JAM3
Name	junctional adhesion molecule 3
Location	11q25
Locus type	gene with protein product
Status	Approved
Aliases	JAM-C, JAMC, JAM-3
Ensembl gene	ENSG00000166086
Ensembl biotype	protein_coding
OMIM	606871
Entrez	83700

Gene structure

Transcript identifiers

Ensembl transcripts: 14 — 9 protein_coding, 2 protein_coding_CDS_not_defined, 2 retained_intron, 1 nonsense_mediated_decay

ENST00000299106, ENST00000441717, ENST00000524969, ENST00000531302, ENST00000532165, ENST00000532252, ENST00000533711, ENST00000534549, ENST00000876942, ENST00000927997, ENST00000963684, ENST00000963685, ENST00000963686, ENST00000963687

RefSeq mRNA: 2 — MANE Select: NM_032801 NM_001205329, NM_032801

CCDS: CCDS55799, CCDS8494

Canonical transcript exons

ENST00000299106 — 9 exons

Exon	Start	End
ENSE00001099651	134148547	134148676
ENSE00001099652	134145946	134146045
ENSE00001099660	134144792	134144994
ENSE00001160468	134069072	134069159
ENSE00002155328	134149146	134152001
ENSE00003473175	134144241	134144393
ENSE00003533714	134148764	134148818
ENSE00003584081	134140657	134140770
ENSE00003653120	134139851	134139916

Expression profiles

Bgee: expression breadth ubiquitous, 289 present calls, max score 98.84.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 44.4764 / max 732.0330, expressed in 1324 samples.

FANTOM5 promoters (5 alternative TSS)

Promoter ID	TPM avg	Samples expressed
117693	35.0713	1294
117692	8.5719	1243
117691	0.7659	578
117696	0.0528	23
117697	0.0145	7

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
corpus callosum	UBERON:0002336	98.84	gold quality
inferior vagus X ganglion	UBERON:0005363	98.72	gold quality
ventricular zone	UBERON:0003053	98.62	gold quality
olfactory bulb	UBERON:0002264	98.61	gold quality
globus pallidus	UBERON:0001875	98.57	gold quality
medial globus pallidus	UBERON:0002477	98.57	gold quality
lateral globus pallidus	UBERON:0002476	98.39	gold quality
trigeminal ganglion	UBERON:0001675	98.30	gold quality
saphenous vein	UBERON:0007318	98.12	gold quality
subthalamic nucleus	UBERON:0001906	98.00	gold quality
substantia nigra pars reticulata	UBERON:0001966	97.95	gold quality
middle frontal gyrus	UBERON:0002702	97.75	gold quality
superficial temporal artery	UBERON:0001614	97.34	gold quality
dorsal plus ventral thalamus	UBERON:0001897	97.25	gold quality
medulla oblongata	UBERON:0001896	97.24	gold quality
inferior olivary complex	UBERON:0002127	97.18	gold quality
right coronary artery	UBERON:0001625	97.14	gold quality
ventral tegmental area	UBERON:0002691	97.11	gold quality
cartilage tissue	UBERON:0002418	97.10	gold quality
urethra	UBERON:0000057	97.06	gold quality
substantia nigra pars compacta	UBERON:0001965	96.88	gold quality
popliteal artery	UBERON:0002250	96.87	gold quality
tibial artery	UBERON:0007610	96.86	gold quality
superior vestibular nucleus	UBERON:0007227	96.79	gold quality
spinal cord	UBERON:0002240	96.74	gold quality
C1 segment of cervical spinal cord	UBERON:0006469	96.71	gold quality
dorsal root ganglion	UBERON:0000044	96.61	gold quality
aorta	UBERON:0000947	96.53	gold quality
cranial nerve II	UBERON:0000941	96.37	gold quality
stromal cell of endometrium	CL:0002255	96.22	gold quality

Single-cell (SCXA)

Detected in 4 experiment(s), a significant marker in 3.

Experiment	Marker?	Max mean expression
E-MTAB-6701	yes	11.54
E-ANND-3	yes	10.25
E-GEOD-93593	yes	9.93
E-HCAD-5	no	2.35

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

61 targeting JAM3, 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-3163	100.00	77.23	8605
HSA-MIR-340-5P	100.00	72.50	4437
HSA-MIR-6740-5P	100.00	65.64	932
HSA-MIR-4713-3P	100.00	65.92	505
HSA-MIR-4282	99.99	75.36	6408
HSA-MIR-548P	99.98	72.25	3784
HSA-MIR-302C-5P	99.97	72.56	3642
HSA-MIR-495-3P	99.96	72.81	4197
HSA-MIR-205-3P	99.92	69.92	3165
HSA-MIR-7-1-3P	99.91	71.53	4384
HSA-MIR-7-2-3P	99.91	71.40	4394
HSA-MIR-1305	99.91	71.43	3443
HSA-MIR-3140-3P	99.88	68.47	2069
HSA-MIR-5582-3P	99.86	72.48	4221
HSA-MIR-4698	99.84	71.41	4303
HSA-MIR-3121-3P	99.82	71.96	3630
HSA-MIR-4659A-3P	99.80	72.62	4248
HSA-MIR-4659B-3P	99.80	72.62	4248
HSA-MIR-4699-3P	99.71	70.15	3142
HSA-MIR-6762-3P	99.66	66.94	1188
HSA-MIR-6836-5P	99.60	65.62	1538
HSA-MIR-3942-3P	99.57	69.03	2854
HSA-MIR-1252-3P	99.55	67.71	2862
HSA-MIR-4761-5P	99.51	66.69	804
HSA-MIR-582-5P	99.47	70.79	2635
HSA-MIR-4728-3P	99.47	68.94	981
HSA-MIR-3915	99.45	68.49	1905
HSA-MIR-208A-5P	99.42	70.83	1913
HSA-MIR-208B-5P	99.42	70.83	1952
HSA-MIR-6839-3P	99.39	68.86	1301

Functional genomics

ClinGen dosage: haploinsufficiency 30 (autosomal recessive), triplosensitivity 0 (no evidence). ClinGen Gene Dosage Map

Literature-anchored findings (GeneRIF, showing 40)

• Cloning of human junctional adhesion molecule 3 (JAM3) and its identification as the JAM2 counter-receptor. (PMID:11590146)
• molecular cloning & role as VE-JAM/JAM 2 receptor (PMID:11823489)
• JAM3 is a strong candidate gene for hypoplastic left heart syndrome (PMID:11944976)
• Facilitates JAM2 interaction with alpha4beta1 (PMID:12070135)
• Functions as a facilitator for JAM2/alpha4beta1 interactions (PMID:12070135)
• The junctional adhesion molecule 3 (JAM-3) on human platelets is a counterreceptor for the leukocyte integrin Mac-1. (PMID:12208882)
• JAM-C(3) MAY play a role in desmosomal structure/function. (PMID:15194813)
• JAM-C participates in neutrophil transmigration and thereby provides a novel molecular target for antagonizing interactions between vascular cells that promote inflammatory vascular pathologies (PMID:15485832)
• Junctional adhesion molecule-C participates in the later steps of the leukoendothelial adhesion and transmigration cascade in an acute pulmonary inflammation model using transgenic mouse tissue overexpressing JAM-C. (PMID:15879142)
• the homophilic interaction of JAM-C can mediate tumor cell-endothelial cell interactions and may have a role in tumor cell metastasis (PMID:16118203)
• JAM-C is up-regulated by oxLDL and may thereby contribute to increased inflammatory cell recruitment during atherosclerosis (PMID:16195363)
• These studies suggest a function for coxsackievirus and adenovirus receptor (CAR) in male fertility. (PMID:16410001)
• JAM-C is an integral component of the dermal fibroblast adherens-like junction, and co-localizes with ZO-1. (PMID:16916751)
• Helps to regulate vascular permeability and pathologic angiogenesis through modulation of vascular endothelium (VE) contractility and VE-cadherin-mediated adhesion. (PMID:17116731)
• the expression of JAM-C promotes metastasis by enhancing both the adhesion of cancer cells to extracellular matrices and the subsequent invasion (PMID:17227766)
• expression of JAM-C in different B-cell lymphomas reveals a disease-specific pattern and allows a clear distinction between JAM-C-lymphoproliferative syndromes and JAM-C+ ones (PMID:17429428)
• The results of these studies suggest a role for JAM-C in the pathogenesis of arthritis. (PMID:17612407)
• blockade of JAM-B/-C interaction reduced monocyte numbers in the extravascular compartment through increased reverse transmigration rather than by reduced transmigration (PMID:17625065)
• Examine JAM-3 expression in normal/inflammed lymphatic endothelium. (PMID:17822725)
• study shows JAM-C was expressed in human sural nerves with an expression profile similar to that seen in mice (PMID:18048693)
• JAM-C *junctional adhesion molecule C) mediates recruiting and retaining leukocytes in the Rheumatoid arthritis synovium (PMID:18821692)
• JAM-C expression is variable in different epithelial cell lines with co-localization at tight junctions. (PMID:19143587)
• JAM-C gene expression is transcriptionally induced during activation of T lymphocytes via a calcineurin-dependent signaling pathway. (PMID:19204148)
• The regulation of EC junctional integrity involves the coordinated and dynamic modification of localization and activity of junctional stabilizers such as the integrin beta(3) and the destabilizer, JAM-C. (PMID:19461049)
• Letter: investigated platelet JAM-C following platelet activation by several agonists. (PMID:20135068)
• Soluble JAM-C mediates facets of angiogenesis in vitro and contributes the angiogenic potential of rheumatoid arthritis synovial fluid. (PMID:20592283)
• Our results suggest that JAM3 is essential for maintaining the integrity of the cerebrovascular endothelium as well as for normal lens development in humans (PMID:21109224)
• JAM-C expression was identified in human and murine melanoma cell lines, in human malignant melanoma, as well as in metastatic melanoma including melanoma lung metastasis (PMID:21593193)
• Data suggest that the four-gene methylation panel might provide an alternative triage test after primary high-risk papillomavirus (hr-HPV) testing. (PMID:21796628)
• In the present study, we investigated the role of JAM-C in homing of human B cells, using a xenogeneic nonobese diabetic/severe combined immunodeficient mouse model. (PMID:23221386)
• Our study confirms the importance of JAM3 as a component of the junctional complexes and its deficiency leading to a distinctive and catastrophic neonatal presentation of cataracts and hemorrhagic destruction of the brain. (PMID:23255084)
• These data brought new evidences for the role of JAM2 and JAM3 in progression of gastric adenocarcinoma (PMID:23277282)
• These findings provide evidence for a role for endothelial cell JAM-C in tumor growth and aggressiveness as well as recruitment of pericytes to newly formed blood vessels in a model of ovarian cancer. (PMID:23825230)
• Function of Jam-B/Jam-C interaction in homing and mobilization of human and mouse hematopoietic stem and progenitor cells. (PMID:24357068)
• indicate that JAM-C may be a therapeutic target for preventing and treating lymphatic metastases (PMID:24584816)
• JAM-C inactivation in endothelial cells resulted in increased spreading on fibronectin and enhanced sprouting in vitro in a manner dependent on beta1-integrin and on the activation of the small GTPase RAP1. (PMID:26311310)
• Suggest JAM3-M4 methylation as a biomarker for diagnosis of preneoplastic and neoplastic lesions of the cervix. (PMID:26517242)
• Study provides evidence that JAM-C downregulation may contribute to acute pancreatitis-associated lung injury via reverse transendothelial migration of neutrophils. (PMID:26841848)
• The role of JAM-C in the engraftment of human lymphoma B cells in mice was investigated. The binding of anti-JAM-C antibodies inhibited the phosphorylation of ERK1/2, without affecting other signaling pathways, identifying for the first time the intracellular MAPK cascade as the JAM-C-driven signaling pathway in JAM-C(+) B cells. (PMID:27256571)
• blocking JAM-C can reduce the number of atherogenic monocytes/macrophages in plaques by emigration. (PMID:27442505)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
danio_rerio	jam3b	ENSDARG00000061794
danio_rerio	jam3a	ENSDARG00000114589
mus_musculus	Jam3	ENSMUSG00000031990
rattus_norvegicus	Jam3	ENSRNOG00000009149

Paralogs (14): VSIG2 (ENSG00000019102), VSIG1 (ENSG00000101842), VSIR (ENSG00000107738), GPA33 (ENSG00000143167), IGSF11 (ENSG00000144847), ESAM (ENSG00000149564), CXADR (ENSG00000154639), JAM2 (ENSG00000154721), F11R (ENSG00000158769), MXRA8 (ENSG00000162576), CLMP (ENSG00000166250), MUC15 (ENSG00000169550), VSTM2B (ENSG00000187135), VSIG8 (ENSG00000243284)

Protein

Protein identifiers

Junctional adhesion molecule C — Q9BX67 (reviewed: Q9BX67)

Alternative names: JAM-2, Junctional adhesion molecule 3

All UniProt accessions (3): Q9BX67, H0YCW9, H0YD98

UniProt curated annotations — full annotation on UniProt →

Function. Junctional adhesion protein that mediates heterotypic cell-cell interactions with its cognate receptor JAM2 to regulate different cellular processes. Plays a role in homing and mobilization of hematopoietic stem and progenitor cells within the bone marrow. At the surface of bone marrow stromal cells, it contributes to the retention of the hematopoietic stem and progenitor cells expressing JAM3. Plays a central role in leukocytes extravasation by facilitating transmigration through the endothelium. Plays a role in spermatogenesis where JAM2 and JAM3, which are respectively expressed by Sertoli and germ cells, mediate an interaction between both cell types and play an essential role in the anchorage of germ cells onto Sertoli cells and the assembly of cell polarity complexes during spermatid differentiation. Also functions as a counter-receptor for ITGAM, mediating leukocyte-platelet interactions and is involved in the regulation of transepithelial migration of polymorphonuclear neutrophils (PMN). Plays a role in angiogenesis. Plays a role in the regulation of cell migration. During myogenesis, it is involved in myocyte fusion. Promotes chemotaxis of vascular endothelial cells and stimulates angiogenesis.

Subunit / interactions. Interacts with ITGAM. Interacts with GORASP2.

Subcellular location. Cell membrane. Cell junction. Desmosome. Tight junction Secreted.

Tissue specificity. Detected on round and elongated spermatids (at protein level). Highest expression in placenta, brain and kidney. Significant expression is detected on platelets. Expressed in intestinal mucosa cells. Expressed in the vascular endothelium. Found in serum (at protein level). Also detected in the synovial fluid of patients with rheumatoid arthritis, psoriatic arthritis or ostearthritis (at protein level).

Post-translational modifications. Proteolytically cleaved from endothelial cells surface into a soluble form by ADAM10 and ADAM17; the release of soluble JAM3 is increased by pro-inflammatory factors. S-palmitoylated by ZDHHC7. S-palmitoylation promotes expression at tight junctions.

Disease relevance. Hemorrhagic destruction of the brain with subependymal calcification and cataracts (HDBSCC) [MIM:613730] A syndrome characterized by congenital cataracts and severe brain abnormalities apparently resulting from hemorrhagic destruction of the brain parenchyma, including the cerebral white matter and basal ganglia. Patients manifest profound developmental delay, and other neurologic features included seizures, spasticity, and hyperreflexia. The clinical course is very severe resulting in death in infancy. Brain imaging shows multifocal intraparenchymal hemorrhage with associated liquefaction and massive cystic degeneration, and calcification in the subependymal region and in brain tissue. The disease is caused by variants affecting the gene represented in this entry.

Domain organisation. The Ig-like V-type domain mediates interaction with JAM2.

Similarity. Belongs to the immunoglobulin superfamily.

Isoforms (2)

UniProt ID	Names	Canonical?
Q9BX67-1	1	yes
Q9BX67-2	2

RefSeq proteins (2): NP_001192258, NP_116190* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR003598	Ig_sub2	Domain
IPR003599	Ig_sub	Domain
IPR007110	Ig-like_dom	Domain
IPR013106	Ig_V-set	Domain
IPR013783	Ig-like_fold	Homologous_superfamily
IPR036179	Ig-like_dom_sf	Homologous_superfamily
IPR042974	JAM-C	Family

Pfam: PF07686, PF13927

UniProt features (20 total): chain 2, glycosylation site 2, disulfide bond 2, sequence variant 2, mutagenesis site 2, topological domain 2, domain 2, lipid moiety-binding region 2, signal peptide 1, splice variant 1, sequence conflict 1, transmembrane region 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9BX67-F1	84.67	0.70

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 (2): 264, 265

Disulfide bonds (2): 53–115, 160–219

Glycosylation sites (2): 104, 192

Mutagenesis-validated functional residues (2):

Position	Phenotype
264	decreased palmitoylation. abolishes palmitoylation; when associated with s-265.
265	decreased palmitoylation. abolishes palmitoylation; when associated with s-264.

Function

Pathways and Gene Ontology

Reactome pathways

4 pathways

ID	Pathway
R-HSA-202733	Cell surface interactions at the vascular wall
R-HSA-216083	Integrin cell surface interactions
R-HSA-109582	Hemostasis
R-HSA-1474244	Extracellular matrix organization

MSigDB gene sets: 326 (showing top): GOBP_APICAL_PROTEIN_LOCALIZATION, GOBP_NEGATIVE_REGULATION_OF_PROTEIN_CONTAINING_COMPLEX_ASSEMBLY, GOBP_HEMATOPOIETIC_PROGENITOR_CELL_DIFFERENTIATION, TONKS_TARGETS_OF_RUNX1_RUNX1T1_FUSION_MONOCYTE_UP, RRAGTTGT_UNKNOWN, GOBP_MYELOID_CELL_HOMEOSTASIS, GOBP_ESTABLISHMENT_OR_MAINTENANCE_OF_CELL_POLARITY, GOBP_MYELOID_LEUKOCYTE_MIGRATION, GOBP_CELL_CHEMOTAXIS, GOBP_INFLAMMATORY_RESPONSE, GOBP_POSITIVE_REGULATION_OF_CELLULAR_EXTRAVASATION, ASTON_MAJOR_DEPRESSIVE_DISORDER_DN, KEGG_TIGHT_JUNCTION, GOBP_MALE_GAMETE_GENERATION, GOBP_REGULATION_OF_CELLULAR_COMPONENT_BIOGENESIS

GO Biological Process (31): angiogenesis (GO:0001525), neutrophil homeostasis (GO:0001780), adaptive immune response (GO:0002250), myeloid progenitor cell differentiation (GO:0002318), leukocyte migration involved in inflammatory response (GO:0002523), cell-matrix adhesion (GO:0007160), spermatid development (GO:0007286), cell migration (GO:0016477), transmission of nerve impulse (GO:0019226), establishment of cell polarity (GO:0030010), negative regulation of integrin activation (GO:0033624), negative regulation of cell adhesion mediated by integrin (GO:0033629), heterotypic cell-cell adhesion (GO:0034113), adherens junction assembly (GO:0034333), protein localization to cell surface (GO:0034394), maintenance of blood-brain barrier (GO:0035633), myelination (GO:0042552), apical protein localization (GO:0045176), regulation of neutrophil chemotaxis (GO:0090022), regulation of actin cytoskeleton organization by cell-cell adhesion (GO:0090138), hematopoietic stem cell migration to bone marrow (GO:0097241), granulocyte migration (GO:0097530), cell-cell adhesion (GO:0098609), protein localization to cell junction (GO:1902414), positive regulation of membrane permeability (GO:1905710), positive regulation of monocyte extravasation (GO:2000439), cell adhesion (GO:0007155), spermatogenesis (GO:0007283), cell differentiation (GO:0030154), system development (GO:0048731), leukocyte migration (GO:0050900)

GO Molecular Function (6): integrin binding (GO:0005178), protein homodimerization activity (GO:0042803), protein heterodimerization activity (GO:0046982), cell-cell adhesion mediator activity (GO:0098632), protein binding (GO:0005515), identical protein binding (GO:0042802)

GO Cellular Component (16): obsolete extracellular space (GO:0005615), Golgi apparatus (GO:0005794), plasma membrane (GO:0005886), microvillus (GO:0005902), cell-cell junction (GO:0005911), bicellular tight junction (GO:0005923), desmosome (GO:0030057), filamentous actin (GO:0031941), paranodal junction (GO:0033010), Schmidt-Lanterman incisure (GO:0043220), cell-cell contact zone (GO:0044291), tight junction (GO:0070160), protein complex involved in cell adhesion (GO:0098636), extracellular region (GO:0005576), membrane (GO:0016020), anchoring junction (GO:0070161)

Reactome top-level categories

Rollup of top-2 pathways:

Category	Pathways
Hemostasis	1
Extracellular matrix organization	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cell-cell junction	4
cell-cell adhesion	3
cellular anatomical structure	3
intracellular protein localization	2
protein dimerization activity	2
protein-containing complex	2
blood vessel morphogenesis	1
anatomical structure formation involved in morphogenesis	1
leukocyte homeostasis	1
myeloid cell homeostasis	1
immune response	1
hematopoietic progenitor cell differentiation	1
inflammatory response	1
leukocyte migration	1
cell-substrate adhesion	1
germ cell development	1
spermatid differentiation	1
cell motility	1
action potential	1
cell communication	1
chemical synaptic transmission	1
nervous system process	1
establishment or maintenance of cell polarity	1
negative regulation of protein-containing complex assembly	1
integrin activation	1
regulation of integrin activation	1
negative regulation of cell adhesion	1
cell adhesion mediated by integrin	1
regulation of cell adhesion mediated by integrin	1
cell-cell junction assembly	1
adherens junction organization	1
tissue homeostasis	1
axon ensheathment	1
neutrophil chemotaxis	1
regulation of granulocyte chemotaxis	1
regulation of neutrophil migration	1
actin cytoskeleton organization	1
regulation of actin cytoskeleton organization	1
signaling receptor binding	1
protein-containing complex binding	1

Protein interactions and networks

STRING

1036 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
JAM3	ITGB2	P05107	983
JAM3	TJP1	Q07157	967
JAM3	ITGAM	P11215	940
JAM3	JAM2	P57087	854
JAM3	PATJ	Q8NI35	812
JAM3	OCLN	Q16625	731
JAM3	F11R	Q9Y624	697
JAM3	IGSF5	Q9NSI5	692
JAM3	ITGA4	P13612	679
JAM3	TJP3	O95049	652
JAM3	ITGA5	P08648	647
JAM3	ICAM2	P13598	646
JAM3	VCAM1	P19320	639
JAM3	PARD3	Q8TEW0	629
JAM3	ICAM1	P05362	625

IntAct

155 interactions, top by confidence:

A	B	Type	Score
CFTR	ESYT2	psi-mi:“MI:2364”(proximity)	0.710
JAM2	JAM3	psi-mi:“MI:0915”(physical association)	0.710
JAM3	JAM2	psi-mi:“MI:0915”(physical association)	0.710
JAM3	JAM2	psi-mi:“MI:0407”(direct interaction)	0.710
JAM3	JAM3	psi-mi:“MI:0915”(physical association)	0.610
JAM3	JAM3	psi-mi:“MI:0407”(direct interaction)	0.610
JAM3	PARD3	psi-mi:“MI:0407”(direct interaction)	0.610
JAM3	PARD3	psi-mi:“MI:0915”(physical association)	0.610
JAM3	PICK1	psi-mi:“MI:0407”(direct interaction)	0.590
MEOX2	JAM3	psi-mi:“MI:0915”(physical association)	0.560
PICK1	ILVBL	psi-mi:“MI:0914”(association)	0.530
NRAS	ESYT2	psi-mi:“MI:2364”(proximity)	0.480
JAM3	GORASP2	psi-mi:“MI:0407”(direct interaction)	0.440
JAM3	PARD3B	psi-mi:“MI:0407”(direct interaction)	0.440
JAM3	PDZD7	psi-mi:“MI:0407”(direct interaction)	0.440
JAM3	GORASP1	psi-mi:“MI:0407”(direct interaction)	0.440
JAM3	HTRA1	psi-mi:“MI:0407”(direct interaction)	0.440
JAM3	PATJ	psi-mi:“MI:0407”(direct interaction)	0.440
JAM3	DLG3	psi-mi:“MI:0407”(direct interaction)	0.440
JAM3	LNX2	psi-mi:“MI:0407”(direct interaction)	0.440
JAM3	GRIP2	psi-mi:“MI:0407”(direct interaction)	0.440
JAM3	TIAM2	psi-mi:“MI:0407”(direct interaction)	0.440
JAM3	RADIL	psi-mi:“MI:0407”(direct interaction)	0.440
JAM3	LIN7C	psi-mi:“MI:0407”(direct interaction)	0.440
APBA3	JAM3	psi-mi:“MI:0407”(direct interaction)	0.440
JAM3	SNX27	psi-mi:“MI:0407”(direct interaction)	0.440

BioGRID (49): JAM3 (Reconstituted Complex), JAM3 (Affinity Capture-MS), JAM3 (Proximity Label-MS), JAM3 (Reconstituted Complex), PARD3 (Affinity Capture-Western), JAM3 (Reconstituted Complex), JAM3 (Proximity Label-MS), JAM3 (Proximity Label-MS), JAM3 (Proximity Label-MS), JAM3 (Affinity Capture-RNA), JAM3 (Two-hybrid), JAM3 (Affinity Capture-MS), JAM3 (Proximity Label-MS), JAM3 (Proximity Label-MS), JAM3 (Proximity Label-MS)

ESM2 similar proteins: A0A8M2B818, A3KPA0, A5D7C3, B0JYH6, O35112, O46634, O46651, O88792, P17790, P18461, P18572, P21802, P21803, P26453, P35613, P42292, P57087, P78310, P97792, Q01638, Q13740, Q15198, Q1WIM2, Q2PFX1, Q2WGK2, Q3V3F6, Q5R764, Q5RJP7, Q61490, Q66KX2, Q68FQ2, Q6DJ83, Q6PE55, Q6UWV2, Q7ZXX1, Q8BLQ9, Q8N3J6, Q8WMV3, Q90Y50, Q99795

Diamond homologs: A0A087WV53, A1KZ92, A2AJ76, A4IFW2, A4IGL7, A6NDA9, B0BNK7, B0V2N1, D2HFT7, D3YXG0, D4A1J9, D4ABX8, F1NWE3, G5EG78, O15146, O73775, O75325, O94898, P07722, P15364, P20916, P20917, P23468, P43146, P48960, P53813, P70193, P70211, Q03142, Q08761, Q08879, Q13332, Q13449, Q1ENI8, Q1RMS4, Q1WIM1, Q21038, Q24372, Q26474, Q2Q421

SIGNOR signaling

0 interactions.

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 104 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
Ras activation upon Ca2+ influx through NMDA receptor	8	64.3×	7e-11
Unblocking of NMDA receptors, glutamate binding and activation	5	38.3×	1e-05
Negative regulation of NMDA receptor-mediated neuronal transmission	5	38.3×	1e-05
Long-term potentiation	5	33.5×	1e-05
Assembly and cell surface presentation of NMDA receptors	9	32.2×	8e-10
Neurexins and neuroligins	10	27.7×	4e-10
Protein-protein interactions at synapses	6	22.4×	1e-05
RND3 GTPase cycle	5	18.3×	1e-04

GO biological processes:

GO term	Partners	Fold	FDR
establishment or maintenance of epithelial cell apical/basal polarity	11	64.6×	4e-15
protein localization to synapse	6	46.4×	5e-07
receptor clustering	7	44.1×	6e-08
regulation of postsynaptic membrane neurotransmitter receptor levels	7	35.0×	2e-07
cell-cell adhesion	11	11.3×	5e-07
Ras protein signal transduction	5	10.4×	5e-03
protein-containing complex assembly	9	10.3×	2e-05
chemical synaptic transmission	8	6.2×	2e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	11
Likely pathogenic	5
Uncertain significance	98
Likely benign	83
Benign	36

Top pathogenic / likely-pathogenic (16)

Variant ID	HGVS	Classification
1415485	NM_032801.5(JAM3):c.745del (p.Val249fs)	Pathogenic
1457137	NM_032801.5(JAM3):c.745dup (p.Val249fs)	Pathogenic
1701178	NM_032801.5(JAM3):c.358C>T (p.Arg120Ter)	Pathogenic
2124726	NM_032801.5(JAM3):c.572dup (p.Asn192fs)	Pathogenic
30607	NM_032801.5(JAM3):c.612+1G>T	Pathogenic
41881	NM_032801.5(JAM3):c.656G>A (p.Cys219Tyr)	Pathogenic
41882	NM_032801.5(JAM3):c.346G>A (p.Glu116Lys)	Pathogenic
41883	NM_032801.5(JAM3):c.2T>G (p.Met1Arg)	Pathogenic
827781	NM_032801.5(JAM3):c.1A>G (p.Met1Val)	Pathogenic
872565	NM_032801.5(JAM3):c.230_231del (p.Tyr77fs)	Pathogenic
995567	NM_032801.5(JAM3):c.410-1G>A	Pathogenic
2574152	NM_032801.5(JAM3):c.690T>G (p.Cys230Trp)	Likely pathogenic
2664218	NM_032801.5(JAM3):c.231del (p.Thr76_Tyr77insTer)	Likely pathogenic
4277822	NM_032801.5(JAM3):c.406C>T (p.Gln136Ter)	Likely pathogenic
931312	NM_032801.5(JAM3):c.2T>A (p.Met1Lys)	Likely pathogenic
993262	NM_032801.5(JAM3):c.256+1260G>C	Likely pathogenic

SpliceAI

1918 predictions. Top by Δscore:

Variant	Effect	Δscore
11:134069157:GGG:G	donor_gain	1.0000
11:134069158:GGG:G	donor_gain	1.0000
11:134139846:TTCA:T	acceptor_loss	1.0000
11:134139847:TCA:T	acceptor_loss	1.0000
11:134139848:CA:C	acceptor_loss	1.0000
11:134139849:A:AG	acceptor_gain	1.0000
11:134139849:AGG:A	acceptor_loss	1.0000
11:134139850:G:GG	acceptor_gain	1.0000
11:134139850:G:T	acceptor_loss	1.0000
11:134139917:G:GG	donor_gain	1.0000
11:134140742:A:G	donor_gain	1.0000
11:134140769:GG:G	donor_gain	1.0000
11:134140770:GG:G	donor_gain	1.0000
11:134144236:TGTAG:T	acceptor_loss	1.0000
11:134144237:GTAGG:G	acceptor_loss	1.0000
11:134144239:A:AG	acceptor_gain	1.0000
11:134144240:G:GA	acceptor_loss	1.0000
11:134144240:G:GG	acceptor_gain	1.0000
11:134144240:GGA:G	acceptor_gain	1.0000
11:134144393:G:GT	donor_loss	1.0000
11:134144395:T:A	donor_loss	1.0000
11:134146039:G:GT	donor_gain	1.0000
11:134146042:GTCT:G	donor_gain	1.0000
11:134146046:G:GG	donor_gain	1.0000
11:134146085:G:GT	donor_gain	1.0000
11:134146085:G:T	donor_gain	1.0000
11:134148666:G:GT	donor_gain	1.0000
11:134148673:AAAG:A	donor_loss	1.0000
11:134148674:AAGGT:A	donor_loss	1.0000
11:134148675:AGGTG:A	donor_loss	1.0000

AlphaMissense

2018 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
11:134140713:T:A	W67R	1.000
11:134140713:T:C	W67R	1.000
11:134140715:G:C	W67C	1.000
11:134140715:G:T	W67C	1.000
11:134144899:T:A	W173R	1.000
11:134144899:T:C	W173R	1.000
11:134144901:G:C	W173C	1.000
11:134144901:G:T	W173C	1.000
11:134140666:T:C	L51P	0.999
11:134140671:T:C	C53R	0.999
11:134140672:G:A	C53Y	0.999
11:134140714:G:C	W67S	0.999
11:134144283:T:C	L100P	0.999
11:134144321:T:G	Y113D	0.999
11:134144327:T:A	C115S	0.999
11:134144327:T:C	C115R	0.999
11:134144328:G:A	C115Y	0.999
11:134144328:G:C	C115S	0.999
11:134144329:T:G	C115W	0.999
11:134144860:T:A	C160S	0.999
11:134144860:T:C	C160R	0.999
11:134144861:G:A	C160Y	0.999
11:134144861:G:C	C160S	0.999
11:134144862:C:G	C160W	0.999
11:134145982:T:G	Y217D	0.999
11:134145988:T:A	C219S	0.999
11:134145988:T:C	C219R	0.999
11:134145989:G:A	C219Y	0.999
11:134145989:G:C	C219S	0.999
11:134145990:C:G	C219W	0.999

dbSNP variants (sampled 300 via entrez): RS1000001980 (11:134078282 G>A,T), RS1000025869 (11:134141010 G>A,T), RS1000042481 (11:134152110 G>A,C), RS1000061182 (11:134120323 C>T), RS1000103412 (11:134147804 T>C), RS1000117499 (11:134145943 C>T), RS1000129918 (11:134094489 G>C), RS1000141026 (11:134082734 G>A), RS1000162874 (11:134114701 A>C,G), RS1000243143 (11:134094958 C>T), RS1000252854 (11:134077369 T>C), RS1000254044 (11:134100165 C>T), RS1000255123 (11:134072359 G>A,T), RS1000288625 (11:134139425 C>G), RS1000293553 (11:134118933 ATCTG>A)

Disease associations

OMIM: gene MIM:606871 | disease phenotypes: MIM:613730, MIM:181500

GenCC curated gene-disease

Disease	Classification	Inheritance
porencephaly-microcephaly-bilateral congenital cataract syndrome	Strong	Autosomal recessive

Mondo (2): porencephaly-microcephaly-bilateral congenital cataract syndrome (MONDO:0013394), schizophrenia (MONDO:0005090)

Orphanet (2): Porencephaly-microcephaly-bilateral congenital cataract syndrome (Orphanet:306547), NON RARE IN EUROPE: Schizophrenia (Orphanet:3140)

HPO phenotypes

19 total (20 of 19 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000028	Cryptorchidism
HP:0000086	Ectopic kidney
HP:0000518	Cataract
HP:0000543	Optic disc pallor
HP:0000568	Microphthalmia
HP:0000800	Cystic renal dysplasia
HP:0001250	Seizure
HP:0001257	Spasticity
HP:0001263	Global developmental delay
HP:0001321	Cerebellar hypoplasia
HP:0001347	Hyperreflexia
HP:0001522	Death in infancy
HP:0001629	Ventricular septal defect
HP:0002119	Ventriculomegaly
HP:0002240	Hepatomegaly
HP:0003577	Congenital onset
HP:0003811	Neonatal death
HP:0005484	Secondary microcephaly
HP:0100753	Schizophrenia

GWAS associations

2 associations (top):

Study	Trait	p-value
GCST006585_236	Blood protein levels	4.000000e-14
GCST90002398_135	Neutrophil count	1.000000e-10

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0004833	neutrophil count

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
bisphenol A	affects cotreatment, increases methylation, increases expression	2
Benzo(a)pyrene	affects methylation, increases expression, increases methylation	2
Dexamethasone	increases expression, affects cotreatment, decreases expression	2
aristolochic acid I	decreases expression	1
FR900359	decreases phosphorylation	1
bisphenol F	decreases expression, affects cotreatment	1
triphenyl phosphate	affects expression	1
bis(tri-n-butyltin)oxide	increases expression	1
sodium arsenate	decreases expression, increases abundance	1
tributyltin	increases expression	1
terbufos	increases methylation	1
11-nor-delta(9)-tetrahydrocannabinol-9-carboxylic acid	affects methylation, increases abundance	1
cobaltous chloride	increases expression	1
perfluorooctanoic acid	decreases expression	1
ochratoxin A	increases expression	1
benzo(e)pyrene	increases methylation	1
methylmercury II	increases expression	1
di-n-butylphosphoric acid	affects expression	1
abrine	decreases expression	1
Fulvestrant	affects cotreatment, increases methylation	1
Gemcitabine	decreases expression	1
Arsenic	decreases expression, increases abundance	1
Benztropine	affects cotreatment, decreases expression	1
Cannabinoids	affects methylation, increases abundance	1
Cuprizone	affects cotreatment, decreases expression	1
Fonofos	increases methylation	1
Indomethacin	increases expression, decreases expression, affects cotreatment	1
Lead	affects expression	1
Methapyrilene	increases methylation	1
Ozone	increases 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_D8GY	Ubigene hCMEC/D3 JAM3 KO	Transformed cell line	Female

Clinical trials (associated diseases)

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

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