TSPAN2

Summary

TSPAN2 (tetraspanin 2, HGNC:20659) is a protein-coding gene on chromosome 1p13.2, encoding Tetraspanin-2 (O60636). May play a role in signalling in oligodendrocytes in the early stages of their terminal differentiation into myelin-forming glia and may also function in stabilizing the mature sheath.

The protein encoded by this gene is a member of the transmembrane 4 superfamily, also known as the tetraspanin family. Most of these members are cell-surface proteins that are characterized by the presence of four hydrophobic domains. The proteins mediate signal transduction events that play a role in the regulation of cell development, activation, growth and motility. Alternative splicing results in multiple transcript variants encoding different isoforms.

Source: NCBI Gene 10100 — RefSeq curated summary.

At a glance

• GWAS associations: 12
• Clinical variants (ClinVar): 46 total
• MANE Select transcript: NM_005725

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:20659
Approved symbol	TSPAN2
Name	tetraspanin 2
Location	1p13.2
Locus type	gene with protein product
Status	Approved
Aliases	TSPAN-2, TSN2, FLJ12082
Ensembl gene	ENSG00000134198
Ensembl biotype	protein_coding
OMIM	613133
Entrez	10100

Gene structure

Transcript identifiers

Ensembl transcripts: 13 — 12 protein_coding, 1 protein_coding_CDS_not_defined

ENST00000369515, ENST00000369516, ENST00000433172, ENST00000491992, ENST00000894821, ENST00000894822, ENST00000926199, ENST00000926200, ENST00000926201, ENST00000926202, ENST00000926203, ENST00000966808, ENST00000966809

RefSeq mRNA: 3 — MANE Select: NM_005725 NM_001308315, NM_001308316, NM_005725

CCDS: CCDS76193, CCDS881

Canonical transcript exons

ENST00000369516 — 8 exons

Exon	Start	End
ENSE00000800132	115062135	115062232
ENSE00000957978	115072905	115073007
ENSE00001020901	115060464	115060538
ENSE00001020902	115058883	115058981
ENSE00001124058	115048011	115050555
ENSE00001817381	115089364	115089503
ENSE00003634510	115053379	115053462
ENSE00003657578	115057537	115057608

Expression profiles

Bgee: expression breadth ubiquitous, 228 present calls, max score 93.54.

FANTOM5 (CAGE): breadth broad, TPM avg 3.5996 / max 225.7713, expressed in 804 samples.

FANTOM5 promoters (1 alternative TSS)

Promoter ID	TPM avg	Samples expressed
13975	3.5996	804

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
body of uterus	UBERON:0009853	93.54	gold quality
muscle layer of sigmoid colon	UBERON:0035805	93.19	gold quality
popliteal artery	UBERON:0002250	93.08	gold quality
tibial artery	UBERON:0007610	93.07	gold quality
aorta	UBERON:0000947	92.15	gold quality
right coronary artery	UBERON:0001625	92.09	gold quality
cauda epididymis	UBERON:0004360	91.84	gold quality
descending thoracic aorta	UBERON:0002345	91.71	gold quality
esophagogastric junction muscularis propria	UBERON:0035841	91.01	gold quality
thoracic aorta	UBERON:0001515	90.95	gold quality
ascending aorta	UBERON:0001496	90.90	gold quality
islet of Langerhans	UBERON:0000006	90.88	gold quality
lower esophagus muscularis layer	UBERON:0035833	90.61	gold quality
lower esophagus	UBERON:0013473	90.54	gold quality
mucosa of stomach	UBERON:0001199	90.41	gold quality
myometrium	UBERON:0001296	89.32	gold quality
calcaneal tendon	UBERON:0003701	88.71	gold quality
smooth muscle tissue	UBERON:0001135	88.57	gold quality
left uterine tube	UBERON:0001303	88.05	gold quality
cortical plate	UBERON:0005343	87.99	gold quality
left coronary artery	UBERON:0001626	87.76	gold quality
sigmoid colon	UBERON:0001159	87.54	gold quality
saphenous vein	UBERON:0007318	87.10	gold quality
coronary artery	UBERON:0001621	86.92	gold quality
colonic epithelium	UBERON:0000397	86.78	gold quality
bone marrow	UBERON:0002371	86.67	gold quality
blood	UBERON:0000178	86.09	gold quality
seminal vesicle	UBERON:0000998	85.89	gold quality
trabecular bone tissue	UBERON:0002483	85.60	gold quality
urinary bladder	UBERON:0001255	84.59	gold quality

Single-cell (SCXA)

Detected in 3 experiment(s), a significant marker in 2.

Experiment	Marker?	Max mean expression
E-MTAB-9801	yes	8.34
E-ANND-3	yes	3.24
E-CURD-112	no	2.85

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

208 targeting TSPAN2, 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-190A-3P	100.00	80.35	5520
HSA-MIR-5011-5P	100.00	83.46	5820
HSA-MIR-3924	100.00	72.09	2394
HSA-MIR-8485	100.00	77.57	4731
HSA-MIR-6867-5P	100.00	82.21	3464
HSA-MIR-4692	100.00	67.32	2066
HSA-MIR-188-3P	100.00	68.76	1240
HSA-MIR-4682	100.00	68.89	1258
HSA-MIR-3163	100.00	77.23	8605
HSA-MIR-30A-5P	100.00	76.31	3233
HSA-MIR-30B-5P	100.00	76.29	3248
HSA-MIR-30C-5P	100.00	76.29	3248
HSA-MIR-30D-5P	100.00	76.32	3233
HSA-MIR-30E-5P	100.00	76.32	3242
HSA-MIR-656-3P	100.00	72.15	2788
HSA-MIR-6740-5P	100.00	65.64	932
HSA-MIR-340-5P	100.00	72.50	4437
HSA-MIR-4668-3P	100.00	68.74	2635
HSA-MIR-3646	100.00	73.56	5283
HSA-MIR-4282	99.99	75.36	6408
HSA-MIR-548C-3P	99.99	74.01	7587
HSA-MIR-4514	99.99	67.10	1870
HSA-MIR-371B-5P	99.99	75.34	4759
HSA-MIR-3662	99.99	73.82	5684
HSA-MIR-4531	99.99	69.70	3181
HSA-MIR-511-3P	99.99	68.85	1467
HSA-MIR-4775	99.98	75.00	6394
HSA-MIR-616-5P	99.98	75.58	4775
HSA-MIR-373-5P	99.98	75.36	4753
HSA-MIR-12136	99.98	72.81	5713

Literature-anchored findings (GeneRIF, showing 7)

• the C-allele of rs2078371 near TSPAN-2 also reached genome-wide significance for association with migraine. (PMID:23294458)
• TSPAN2 is identified as a factor responsible for invasion, motility, and metastasis. (PMID:24726368)
• A novel locus (G allele at rs12122341) at 1p13.2 near TSPAN2 that was associated with large artery atherosclerosis-related stroke. (PMID:26708676)
• TSPAN2 may promote apoptosis of RNAKT-15 cells by regulating the JNK/beta-catenin pathway in response to high glucose concentrations. Targeting TSPAN2 could be a potential therapeutic strategy to treat glucose toxicity-induced beta-cell failure. (PMID:27247127)
• Studies suggest that TSPAN2 may contribute to the early stages of the oligodendrocyte differentiation into myelin-forming glia. Furthermore, in human lung cancer, Tspan2 could be involved in the progression of the tumour metastasis by modulating cancer cell motility and invasion functions. [review] (PMID:28408487)
• the authors have identified TSPAN2 as a candidate gene for Blood Pressure Regulation that is regulated by heritable DNA methylation (PMID:29198723)
• Transmigration of Tetraspanin 2 (Tspan2) siRNA Via Microglia Derived Exosomes across the Blood Brain Barrier Modifies the Production of Immune Mediators by Microglia Cells. (PMID:31823250)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
danio_rerio	tspan2a	ENSDARG00000003754
danio_rerio	tspan2b	ENSDARG00000059202
mus_musculus	Tspan2	ENSMUSG00000027858
rattus_norvegicus	Tspan2	ENSRNOG00000082472

Paralogs (32): TSPAN6 (ENSG00000000003), CD9 (ENSG00000010278), TSPAN9 (ENSG00000011105), TSPAN17 (ENSG00000048140), TSPAN32 (ENSG00000064201), CD82 (ENSG00000085117), TSPAN15 (ENSG00000099282), CD37 (ENSG00000104894), UPK1A (ENSG00000105668), TSPAN12 (ENSG00000106025), TSPAN13 (ENSG00000106537), TSPAN14 (ENSG00000108219), CD81 (ENSG00000110651), TSPAN11 (ENSG00000110900), PRPH2 (ENSG00000112619), UPK1B (ENSG00000114638), TSPAN1 (ENSG00000117472), TSPAN8 (ENSG00000127324), TSPAN16 (ENSG00000130167), CD63 (ENSG00000135404), TSPAN31 (ENSG00000135452), TSPAN3 (ENSG00000140391), CD53 (ENSG00000143119), ROM1 (ENSG00000149489), TSPAN7 (ENSG00000156298), TSPAN18 (ENSG00000157570), TSPAN33 (ENSG00000158457), TSPAN5 (ENSG00000168785), CD151 (ENSG00000177697), TSPAN10 (ENSG00000182612), TSPAN4 (ENSG00000214063), TSPAN19 (ENSG00000231738)

Protein

Protein identifiers

Tetraspanin-2 — O60636 (reviewed: O60636)

Alternative names: Tetraspan NET-3

All UniProt accessions (3): B1AKP1, B1AKP2, O60636

UniProt curated annotations — full annotation on UniProt →

Function. May play a role in signalling in oligodendrocytes in the early stages of their terminal differentiation into myelin-forming glia and may also function in stabilizing the mature sheath.

Subcellular location. Membrane.

Similarity. Belongs to the tetraspanin (TM4SF) family.

Isoforms (2)

UniProt ID	Names	Canonical?
O60636-1	1	yes
O60636-2	2

RefSeq proteins (3): NP_001295244, NP_001295245, NP_005716* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000301	Tetraspanin_animals	Family
IPR008952	Tetraspanin_EC2_sf	Homologous_superfamily
IPR018499	Tetraspanin/Peripherin	Family
IPR018503	Tetraspanin_CS	Conserved_site

Pfam: PF00335

UniProt features (16 total): topological domain 5, transmembrane region 4, sequence conflict 3, chain 1, glycosylation site 1, splice variant 1, sequence variant 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-O60636-F1	87.26	0.52

Functional residue map

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

Glycosylation sites (1): 139

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 280 (showing top): GOBP_MYELOID_CELL_DIFFERENTIATION, GOBP_MYELOID_CELL_DEVELOPMENT, GOBP_INFLAMMATORY_RESPONSE, NKX25_02, ATACCTC_MIR202, AREB6_03, MORF_BRCA1, GRAESSMANN_APOPTOSIS_BY_DOXORUBICIN_DN, GRAESSMANN_RESPONSE_TO_MC_AND_DOXORUBICIN_DN, GOBP_GLIAL_CELL_DEVELOPMENT, GOBP_NEUROGENESIS, GOBP_MYELOID_LEUKOCYTE_DIFFERENTIATION, CHANDRAN_METASTASIS_DN, MORF_RAD51L3, SHEPARD_BMYB_MORPHOLINO_DN

GO Biological Process (6): inflammatory response (GO:0006954), astrocyte development (GO:0014002), microglia development (GO:0014005), myelination (GO:0042552), oligodendrocyte differentiation (GO:0048709), axon development (GO:0061564)

GO Molecular Function (1): protein binding (GO:0005515)

GO Cellular Component (4): nucleoplasm (GO:0005654), plasma membrane (GO:0005886), membrane (GO:0016020), myelin sheath (GO:0043209)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	3
glial cell development	2
defense response	1
astrocyte differentiation	1
microglia differentiation	1
myeloid cell development	1
axon ensheathment	1
central nervous system development	1
glial cell differentiation	1
neuron projection development	1
binding	1
nuclear lumen	1
membrane	1
cell periphery	1

Protein interactions and networks

STRING

862 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
TSPAN2	ITGB1	P05556	597
TSPAN2	TSPAN19	P0C672	540
TSPAN2	B4E171	B4E171	486
TSPAN2	ZFHX3	Q15911	484
TSPAN2	THBS2	P35442	481
TSPAN2	SUGCT	Q9HAC7	480
TSPAN2	TSPAN31	Q12999	476
TSPAN2	PHACTR1	Q9C0D0	475
TSPAN2	TMEM86A	Q8N2M4	457
TSPAN2	TSPAN32	Q96QS1	445
TSPAN2	ZER1	Q7Z7L7	420
TSPAN2	AJAP1	Q9UKB5	419
TSPAN2	PITX2	Q99697	418
TSPAN2	SPTSSA	Q969W0	414
TSPAN2	CD151	P48509	411
TSPAN2	ASTN2	O75129	411

IntAct

144 interactions, top by confidence:

A	B	Type	Score
GRB2	TSPAN2	psi-mi:“MI:0915”(physical association)	0.670
GRB2	TSPAN2	psi-mi:“MI:0407”(direct interaction)	0.670
TSPAN2	GRB2	psi-mi:“MI:0915”(physical association)	0.670
TSPAN2	PIK3R3	psi-mi:“MI:0915”(physical association)	0.590
PIK3R3	TSPAN2	psi-mi:“MI:0407”(direct interaction)	0.590
TSPAN2	CLEC14A	psi-mi:“MI:0915”(physical association)	0.560
TSPAN2	LEPROTL1	psi-mi:“MI:0915”(physical association)	0.560
TSPAN2	SCN3B	psi-mi:“MI:0915”(physical association)	0.560
TSPAN2	VSIR	psi-mi:“MI:0915”(physical association)	0.560
TSPAN2	IFNGR2	psi-mi:“MI:0915”(physical association)	0.560
TSPAN2	TMEM14B	psi-mi:“MI:0915”(physical association)	0.560
TSPAN2	ZFYVE27	psi-mi:“MI:0915”(physical association)	0.560
TSPAN2	SLC35C2	psi-mi:“MI:0915”(physical association)	0.560
TSPAN2	FKBP7	psi-mi:“MI:0915”(physical association)	0.560
TSPAN2	SLC10A6	psi-mi:“MI:0915”(physical association)	0.560
TSPAN2	MGST3	psi-mi:“MI:0915”(physical association)	0.560

BioGRID (88): TSPAN2 (Two-hybrid), TSPAN2 (Two-hybrid), GRB2 (Affinity Capture-Luminescence), TSPAN2 (Reconstituted Complex), TSPAN2 (Reconstituted Complex), GRB2 (Protein-peptide), PIK3R3 (Protein-peptide), CREB3 (Two-hybrid), SNX13 (Affinity Capture-MS), SNX14 (Affinity Capture-MS), PTGFRN (Affinity Capture-MS), ZDHHC6 (Affinity Capture-MS), TSPAN3 (Affinity Capture-MS), REEP6 (Affinity Capture-MS), TSPAN15 (Affinity Capture-MS)

ESM2 similar proteins: A0A8M2B5N2, A0A8V0ZLT4, A1L157, F7BWT7, O35566, O60636, O60637, O75841, O95858, P11049, P20274, P21926, P30413, P30932, P31053, P38573, P40239, P40240, P40241, P48509, P54825, P55344, P56563, P61170, P61171, Q1JQA4, Q2KHY8, Q3SZR9, Q3ZBH3, Q566D0, Q58CY8, Q5RE11, Q61470, Q6GQF5, Q6GR34, Q6IP19, Q6PBE5, Q6PFT6, Q7SZ07, Q80WR1

Diamond homologs: A0A8M2B5N2, A0A8V0ZLT4, B0BM39, B3VSC2, B5X3I6, O14817, O60635, O60636, O75954, P11049, P19397, P24485, P30932, P35762, P40240, P62079, P62080, Q06AA5, Q17QJ5, Q22495, Q2KHY8, Q2KIS9, Q3T0S3, Q4R7W6, Q4V8E0, Q568Y5, Q58CY8, Q58DM3, Q5R9S6, Q5RAP3, Q5RC27, Q61451, Q68VK5, Q6AYR9, Q6DCQ3, Q6GMK6, Q80WR1, Q8BJU2, Q8QZY6, Q8R3G9

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	32
Likely benign	1
Benign	2

Top pathogenic / likely-pathogenic (0)

SpliceAI

1475 predictions. Top by Δscore:

Variant	Effect	Δscore
1:115050554:ATC:A	acceptor_loss	1.0000
1:115050555:TC:T	acceptor_loss	1.0000
1:115050556:C:CA	acceptor_loss	1.0000
1:115050556:C:CC	acceptor_gain	1.0000
1:115050557:T:G	acceptor_loss	1.0000
1:115058874:GTTAC:G	donor_loss	1.0000
1:115058875:TTAC:T	donor_loss	1.0000
1:115058876:TAC:T	donor_loss	1.0000
1:115058877:ACT:A	donor_loss	1.0000
1:115058878:CTCA:C	donor_gain	1.0000
1:115058879:TCACT:T	donor_loss	1.0000
1:115058880:CACTG:C	donor_loss	1.0000
1:115058881:A:AC	donor_gain	1.0000
1:115058881:ACTGT:A	donor_loss	1.0000
1:115058882:C:CT	donor_gain	1.0000
1:115058882:CT:C	donor_gain	1.0000
1:115058882:CTG:C	donor_gain	1.0000
1:115058882:CTGT:C	donor_gain	1.0000
1:115058882:CTGTT:C	donor_gain	1.0000
1:115058978:TAGC:T	acceptor_gain	1.0000
1:115058981:CCTGA:C	acceptor_loss	1.0000
1:115058982:C:CC	acceptor_gain	1.0000
1:115058982:CT:C	acceptor_loss	1.0000
1:115058983:T:A	acceptor_loss	1.0000
1:115060462:A:AC	donor_gain	1.0000
1:115060462:ACTAC:A	donor_gain	1.0000
1:115060463:C:CC	donor_gain	1.0000
1:115060463:CTA:C	donor_gain	1.0000
1:115060463:CTACC:C	donor_gain	1.0000
1:115060539:C:CC	acceptor_gain	1.0000

AlphaMissense

1421 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
1:115050535:G:C	S207R	0.997
1:115050535:G:T	S207R	0.997
1:115050537:T:G	S207R	0.997
1:115060516:A:T	I98K	0.994
1:115060529:A:G	C94R	0.994
1:115057601:C:G	C151S	0.993
1:115057602:A:T	C151S	0.993
1:115053457:G:C	C174W	0.992
1:115053458:C:T	C174Y	0.992
1:115057602:A:G	C151R	0.992
1:115060536:A:C	F91L	0.992
1:115060536:A:T	F91L	0.992
1:115060538:A:G	F91L	0.992
1:115053458:C:G	C174S	0.991
1:115053459:A:T	C174S	0.991
1:115053389:G:T	A197E	0.990
1:115058957:A:C	Y124D	0.990
1:115060510:G:T	A100D	0.990
1:115073000:C:T	G26E	0.990
1:115073001:C:G	G26R	0.990
1:115073001:C:T	G26R	0.990
1:115062209:C:A	G66W	0.989
1:115050545:A:C	M204R	0.988
1:115053459:A:G	C174R	0.988
1:115057562:C:G	C164S	0.988
1:115057563:A:T	C164S	0.988
1:115057598:C:G	C152S	0.988
1:115057599:A:T	C152S	0.988
1:115060525:A:G	L95P	0.988
1:115062178:C:T	G76E	0.988

dbSNP variants (sampled 300 via entrez): RS1000107197 (1:115080813 C>T), RS1000176303 (1:115082132 T>C), RS1000191946 (1:115075200 G>C,T), RS1000301851 (1:115081538 G>C), RS1000378698 (1:115069719 G>A,T), RS1000473123 (1:115081381 A>G), RS1000552036 (1:115063690 T>A), RS1000575976 (1:115057052 A>G), RS1000579751 (1:115063131 T>C,G), RS1000645824 (1:115058623 G>A), RS1000748275 (1:115069467 A>G), RS1000791662 (1:115057062 G>A), RS1000870050 (1:115069108 C>T), RS1000882727 (1:115074653 T>C), RS1000884546 (1:115050916 T>G)

Disease associations

OMIM: gene MIM:613133 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

12 associations (top):

Study	Trait	p-value
GCST002078_23	Migraine without aura	5.000000e-08
GCST002081_18	Migraine	5.000000e-14
GCST003259_1	Ischemic stroke (large artery atherosclerosis)	1.000000e-09
GCST003720_14	Migraine	9.000000e-09
GCST003720_23	Migraine	4.000000e-24
GCST003721_1	Migraine without aura	7.000000e-09
GCST003927_1	Dysmenorrheic pain	4.000000e-14
GCST003986_7	Migraine	2.000000e-13
GCST010158_2	Large artery stroke (CCS or TOAST classification)	4.000000e-07
GCST010159_2	Large artery stroke (CCS and TOAST classification)	3.000000e-08
GCST010161_2	Large artery stroke (CCSp classification)j	6.000000e-09
GCST90026415_5	Mild obesity-related type 2 diabetes	8.000000e-06

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0007889	dysmenorrheic pain measurement

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	increases expression, affects expression	4
trichostatin A	decreases expression, increases expression, affects cotreatment	3
bisphenol A	affects expression, decreases expression	2
sodium arsenite	decreases expression	2
Benzo(a)pyrene	decreases expression, increases methylation	2
Lead	affects expression, increases expression	2
aristolochic acid I	decreases expression	1
triphenyl phosphate	affects expression	1
glycidyl methacrylate	increases expression	1
nickel sulfate	decreases expression	1
rofecoxib	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	increases expression	1
dorsomorphin	affects cotreatment, decreases expression	1
jinfukang	affects cotreatment, decreases expression	1
incobotulinumtoxinA	decreases expression	1
(+)-JQ1 compound	decreases expression	1
Dasatinib	increases expression	1
Sunitinib	increases expression	1
Carbamazepine	affects expression	1
Cisplatin	affects cotreatment, decreases expression	1
Estradiol	affects expression	1
Smoke	decreases expression	1
Tetrachlorodibenzodioxin	increases expression	1
Tobacco Smoke Pollution	decreases expression	1
Tretinoin	decreases expression	1
Triclosan	decreases expression	1
Cyclosporine	decreases expression	1
Aflatoxin B1	decreases methylation	1
Antirheumatic Agents	increases expression	1

Clinical trials (associated diseases)

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