TRO

Summary

TRO (trophinin, HGNC:12326) is a protein-coding gene on chromosome Xp11.21, encoding Trophinin (Q12816). Could be involved with bystin and tastin in a cell adhesion molecule complex that mediates an initial attachment of the blastocyst to uterine epithelial cells at the time of the embryo implantation.

This gene encodes a membrane protein that mediates cell adhesion between trophoblastic cells and the epithelial cells of the endometrium. The encoded protein participates in cell signalling during embryo implantation, and may also be involved in cancer formation. This gene is located near several other closely related genes on chromosome X. Alternative splicing results in multiple transcript variants.

Source: NCBI Gene 7216 — RefSeq curated summary.

At a glance

• Clinical variants (ClinVar): 233 total
• MANE Select transcript: NM_001039705

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:12326
Approved symbol	TRO
Name	trophinin
Location	Xp11.21
Locus type	gene with protein product
Status	Approved
Aliases	MAGE-D3, KIAA1114, MAGED3
Ensembl gene	ENSG00000067445
Ensembl biotype	protein_coding
OMIM	300132
Entrez	7216

Gene structure

Transcript identifiers

Ensembl transcripts: 41 — 33 protein_coding, 4 protein_coding_CDS_not_defined, 2 nonsense_mediated_decay, 2 retained_intron

ENST00000173898, ENST00000319167, ENST00000375022, ENST00000375041, ENST00000399736, ENST00000411534, ENST00000416704, ENST00000420798, ENST00000427099, ENST00000430420, ENST00000431115, ENST00000440072, ENST00000440759, ENST00000442098, ENST00000445561, ENST00000449980, ENST00000452830, ENST00000453081, ENST00000469211, ENST00000474933, ENST00000475183, ENST00000484031, ENST00000492142, ENST00000492706, ENST00000622017, ENST00000854214, ENST00000854215, ENST00000854216, ENST00000854217, ENST00000854218, ENST00000919321, ENST00000919322, ENST00000919323, ENST00000919324, ENST00000919325, ENST00000919326, ENST00000919327, ENST00000919328, ENST00000919329, ENST00000919330, ENST00000968992

RefSeq mRNA: 6 — MANE Select: NM_001039705 NM_001039705, NM_001271183, NM_001271184, NM_016157, NM_177556, NM_177557

CCDS: CCDS43958, CCDS43959, CCDS59527, CCDS59528, CCDS59529

Canonical transcript exons

ENST00000173898 — 13 exons

Exon	Start	End
ENSE00001465497	54922203	54922291
ENSE00001711189	54927043	54927105
ENSE00001750087	54926583	54926625
ENSE00001802730	54922578	54923768
ENSE00003474786	54927667	54927781
ENSE00003483472	54924670	54924733
ENSE00003489742	54931204	54931431
ENSE00003582748	54924989	54925068
ENSE00003610668	54924451	54924555
ENSE00003618576	54925592	54925683
ENSE00003636549	54928603	54931031
ENSE00003666549	54926410	54926489
ENSE00003888723	54920824	54920878

Expression profiles

Bgee: expression breadth ubiquitous, 235 present calls, max score 96.10.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 15.5504 / max 422.9215, expressed in 1167 samples.

FANTOM5 promoters (2 alternative TSS)

Promoter ID	TPM avg	Samples expressed
196448	15.2080	1163
196449	0.3424	183

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
adenohypophysis	UBERON:0002196	96.10	gold quality
left ovary	UBERON:0002119	95.95	gold quality
tibia	UBERON:0000979	95.89	gold quality
pituitary gland	UBERON:0000007	95.81	gold quality
right ovary	UBERON:0002118	95.38	gold quality
cortical plate	UBERON:0005343	95.35	gold quality
right frontal lobe	UBERON:0002810	95.14	gold quality
ganglionic eminence	UBERON:0004023	95.11	gold quality
middle temporal gyrus	UBERON:0002771	94.24	gold quality
frontal pole	UBERON:0002795	94.23	gold quality
endocervix	UBERON:0000458	93.93	gold quality
Brodmann (1909) area 10	UBERON:0013541	93.83	gold quality
embryo	UBERON:0000922	93.67	gold quality
middle frontal gyrus	UBERON:0002702	93.49	gold quality
anterior cingulate cortex	UBERON:0009835	93.45	gold quality
cingulate cortex	UBERON:0003027	93.43	gold quality
ventricular zone	UBERON:0003053	93.20	gold quality
Brodmann (1909) area 9	UBERON:0013540	93.18	gold quality
paraflocculus	UBERON:0005351	92.98	gold quality
prefrontal cortex	UBERON:0000451	92.79	gold quality
dorsolateral prefrontal cortex	UBERON:0009834	92.41	gold quality
right hemisphere of cerebellum	UBERON:0014890	92.41	gold quality
ovary	UBERON:0000992	92.35	gold quality
neocortex	UBERON:0001950	92.17	gold quality
body of uterus	UBERON:0009853	91.98	gold quality
stromal cell of endometrium	CL:0002255	91.91	gold quality
frontal cortex	UBERON:0001870	91.82	gold quality
frontal lobe	UBERON:0016525	91.82	gold quality
hypothalamus	UBERON:0001898	91.56	gold quality
primary visual cortex	UBERON:0002436	91.55	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	6.46

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): CTCF

Literature-anchored findings (GeneRIF, showing 16)

• infertile women with endometriosis or unexplained infertility had significantly weakened trophinin expression in the endometrium in the mid-luteal phase (PMID:12297480)
• HCG from the human embryo induces trophinin expression by maternal cells. Unique role of hCG and trophinin in human embryo implantation, including the pathogenesis of ectopic pregnancy. (PMID:14633596)
• Maged3 expression is restricted to the central nervous system where it was mostly detected in postmitotic neurons (PMID:15162511)
• Fluorescence photobleaching of GFP-trophinin expressed in COS-1 cells showed the stable association of trophinin with the nuclear envelope. (PMID:16288751)
• trophinin-mediated cell adhesion functions as a molecular switch for trophectoderm activation in human embryo implantation (PMID:17360433)
• results suggest that trophinin promotes colorectal cancer invasion through a mechanism involving HMGB1/RAGE (PMID:17487845)
• Trophinin functions as an adhesion molecule on the cell surface and as a molecular switch for trophoblast activation in the cytoplasm. (PMID:17495530)
• Confocal microscopy analysis of ectopically expressed magphinins revealed that magphinin-alpha and -beta localize in the cytoplasm, whereas magphinin-gamma lacking the peptide encoded by exon-3 is nuclear. (PMID:17559068)
• When magphinin-gamma was expressed in NIH3T3 cells, cells underwent G1 arrest. These results suggest that human magphinin-gamma inhibits cell cycle progression through nuclear activity. (PMID:17559068)
• TROPHONIN (TRO) is among the genes most downregulated by RAS. TRO expression is higher in cisplatin-sensitive cancer cell lines and positively correlates with prognoses in ovarian cancers. (PMID:17597582)
• These findings underscore the importance of TRO in tumorigenesis, and suggest that TRO may be a useful biomarker for cisplatin sensitivity and invasive potential. (PMID:17597582)
• results provide a mechanism for trophinin-mediated adhesion of human blastocyst to endometrium by a spatially and temporally restricted paracrine effect of hCG derived from the blastocyst (PMID:18078818)
• Overexpression of trophinin leads to a more invasive phenotype and metastatic potential in human gallbladder cancer transfected into nude mice. (PMID:18846386)
• Trophinin induced apoptosis in endometrial epithelial cells through protein kinase C-delta. (PMID:21191175)
• report dual roles for trophinin in human cancers in terms of promoting malignancy in some tumor types and suppressing it in others (PMID:22201876)
• Expression of trophinin and dipeptidyl peptidase IV in endometrial co-culture in the presence of an embryo: A comparative immunocytochemical study. (PMID:27035766)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
danio_rerio	ndnl2	ENSDARG00000058212
mus_musculus	Tro	ENSMUSG00000025272
rattus_norvegicus	AABR07037520.1	ENSRNOG00000047491
drosophila_melanogaster	MAGE	FBGN0037481

Paralogs (37): MAGEC2 (ENSG00000046774), MAGEB2 (ENSG00000099399), MAGED2 (ENSG00000102316), MAGEB4 (ENSG00000120289), MAGEA9 (ENSG00000123584), MAGEA10 (ENSG00000124260), MAGEA4 (ENSG00000147381), MAGED4 (ENSG00000154545), MAGEC1 (ENSG00000155495), MAGEA8 (ENSG00000156009), MAGEC3 (ENSG00000165509), MAGEB6 (ENSG00000176746), MAGEB18 (ENSG00000176774), MAGEF1 (ENSG00000177383), MAGEB10 (ENSG00000177689), MAGED1 (ENSG00000179222), NDN (ENSG00000182636), MAGEB17 (ENSG00000182798), MAGEA2B (ENSG00000183305), NSMCE3 (ENSG00000185115), MAGEA11 (ENSG00000185247), MAGEE2 (ENSG00000186675), MAGED4B (ENSG00000187243), MAGEH1 (ENSG00000187601), MAGEB5 (ENSG00000188408), MAGEB16 (ENSG00000189023), MAGEA6 (ENSG00000197172), MAGEA1 (ENSG00000198681), MAGEB3 (ENSG00000198798), MAGEE1 (ENSG00000198934), MAGEA12 (ENSG00000213401), MAGEB1 (ENSG00000214107), MAGEA3 (ENSG00000221867), MAGEB6B (ENSG00000232030), MAGEL2 (ENSG00000254585), MAGEA9B (ENSG00000267978), MAGEA2 (ENSG00000268606)

Protein

Protein identifiers

Trophinin — Q12816 (reviewed: Q12816)

Alternative names: MAGE-D3 antigen

All UniProt accessions (12): Q12816, A0A087X070, B1AKE6, B1AKE7, B1AKE8, B1AKF2, B1AKF3, B1AKF4, B1AKF5, B1AKF6, E7ERU6, G5E9N2

UniProt curated annotations — full annotation on UniProt →

Function. Could be involved with bystin and tastin in a cell adhesion molecule complex that mediates an initial attachment of the blastocyst to uterine epithelial cells at the time of the embryo implantation. Directly responsible for homophilic cell adhesion.

Subunit / interactions. Directly binds bystin, and indirectly tastin.

Tissue specificity. Strong expression at implantation sites. Found in the placenta from the sixth week of pregnancy. Was localized in the cytoplasm of the syncytiotrophoblast in the chorionic villi and in endometrial decidual cells at the uteroplacental interface. After week 10, the level decreased and then disappeared from placental villi. Also found in macrophages.

Isoforms (5)

UniProt ID	Names	Canonical?
Q12816-1	1	yes
Q12816-2	2
Q12816-3	3
Q12816-4	4
Q12816-5	5

RefSeq proteins (6): NP_001034794, NP_001258112, NP_001258113, NP_057241, NP_808224, NP_808225 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR002190	MHD_dom	Domain
IPR037445	MAGE	Family
IPR041898	MAGE_WH1	Homologous_superfamily
IPR041899	MAGE_WH2	Homologous_superfamily

Pfam: PF01454

UniProt features (84 total): repeat 62, sequence conflict 6, region of interest 5, splice variant 4, sequence variant 3, compositionally biased region 2, chain 1, domain 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q12816-F1	49.39	0.01

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 0 (showing top):

GO Biological Process (4): negative regulation of transcription by RNA polymerase II (GO:0000122), homophilic cell-cell adhesion (GO:0007156), embryo implantation (GO:0007566), cell adhesion (GO:0007155)

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

GO Cellular Component (2): nucleus (GO:0005634), plasma membrane (GO:0005886)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
regulation of transcription by RNA polymerase II	1
transcription by RNA polymerase II	1
negative regulation of DNA-templated transcription	1
cell-cell adhesion	1
multicellular organism development	1
female pregnancy	1
reproductive process	1
cellular process	1
binding	1
intracellular membrane-bounded organelle	1
membrane	1
cell periphery	1

Protein interactions and networks

STRING

432 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
TRO	TROAP	Q12815	999
TRO	BYSL	Q13895	999
TRO	RPS6	P08227	557
TRO	SMAD4	Q13485	418
TRO	GCNT1	Q02742	379
TRO	HDX	Q7Z353	364
TRO	SMIM1	B2RUZ4	325
TRO	MSL1	Q68DK7	310
TRO	GAL3ST4	Q96RP7	305
TRO	GPR152	Q8TDT2	302
TRO	MAGEL2	Q9UJ55	291
TRO	MUC1	P13931	289
TRO	MTMR8	Q96EF0	275
TRO	ZC3H12B	Q5HYM0	261
TRO	ST3GAL1	Q11201	260

IntAct

58 interactions, top by confidence:

A	B	Type	Score
ARPC5	ARPC3	psi-mi:“MI:0914”(association)	0.730
FAF2	UBB	psi-mi:“MI:0914”(association)	0.640
BYSL	TROAP	psi-mi:“MI:0914”(association)	0.600
SPACA1	GOLIM4	psi-mi:“MI:0914”(association)	0.530
MLF1	NDC80	psi-mi:“MI:0914”(association)	0.530
GNAS	CPT2	psi-mi:“MI:0914”(association)	0.530
TIAL1	TRO	psi-mi:“MI:0914”(association)	0.530
FBL	ZNF316	psi-mi:“MI:0914”(association)	0.530
LRP1	NME4	psi-mi:“MI:0914”(association)	0.530
PRKCD	TRO	psi-mi:“MI:0915”(physical association)	0.460
PRKCD	TRO	psi-mi:“MI:0403”(colocalization)	0.460
BYSL	TRO	psi-mi:“MI:0915”(physical association)	0.460
TRO	EBP	psi-mi:“MI:0915”(physical association)	0.400
ERBB4	TRO	psi-mi:“MI:0915”(physical association)	0.400
IRF3	ESYT2	psi-mi:“MI:0914”(association)	0.350
PB1	ESYT2	psi-mi:“MI:0914”(association)	0.350
PB2	HAX1	psi-mi:“MI:0914”(association)	0.350
NBEAL2	HAX1	psi-mi:“MI:0914”(association)	0.350
TNIP2	CHUK	psi-mi:“MI:0914”(association)	0.350
FBL	GXYLT2	psi-mi:“MI:0914”(association)	0.350
NXF2B	MEIOC	psi-mi:“MI:0914”(association)	0.350
NCAPH2	MYO9A	psi-mi:“MI:0914”(association)	0.350
DNAJB2	UBB	psi-mi:“MI:0914”(association)	0.350
RABGAP1L	ACOT7	psi-mi:“MI:0914”(association)	0.350
THBS3	APBB1	psi-mi:“MI:0914”(association)	0.350
RPL28	SDCBP	psi-mi:“MI:0914”(association)	0.350

BioGRID (96): TRO (Two-hybrid), TRO (Affinity Capture-MS), TRO (Affinity Capture-MS), TRO (Affinity Capture-MS), TRO (Affinity Capture-MS), TRO (Affinity Capture-MS), TRO (Affinity Capture-MS), TRO (Affinity Capture-MS), TRO (Affinity Capture-MS), TRO (Affinity Capture-MS), TRO (Affinity Capture-MS), TRO (Two-hybrid), TRO (Affinity Capture-MS), TRO (Affinity Capture-MS), TRO (Affinity Capture-MS)

ESM2 similar proteins: A0A0J9YWL9, A0A0J9YY54, A0A0U1RQI7, A0A494C071, A6NNC1, A6QL64, B3KS81, D3YZV8, E2RYF7, E9Q6E9, F1LWT0, F8W0I5, O60732, P0C8Z4, P0DKJ7, P0DKJ8, P0DKL2, P0DPF3, P18751, P20930, P43537, P53353, P59797, P62521, Q01456, Q08AG5, Q12816, Q3BBV2, Q5H9R4, Q5HY64, Q5JPF3, Q6P902, Q6ZQX7, Q86T75, Q86VE3, Q86VQ3, Q8BGJ3, Q8N307, Q8N7U7, Q8N7X1

Diamond homologs: A0A0J9YX57, A1A5P9, A2A368, A2A9R3, A6NCF6, A6QLI5, A8MXT2, O15479, O15480, O15481, O60732, P25233, P43355, P43356, P43357, P43358, P43360, P43361, P43362, P43363, P43364, P43365, P43366, Q12816, Q4R998, Q5PPP4, Q5RFC2, Q6AY37, Q6ITT4, Q6PCZ4, Q8BQR7, Q8N7X4, Q8TD90, Q8TD91, Q96JG8, Q96LZ2, Q96M61, Q96MG7, Q99608, Q9BE18

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	128
Likely benign	18
Benign	1

Top pathogenic / likely-pathogenic (0)

SpliceAI

1793 predictions. Top by Δscore:

Variant	Effect	Δscore
X:54924983:CTACA:C	acceptor_loss	1.0000
X:54924984:TACA:T	acceptor_loss	1.0000
X:54924985:ACAGA:A	acceptor_loss	1.0000
X:54924986:CA:C	acceptor_loss	1.0000
X:54924987:A:AG	acceptor_gain	1.0000
X:54924987:AGA:A	acceptor_loss	1.0000
X:54924988:G:C	acceptor_loss	1.0000
X:54924988:G:GA	acceptor_gain	1.0000
X:54924988:GAC:G	acceptor_gain	1.0000
X:54925104:G:GT	donor_gain	1.0000
X:54925104:G:T	donor_gain	1.0000
X:54925679:GGAAC:G	donor_gain	1.0000
X:54925680:GAACG:G	donor_gain	1.0000
X:54925681:A:T	donor_gain	1.0000
X:54925684:G:GG	donor_gain	1.0000
X:54926406:TTAG:T	acceptor_loss	1.0000
X:54926407:TA:T	acceptor_loss	1.0000
X:54926408:A:AG	acceptor_gain	1.0000
X:54926409:G:GG	acceptor_gain	1.0000
X:54926488:GG:G	donor_gain	1.0000
X:54926489:GG:G	donor_gain	1.0000
X:54926680:G:GT	donor_gain	1.0000
X:54927103:GAA:G	donor_gain	1.0000
X:54927106:G:GG	donor_gain	1.0000
X:54927661:TCCAA:T	acceptor_loss	1.0000
X:54927662:CCAAG:C	acceptor_loss	1.0000
X:54927664:A:AG	acceptor_gain	1.0000
X:54927664:AAG:A	acceptor_gain	1.0000
X:54927665:A:G	acceptor_gain	1.0000
X:54927665:AGG:A	acceptor_loss	1.0000

AlphaMissense

9470 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
X:54927722:T:A	W607R	0.999
X:54927722:T:C	W607R	0.999
X:54927724:G:C	W607C	0.998
X:54927724:G:T	W607C	0.998
X:54927092:T:C	F584L	0.997
X:54927094:T:A	F584L	0.997
X:54927094:T:G	F584L	0.997
X:54927765:T:C	L621P	0.997
X:54927770:T:C	F623L	0.997
X:54927772:T:A	F623L	0.997
X:54927772:T:G	F623L	0.997
X:54924692:T:C	L455P	0.996
X:54926453:A:C	S541R	0.996
X:54926455:T:A	S541R	0.996
X:54926455:T:G	S541R	0.996
X:54927078:T:C	L579P	0.996
X:54927093:T:C	F584S	0.996
X:54927717:T:C	F605S	0.996
X:54927765:T:A	L621H	0.996
X:54928627:T:A	W635R	0.996
X:54928627:T:C	W635R	0.996
X:54925595:T:C	F497L	0.995
X:54925597:T:A	F497L	0.995
X:54925597:T:G	F497L	0.995
X:54926462:T:C	F544L	0.995
X:54926464:T:A	F544L	0.995
X:54926464:T:G	F544L	0.995
X:54927093:T:G	F584C	0.995
X:54927668:T:C	Y589H	0.995
X:54927716:T:C	F605L	0.995

dbSNP variants (sampled 300 via entrez): RS1000053316 (X:54920596 A>G), RS1000103711 (X:54920829 C>A,T), RS1000942919 (X:54925791 G>C), RS1002399128 (X:54922620 C>T), RS1003307560 (X:54924755 T>A,C), RS1003402511 (X:54925200 T>C), RS1003888870 (X:54919356 C>A), RS1004036343 (X:54929400 A>G), RS1004064151 (X:54930697 G>A), RS1004573113 (X:54919013 G>C,T), RS1005323510 (X:54920046 T>C,G), RS1006378585 (X:54931513 T>C), RS1006536167 (X:54927036 T>C), RS1006591319 (X:54923942 G>C,T), RS1007403623 (X:54925162 G>A)

Disease associations

OMIM: gene MIM:300132 | 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

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

Chemical	Actions (top 5)	PubMed papers
sodium arsenite	decreases expression, affects cotreatment, increases abundance, increases expression	3
Arsenic	affects cotreatment, increases abundance, increases expression, decreases expression	2
Silicon Dioxide	decreases expression, increases expression	2
Valproic Acid	affects expression, decreases expression	2
Cadmium Chloride	decreases expression, increases abundance	2
p-Chloromercuribenzoic Acid	affects cotreatment, increases expression	2
propionaldehyde	increases expression	1
tris(2-butoxyethyl) phosphate	affects expression	1
butyraldehyde	increases expression	1
manganese chloride	affects cotreatment, increases abundance, increases expression	1
nickel sulfate	increases expression	1
beta-methylcholine	affects expression	1
pentanal	increases expression	1
di-n-butylphosphoric acid	affects expression	1
perfluorooctane sulfonic acid	increases expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, increases expression	1
nutlin 3	affects cotreatment, increases expression	1
dorsomorphin	increases expression, affects cotreatment	1
Sunitinib	decreases expression	1
Acetaminophen	decreases expression	1
Glyphosate	increases expression	1
Aldehydes	increases expression	1
Benzo(a)pyrene	increases methylation	1
Cadmium	decreases expression, increases abundance	1
Camptothecin	increases expression	1
Dactinomycin	affects cotreatment, increases expression	1
Dexamethasone	decreases expression	1
Doxorubicin	decreases expression	1
Estradiol	affects cotreatment, increases expression	1
Hydrogen Peroxide	affects expression	1

Clinical trials (associated diseases)

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