SSX4

Summary

SSX4 (SSX family member 4, HGNC:11338) is a protein-coding gene on chromosome Xp11.23, encoding Protein SSX4 (O60224). Could act as a modulator of transcription.

The product of this gene belongs to the family of highly homologous synovial sarcoma X (SSX) breakpoint proteins. These proteins may function as transcriptional repressors. They are also capable of eliciting spontaneously humoral and cellular immune responses in cancer patients, and are potentially useful targets in cancer vaccine-based immunotherapy. SSX1, SSX2 and SSX4 genes have been involved in the t(X;18) translocation characteristically found in all synovial sarcomas. This translocation results in the fusion of the synovial sarcoma translocation gene on chromosome 18 to one of the SSX genes on chromosome X. Chromosome Xp11 contains a segmental duplication resulting in two identical copies of synovial sarcoma, X breakpoint 4, SSX4 and SSX4B, in tail-to-tail orientation. This gene, SSX4, represents the more telomeric copy. Two transcript variants encoding distinct isoforms have been identified for this gene.

Source: NCBI Gene 6759 — RefSeq curated summary.

At a glance

• Clinical variants (ClinVar): 5 total
• MANE Select transcript: NM_005636

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:11338
Approved symbol	SSX4
Name	SSX family member 4
Location	Xp11.23
Locus type	gene with protein product
Status	Approved
Aliases	CT5.4
Ensembl gene	ENSG00000268009
Ensembl biotype	protein_coding
OMIM	300326
Entrez	6759

Gene structure

Transcript identifiers

Ensembl transcripts: 2 — 2 protein_coding

ENST00000595689, ENST00000620320

RefSeq mRNA: 2 — MANE Select: NM_005636 NM_005636, NM_175729

CCDS: CCDS35240, CCDS43934

Canonical transcript exons

ENST00000595689 — 8 exons

Exon	Start	End
ENSE00003014653	48389346	48389481
ENSE00003048060	48387311	48387360
ENSE00003063289	48391869	48391973
ENSE00003117579	48385352	48385447
ENSE00003147162	48384561	48384675
ENSE00003176494	48384034	48384122
ENSE00003718558	48383539	48383564
ENSE00003736400	48392756	48393347

Expression profiles

Bgee: expression breadth broad, 23 present calls, max score 83.76.

FANTOM5 (CAGE): breadth tissue_specific, TPM avg 0.0147 / max 18.0098, expressed in 4 samples.

FANTOM5 promoters (1 alternative TSS)

Promoter ID	TPM avg	Samples expressed
209672	0.0147	4

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	83.76	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	68.42	gold quality
right testis	UBERON:0004534	59.23	gold quality
testis	UBERON:0000473	57.91	gold quality
left testis	UBERON:0004533	56.00	gold quality
olfactory segment of nasal mucosa	UBERON:0005386	44.02	gold quality
sural nerve	UBERON:0015488	40.02	gold quality
bone marrow cell	CL:0002092	38.09	gold quality
colonic epithelium	UBERON:0000397	37.20	gold quality
ganglionic eminence	UBERON:0004023	37.11	gold quality
ventricular zone	UBERON:0003053	36.48	gold quality
cortical plate	UBERON:0005343	36.47	gold quality
hindlimb stylopod muscle	UBERON:0004252	35.32	gold quality
apex of heart	UBERON:0002098	34.86	gold quality
thoracic aorta	UBERON:0001515	33.69	silver quality
ascending aorta	UBERON:0001496	33.50	silver quality
skeletal muscle tissue	UBERON:0001134	33.38	gold quality
tibial artery	UBERON:0007610	32.99	gold quality
popliteal artery	UBERON:0002250	32.95	gold quality
spleen	UBERON:0002106	32.93	silver quality
muscle tissue	UBERON:0002385	32.87	gold quality
bone marrow	UBERON:0002371	32.73	gold quality
fallopian tube	UBERON:0003889	32.30	gold quality
mucosa of stomach	UBERON:0001199	32.08	gold quality
descending thoracic aorta	UBERON:0002345	31.51	gold quality
liver	UBERON:0002107	30.94	gold quality
stromal cell of endometrium	CL:0002255	29.87	gold quality
muscle of leg	UBERON:0001383	29.85	gold quality
lower esophagus	UBERON:0013473	29.66	gold quality
lower esophagus muscularis layer	UBERON:0035833	29.64	gold quality

Single-cell (SCXA)

Detected in 1 experiment(s), a significant marker in 0.

Experiment	Marker?	Max mean expression
E-ANND-3	no	0.98

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

42 targeting SSX4, 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-6867-5P	100.00	82.21	3464
HSA-MIR-4531	99.99	69.70	3181
HSA-MIR-4500	99.99	72.72	2367
HSA-MIR-3148	99.97	75.06	6478
HSA-MIR-512-3P	99.97	67.35	1049
HSA-MIR-4697-3P	99.89	67.09	1123
HSA-MIR-7162-3P	99.89	68.16	1682
HSA-MIR-12119	99.87	68.35	1653
HSA-MIR-5003-3P	99.85	69.29	2517
HSA-MIR-4306	99.72	70.50	3630
HSA-MIR-518A-5P	99.70	69.01	2209
HSA-MIR-527	99.70	69.01	2209
HSA-MIR-1208	99.70	68.28	1533
HSA-MIR-586	99.65	70.40	2051
HSA-MIR-8064	99.45	66.92	875
HSA-MIR-185-5P	99.35	68.60	2497
HSA-MIR-4644	99.35	69.12	2514
HSA-MIR-501-3P	99.33	66.12	651
HSA-MIR-502-3P	99.33	66.12	651
HSA-MIR-3678-3P	99.31	67.10	1432
HSA-MIR-4641	99.28	66.64	744
HSA-MIR-5190	99.15	67.76	1234
HSA-MIR-2276-3P	98.76	67.75	1384
HSA-MIR-6804-3P	98.72	64.82	852
HSA-MIR-26B-3P	98.71	67.49	1102
HSA-MIR-2467-3P	98.65	67.18	1969
HSA-MIR-4700-5P	98.63	67.43	1915
HSA-MIR-3650	97.88	64.89	693
HSA-MIR-8089	97.74	66.21	1698
HSA-MIR-4667-5P	97.61	66.67	1683

Literature-anchored findings (GeneRIF, showing 6)

• existence of CD4+ T cells specific for multiple SSX-4 derived sequences in circulating lymphocytes from melanoma patients (PMID:15814740)
• we found that the SSX4 and MAGE-A3 genes are frequently expressed in brain tumor cell lines (PMID:21347689)
• Our results suggest that GAGE, XAGE1 and SSX4 might each have a role in melanoma progression (PMID:23625514)
• SSX2, SSX3, and SSX4 are expressed only in 3.5% early-stage non-small cell lung cancer patients. (PMID:24645645)
• The mRNA levels of SSX1 and SSX4 are associated with multiple myeloma clinical stage (PMID:24710929)
• loss of miR-4731 expression in stage IV patient tumors supports melanoma growth by, in part, reducing its regulatory control of SSX expression levels (PMID:27331623)

Cross-species orthologs

15 orthologs

Organism	Symbol	Gene ID
mus_musculus	Ssxb2	ENSMUSG00000023165
mus_musculus	Ssxb13	ENSMUSG00000035371
mus_musculus	Ssxa1	ENSMUSG00000062814
mus_musculus	Ssxb9	ENSMUSG00000068218
mus_musculus	Ssxb10	ENSMUSG00000068219
mus_musculus	Ssxb5	ENSMUSG00000071816
mus_musculus	Ssxb16	ENSMUSG00000079697
mus_musculus	Ssxb14	ENSMUSG00000079699
mus_musculus	Ssxb3	ENSMUSG00000079701
mus_musculus	Ssxb6	ENSMUSG00000079702
mus_musculus	Ssxb8	ENSMUSG00000079703
mus_musculus	Ssxb15	ENSMUSG00000079704
mus_musculus	Ssxb1	ENSMUSG00000079705
rattus_norvegicus	Ssx1	ENSRNOG00000027850
rattus_norvegicus	Ssx2	ENSRNOG00000049427

Paralogs (7): SSX1 (ENSG00000126752), SSX5 (ENSG00000165583), SSX3 (ENSG00000165584), SSX7 (ENSG00000187754), SSX2 (ENSG00000241476), SSX2B (ENSG00000268447), SSX4B (ENSG00000269791)

Protein

Protein identifiers

Protein SSX4 — O60224 (reviewed: O60224)

Alternative names: Cancer/testis antigen 5.4

All UniProt accessions (1): O60224

UniProt curated annotations — full annotation on UniProt →

Function. Could act as a modulator of transcription.

Similarity. Belongs to the SSX family.

Isoforms (2)

UniProt ID	Names	Canonical?
O60224-1	1	yes
O60224-2	2

RefSeq proteins (2): NP_005627, NP_783856 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001909	KRAB	Domain
IPR003655	aKRAB	Domain
IPR019041	SSXRD_motif	Conserved_site
IPR036051	KRAB_dom_sf	Homologous_superfamily

Pfam: PF09514

UniProt features (8 total): compositionally biased region 3, splice variant 2, chain 1, domain 1, region of interest 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-O60224-F1	69.31	0.29

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 28 (showing top): MULLIGHAN_NPM1_SIGNATURE_3_UP, RIZKI_TUMOR_INVASIVENESS_3D_DN, MISSIAGLIA_REGULATED_BY_METHYLATION_UP, KIM_RESPONSE_TO_TSA_AND_DECITABINE_UP, MODULE_379, MODULE_242, MODULE_104, MODULE_7, MULLIGHAN_NPM1_MUTATED_SIGNATURE_1_UP, MODULE_181, chrXp11, MODULE_41, NAKAYAMA_SOFT_TISSUE_TUMORS_PCA2_UP, ZHONG_RESPONSE_TO_AZACITIDINE_AND_TSA_UP, MIR6867_5P

GO Biological Process (1): regulation of DNA-templated transcription (GO:0006355)

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

GO Cellular Component (1): nucleus (GO:0005634)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
DNA-templated transcription	1
regulation of gene expression	1
regulation of RNA biosynthetic process	1
binding	1
intracellular membrane-bounded organelle	1

Protein interactions and networks

STRING

316 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
SSX4	SS18	Q15532	930
SSX4	SS18L1	O75177	817
SSX4	SSX2IP	Q9Y2D8	806
SSX4	SS18L2	Q9UHA2	720
SSX4	MAGEC1	O60732	654
SSX4	ZNF117	Q03924	639
SSX4	ZNF83	P51522	639
SSX4	CTAG2	O75638	625
SSX4	CTAG1A	P78358	621
SSX4	MAGEA4	P43358	621
SSX4	MAGEA1	P43355	620
SSX4	MAGEA3	P43357	600
SSX4	MAGEA10	P43363	594
SSX4	LUZP4	Q9P127	575
SSX4	RAB3IP	Q96QF0	561

IntAct

17 interactions, top by confidence:

A	B	Type	Score
SSX4	HIF1A	psi-mi:“MI:0915”(physical association)	0.780
HIF1A	SSX4	psi-mi:“MI:0915”(physical association)	0.780
FLACC1	SSX4	psi-mi:“MI:0915”(physical association)	0.560
SSX4	FLACC1	psi-mi:“MI:0915”(physical association)	0.560
SSX4	C14orf119	psi-mi:“MI:0915”(physical association)	0.560
SSX4	CDR2	psi-mi:“MI:0914”(association)	0.530
SSX4		psi-mi:“MI:0915”(physical association)	0.400
PAX9	SSX4	psi-mi:“MI:0915”(physical association)	0.370
SSX4	XBP1	psi-mi:“MI:0915”(physical association)	0.370
SSX4	LZTR1	psi-mi:“MI:0915”(physical association)	0.370
SSX4	POLA1	psi-mi:“MI:0914”(association)	0.350
SSX4	ALOX12B	psi-mi:“MI:0914”(association)	0.350
C14orf119	SSX4	psi-mi:“MI:0915”(physical association)	0.000

BioGRID (12): SSX4 (Two-hybrid), SSX4 (Two-hybrid), SSX4 (Two-hybrid), SSX4B (Two-hybrid), SSX4 (Two-hybrid), SSX4B (Two-hybrid), CDR2 (Affinity Capture-MS), HIF1A (Affinity Capture-MS), HNRNPA1L2 (Affinity Capture-MS), SSX4 (Two-hybrid), XBP1 (Two-hybrid), LZTR1 (Two-hybrid)

ESM2 similar proteins: A6H5X4, B1AUS7, D0QMC3, O35368, O60224, O60225, P0C6Y7, P0DOV1, P0DOV2, P23497, P41218, Q15361, Q16384, Q16385, Q16666, Q2KIN0, Q3U827, Q3ZCI6, Q4R7Q1, Q504N7, Q5H9L4, Q5I0E2, Q5I0J8, Q5RAK3, Q5RCZ8, Q5RD14, Q5W0A0, Q62187, Q6K0P9, Q71F23, Q7RTT3, Q7RTT4, Q7RTT5, Q7RTT6, Q86T96, Q8BV49, Q8BVM9, Q8C0V1, Q8C6C7, Q8CGE8

Diamond homologs: B1AUS7, O60224, O60225, P0C6Y7, Q16384, Q16385, Q7RTT3, Q7RTT4, Q7RTT5, Q7RTT6, Q8BFS8, Q96EQ9, Q99909, Q9NQV7, Q9NQW5, Q6ZMS7, A0A163UT06, A2AGX3, A6QPM3, E9Q3T6, O75626, P52736, Q13029, Q3UZD5, Q5R5M1, Q60636, Q63755, Q6P2A1, Q6PGE4, Q80V63, Q86UQ0, Q8BZ97, Q8TD17, Q9GZV8, Q9NQV5, Q9NQV8, Q9NQX0, Q9QZP2, Q9UDV7, Q9UKN5

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	4
Likely benign	1
Benign	0

Top pathogenic / likely-pathogenic (0)

SpliceAI

1046 predictions. Top by Δscore:

Variant	Effect	Δscore
X:48384555:TTCCA:T	acceptor_loss	1.0000
X:48384556:TCCA:T	acceptor_loss	1.0000
X:48384557:CCA:C	acceptor_loss	1.0000
X:48384558:CAG:C	acceptor_loss	1.0000
X:48384559:A:AC	acceptor_loss	1.0000
X:48384559:A:AG	acceptor_gain	1.0000
X:48384559:AG:A	acceptor_gain	1.0000
X:48384560:G:GT	acceptor_gain	1.0000
X:48384560:GG:G	acceptor_gain	1.0000
X:48384560:GGC:G	acceptor_gain	1.0000
X:48384560:GGCC:G	acceptor_gain	1.0000
X:48384648:C:G	donor_gain	1.0000
X:48384672:C:CG	donor_gain	1.0000
X:48384672:C:G	donor_gain	1.0000
X:48384672:CTAG:C	donor_loss	1.0000
X:48384673:TAGGT:T	donor_loss	1.0000
X:48384674:AGGTA:A	donor_loss	1.0000
X:48384675:GGTA:G	donor_loss	1.0000
X:48385348:CTA:C	acceptor_loss	1.0000
X:48385350:A:AG	acceptor_gain	1.0000
X:48385351:G:GG	acceptor_gain	1.0000
X:48385446:GG:G	donor_gain	1.0000
X:48385447:GG:G	donor_gain	1.0000
X:48385448:G:GG	donor_gain	1.0000
X:48385449:TGA:T	donor_loss	1.0000
X:48385450:GAG:G	donor_loss	1.0000
X:48387309:A:AG	acceptor_gain	1.0000
X:48387310:G:GA	acceptor_gain	1.0000
X:48389335:A:AG	acceptor_gain	1.0000
X:48389335:ACATT:A	acceptor_gain	1.0000

AlphaMissense

1264 scored. Top likely-pathogenic:

dbSNP variants (sampled 300 via entrez): RS1062275 (X:48393018 C>T), RS111557609 (X:48388688 A>T), RS112461287 (X:48389191 A>G), RS113446172 (X:48383679 T>C), RS113925712 (X:48391923 T>C), RS1158297350 (X:48384985 T>C), RS1159769554 (X:48384725 C>G,T), RS1164533192 (X:48384438 G>A), RS1179588296 (X:48384584 C>A), RS1180687530 (X:48384752 C>T), RS1185334214 (X:48384992 GTCTCTC>G,GTC,GTCTC,GTCTCTCTC,GTCTCTCTCTC), RS1187482074 (X:48384271 G>A), RS1191047817 (X:48384452 A>G), RS1196096851 (X:48384567 G>A), RS1198916950 (X:48384480 A>G)

Disease associations

OMIM: gene MIM:300326 | 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: no

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

CTD chemical–gene interactions

11 total (human), top 11 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Decitabine	affects expression, increases expression	4
terbufos	decreases methylation	1
(+)-JQ1 compound	decreases expression	1
Allergens	decreases expression	1
Cadmium	decreases expression	1
Calcitriol	decreases expression, affects cotreatment	1
Fonofos	decreases methylation	1
Parathion	decreases methylation	1
Phenylmercuric Acetate	increases expression	1
Testosterone	decreases expression, affects cotreatment	1
Antirheumatic Agents	increases expression	1

Clinical trials (associated diseases)

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