TMX4

Summary

TMX4 (thioredoxin related transmembrane protein 4, HGNC:25237) is a protein-coding gene on chromosome 20p12.3, encoding Thioredoxin-related transmembrane protein 4 (Q9H1E5).

This gene encodes a member of the disulfide isomerase (PDI) family of endoplasmic reticulum (ER) proteins that catalyze protein folding and thiol-disulfide interchange reactions. The encoded protein has an N-terminal ER-signal sequence, a catalytically active thioredoxin domain, one transmembrane domain and C-terminal ASP/GLU-rich calcium binding domain. Unlike most members of this gene family, it lacks a C-terminal ER-retention sequence. The encoded protein has been shown to have reductase activity in vitro.

Source: NCBI Gene 56255 — RefSeq curated summary.

At a glance

• GWAS associations: 3
• Clinical variants (ClinVar): 54 total — 1 pathogenic
• MANE Select transcript: NM_021156

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:25237
Approved symbol	TMX4
Name	thioredoxin related transmembrane protein 4
Location	20p12.3
Locus type	gene with protein product
Status	Approved
Aliases	DJ971N18.2, KIAA1162, PDIA14
Ensembl gene	ENSG00000125827
Ensembl biotype	protein_coding
OMIM	616766
Entrez	56255

Gene structure

Transcript identifiers

Ensembl transcripts: 9 — 7 protein_coding, 1 nonsense_mediated_decay, 1 protein_coding_CDS_not_defined

ENST00000246024, ENST00000462384, ENST00000527925, ENST00000530935, ENST00000910533, ENST00000910534, ENST00000910535, ENST00000910536, ENST00000971200

RefSeq mRNA: 1 — MANE Select: NM_021156 NM_021156

CCDS: CCDS13101

Canonical transcript exons

ENST00000246024 — 8 exons

Exon	Start	End
ENSE00000858981	7987288	7987389
ENSE00001172449	8019438	8019761
ENSE00001239867	7977346	7982621
ENSE00003462764	8010200	8010315
ENSE00003555127	7999732	7999860
ENSE00003591910	8001496	8001541
ENSE00003663478	7996026	7996071
ENSE00003790334	7983794	7983857

Expression profiles

Bgee: expression breadth ubiquitous, 302 present calls, max score 98.64.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 27.3646 / max 341.6799, expressed in 1808 samples.

FANTOM5 promoters (7 alternative TSS)

Promoter ID	TPM avg	Samples expressed
186387	13.5576	1770
186388	6.6962	1668
186382	3.3554	1388
186386	1.6769	1049
186385	1.3226	745
186383	0.5382	212
186384	0.2177	90

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
germinal epithelium of ovary	UBERON:0001304	98.64	gold quality
Brodmann (1909) area 23	UBERON:0013554	98.57	gold quality
seminal vesicle	UBERON:0000998	98.53	gold quality
cauda epididymis	UBERON:0004360	98.48	gold quality
choroid plexus epithelium	UBERON:0003911	98.47	gold quality
caput epididymis	UBERON:0004358	98.47	gold quality
endothelial cell	CL:0000115	98.43	gold quality
cardiac muscle of right atrium	UBERON:0003379	98.31	gold quality
parotid gland	UBERON:0001831	98.08	gold quality
middle temporal gyrus	UBERON:0002771	98.08	gold quality
heart right ventricle	UBERON:0002080	98.01	gold quality
myocardium	UBERON:0002349	97.90	gold quality
adult organism	UBERON:0007023	97.47	gold quality
corpus epididymis	UBERON:0004359	97.25	gold quality
parietal pleura	UBERON:0002400	97.23	gold quality
type B pancreatic cell	CL:0000169	97.16	gold quality
left ventricle myocardium	UBERON:0006566	97.06	gold quality
pigmented layer of retina	UBERON:0001782	96.83	gold quality
retina	UBERON:0000966	96.80	gold quality
cartilage tissue	UBERON:0002418	96.73	gold quality
lateral globus pallidus	UBERON:0002476	96.73	gold quality
synovial joint	UBERON:0002217	96.67	gold quality
superior vestibular nucleus	UBERON:0007227	96.66	gold quality
biceps brachii	UBERON:0001507	96.60	gold quality
orbitofrontal cortex	UBERON:0004167	96.41	gold quality
substantia nigra pars compacta	UBERON:0001965	96.38	gold quality
pons	UBERON:0000988	96.35	gold quality
dorsal root ganglion	UBERON:0000044	96.33	gold quality
pleura	UBERON:0000977	96.32	gold quality
lateral nuclear group of thalamus	UBERON:0002736	96.32	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-MTAB-10287	yes	26.74
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

240 targeting TMX4, 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-4795-3P	100.00	74.62	4024
HSA-MIR-200B-3P	100.00	73.31	2693
HSA-MIR-200C-3P	100.00	73.35	2685
HSA-MIR-429	100.00	73.44	2698
HSA-MIR-5011-5P	100.00	83.46	5820
HSA-MIR-126-5P	100.00	72.71	3180
HSA-MIR-3646	100.00	73.56	5283
HSA-MIR-4668-3P	100.00	68.74	2635
HSA-LET-7A-3P	100.00	74.03	3932
HSA-LET-7B-3P	100.00	74.08	3913
HSA-LET-7F-1-3P	100.00	74.02	3928
HSA-MIR-98-3P	100.00	74.08	3907
HSA-MIR-3163	100.00	77.23	8605
HSA-MIR-1252-5P	100.00	69.80	2774
HSA-MIR-3613-3P	100.00	76.36	7965
HSA-MIR-656-3P	100.00	72.15	2788
HSA-MIR-4768-5P	100.00	69.49	2861
HSA-MIR-1277-5P	100.00	73.95	5056
HSA-MIR-6833-3P	100.00	70.63	3197
HSA-MIR-548C-3P	99.99	74.01	7587
HSA-MIR-3662	99.99	73.82	5684
HSA-MIR-196A-1-3P	99.99	72.15	2772
HSA-MIR-4282	99.99	75.36	6408
HSA-MIR-4500	99.99	72.72	2367
HSA-MIR-33A-5P	99.99	68.62	1055
HSA-MIR-33B-5P	99.99	68.58	1062
HSA-MIR-371B-5P	99.99	75.34	4759
HSA-MIR-186-5P	99.99	70.83	3707
HSA-MIR-4789-3P	99.99	70.75	2484

Literature-anchored findings (GeneRIF, showing 2)

• Data show that features not commonly found in other PDIs characterize TMX4 and suggest unique functional properties of the protein. (PMID:19811453)
• Data identify a novel transmembrane Trx-like protein 4 (TMX4), in the ER of mammalian cells, and confirm that the Trx-like domain has reductase activity in vitro. (PMID:20056998)

Cross-species orthologs

11 orthologs

Organism	Symbol	Gene ID
danio_rerio	tmx4	ENSDARG00000101512
mus_musculus	Tmx4	ENSMUSG00000034723
rattus_norvegicus	Tmx4	ENSRNOG00000024852
drosophila_melanogaster	ERp60	FBGN0033663
drosophila_melanogaster	Tmx3	FBGN0036579
drosophila_melanogaster	Pdi	FBGN0286818
caenorhabditis_elegans		WBGENE00003962
caenorhabditis_elegans		WBGENE00003963
caenorhabditis_elegans	pdi-3	WBGENE00003964
caenorhabditis_elegans	M04D5.1	WBGENE00014807
caenorhabditis_elegans	ZK973.11	WBGENE00022836

Paralogs (13): ERP44 (ENSG00000023318), PDIA5 (ENSG00000065485), ERP27 (ENSG00000139055), TMX1 (ENSG00000139921), PDIA6 (ENSG00000143870), TXNDC11 (ENSG00000153066), PDIA4 (ENSG00000155660), TMX3 (ENSG00000166479), PDIA3 (ENSG00000167004), PDILT (ENSG00000169340), PDIA2 (ENSG00000185615), P4HB (ENSG00000185624), TXNDC5 (ENSG00000239264)

Protein

Protein identifiers

Thioredoxin-related transmembrane protein 4 — Q9H1E5 (reviewed: Q9H1E5)

Alternative names: Thioredoxin domain-containing protein 13

All UniProt accessions (3): Q9H1E5, E9PIN7, E9PIU6

UniProt curated annotations — full annotation on UniProt →

Subcellular location. Nucleus inner membrane. Endoplasmic reticulum membrane.

RefSeq proteins (1): NP_066979* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR013766	Thioredoxin_domain	Domain
IPR017937	Thioredoxin_CS	Conserved_site
IPR036249	Thioredoxin-like_sf	Homologous_superfamily
IPR052454	TMX_domain-containing	Family

Pfam: PF00085

UniProt features (17 total): compositionally biased region 4, active site 2, modified residue 2, sequence variant 2, signal peptide 1, chain 1, disulfide bond 1, sequence conflict 1, transmembrane region 1, domain 1, region of interest 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9H1E5-F1	72.88	0.38

Functional residue map

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

Catalytic / active sites (2): 67 (nucleophile); 64 (nucleophile)

Post-translational modifications (2): 251, 259

Disulfide bonds (1): 64–67

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 238 (showing top): WAMUNYOKOLI_OVARIAN_CANCER_LMP_DN, WALLACE_PROSTATE_CANCER_RACE_UP, BUYTAERT_PHOTODYNAMIC_THERAPY_STRESS_DN, FAELT_B_CLL_WITH_VH_REARRANGEMENTS_DN, IVANOVA_HEMATOPOIESIS_LATE_PROGENITOR, DACOSTA_UV_RESPONSE_VIA_ERCC3_UP, LINDGREN_BLADDER_CANCER_CLUSTER_2A_DN, MODULE_66, DAVICIONI_RHABDOMYOSARCOMA_PAX_FOXO1_FUSION_UP, CASORELLI_APL_SECONDARY_VS_DE_NOVO_UP, RFX1_02, ROSS_AML_WITH_PML_RARA_FUSION, MODULE_568, MODULE_11, MODULE_491

GO Biological Process (0):

GO Molecular Function (1): disulfide oxidoreductase activity (GO:0015036)

GO Cellular Component (6): nuclear inner membrane (GO:0005637), endoplasmic reticulum (GO:0005783), endoplasmic reticulum membrane (GO:0005789), endomembrane system (GO:0012505), nucleus (GO:0005634), membrane (GO:0016020)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
intracellular membrane-bounded organelle	2
cellular anatomical structure	2
oxidoreductase activity, acting on a sulfur group of donors	1
organelle inner membrane	1
nuclear membrane	1
cytoplasm	1
endomembrane system	1
organelle membrane	1
nuclear outer membrane-endoplasmic reticulum membrane network	1
endoplasmic reticulum subcompartment	1
vacuole	1
plasma membrane	1

Protein interactions and networks

STRING

1319 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
TMX4	TXNDC12	O95881	715
TMX4	TMX3	Q96JJ7	661
TMX4	TMX2	Q9Y320	629
TMX4	PDIA2	Q13087	500
TMX4	ERP44	Q9BS26	487
TMX4	VKORC1	Q9BQB6	483
TMX4	ERP27	Q96DN0	476
TMX4	PDIA5	Q14554	463
TMX4	SCCPDH	Q8NBX0	462
TMX4	GPCPD1	Q9NPB8	449
TMX4	PROS1	P07225	443
TMX4	AGR3	Q8TD06	439
TMX4	HAO1	Q9UJM8	434
TMX4	SLC75A1	Q14728	425
TMX4	ITPRIPL2	Q3MIP1	425

IntAct

80 interactions, top by confidence:

A	B	Type	Score
FAM234B	ABCD4	psi-mi:“MI:0914”(association)	0.620
ADGRG5	KLRG2	psi-mi:“MI:0914”(association)	0.530
BTN2A1	POTEF	psi-mi:“MI:0914”(association)	0.530
MCOLN3	UPK3BL1	psi-mi:“MI:0914”(association)	0.530
TEX29	TOR1A	psi-mi:“MI:0914”(association)	0.530
VASN	AP3B1	psi-mi:“MI:0914”(association)	0.530
CDH13	INSIG1	psi-mi:“MI:0914”(association)	0.530
ZACN	GPAA1	psi-mi:“MI:0914”(association)	0.530
IL9R	RETSAT	psi-mi:“MI:0914”(association)	0.530
CD226	MEN1	psi-mi:“MI:0914”(association)	0.530
CSGALNACT2	GOLIM4	psi-mi:“MI:0914”(association)	0.530
FUT1	GOLIM4	psi-mi:“MI:0914”(association)	0.530
IGSF8	CLGN	psi-mi:“MI:0914”(association)	0.530
IL27RA	B4GALT5	psi-mi:“MI:0914”(association)	0.530
EREG	RAB4A	psi-mi:“MI:0914”(association)	0.530
IL27RA	AP1G2	psi-mi:“MI:0914”(association)	0.530
CHRNA4	FZD6	psi-mi:“MI:0914”(association)	0.530
CSGALNACT2	TPST1	psi-mi:“MI:0914”(association)	0.530
CANX	TMX3	psi-mi:“MI:0403”(colocalization)	0.530
NRAS	ESYT2	psi-mi:“MI:2364”(proximity)	0.480
	TK2	psi-mi:“MI:0915”(physical association)	0.400
CLEC2D	TMEM120B	psi-mi:“MI:0914”(association)	0.350
TMEM30A	UPK3BL1	psi-mi:“MI:0914”(association)	0.350
CSGALNACT2	CLASP2	psi-mi:“MI:0914”(association)	0.350
IL27RA	NRP1	psi-mi:“MI:0914”(association)	0.350
HTR3A	GPAA1	psi-mi:“MI:0914”(association)	0.350

BioGRID (119): TMX4 (Affinity Capture-MS), TMX4 (Affinity Capture-MS), TMX4 (Affinity Capture-MS), TMX4 (Affinity Capture-MS), TMX4 (Affinity Capture-MS), TMX4 (Affinity Capture-MS), TMX4 (Proximity Label-MS), TMX4 (Affinity Capture-MS), TMX4 (Affinity Capture-MS), TMX4 (Affinity Capture-MS), TMX4 (Affinity Capture-MS), TMX4 (Affinity Capture-MS), TMX4 (Affinity Capture-MS), TMX4 (Affinity Capture-MS), TMX4 (Affinity Capture-MS)

ESM2 similar proteins: A0A494C1R9, A2AKB4, A2APT9, A6NKD2, A8MT33, B0BN44, E9PGG2, F5GYI3, O19110, O88852, P0CV98, P0CV99, P0CW00, P0CW01, Q01534, Q03386, Q0P5N2, Q12967, Q14684, Q2M329, Q3U3N0, Q5F267, Q5I0E2, Q5R5G8, Q5R866, Q5SYB0, Q5VTJ3, Q60953, Q69ZB3, Q6ZUX3, Q7TQI8, Q80VJ8, Q80VR2, Q86VY4, Q8BSI6, Q8IZJ4, Q8N831, Q8VD63, Q95LS7, Q96FG2

Diamond homologs: A0A8M1N5Y4, D3Z6P0, O22263, O48773, P00275, P08003, P0A4L3, P0A4L4, P0AGG4, P0AGG5, P0AGG6, P0AGG7, P10472, P11598, P13667, P14949, P27773, P29828, P30101, P34329, P38657, P38659, P38660, P38661, P40557, P52588, P52589, P54399, P55059, P80284, P80579, Q00216, Q00248, Q0Z7W6, Q10057, Q14554, Q15084, Q17424, Q17967, Q1RKN1

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	1
Likely pathogenic	0
Uncertain significance	42
Likely benign	0
Benign	0

Top pathogenic / likely-pathogenic (1)

Variant ID	HGVS	Classification
57514	GRCh38/hg38 20p13-11.21(chr20:89939-25697564)x3	Pathogenic

SpliceAI

1408 predictions. Top by Δscore:

Variant	Effect	Δscore
20:7983788:ACTT:A	donor_loss	1.0000
20:7983790:TTA:T	donor_loss	1.0000
20:7983791:TACCA:T	donor_loss	1.0000
20:7983792:A:AC	donor_gain	1.0000
20:7983792:ACC:A	donor_loss	1.0000
20:7983793:C:A	donor_loss	1.0000
20:7983793:C:CC	donor_gain	1.0000
20:7983854:AGACC:A	acceptor_loss	1.0000
20:7983858:C:CC	acceptor_gain	1.0000
20:7983858:CT:C	acceptor_loss	1.0000
20:7983859:T:A	acceptor_loss	1.0000
20:7987397:C:CT	acceptor_gain	1.0000
20:7987398:A:T	acceptor_gain	1.0000
20:7999730:A:AC	donor_gain	1.0000
20:7999731:C:CC	donor_gain	1.0000
20:7999751:T:TA	donor_gain	1.0000
20:7999870:A:C	acceptor_gain	1.0000
20:8001494:A:AC	donor_gain	1.0000
20:8001495:C:CC	donor_gain	1.0000
20:7982258:C:A	donor_gain	0.9900
20:7982276:CTT:C	donor_gain	0.9900
20:7982277:TTT:T	donor_gain	0.9900
20:7982278:TTT:T	donor_gain	0.9900
20:7982304:C:CT	donor_gain	0.9900
20:7982305:C:CT	donor_gain	0.9900
20:7982369:T:TA	donor_gain	0.9900
20:7982617:CTGCT:C	acceptor_gain	0.9900
20:7982618:TGCT:T	acceptor_gain	0.9900
20:7982620:CT:C	acceptor_gain	0.9900
20:7982622:C:CC	acceptor_gain	0.9900

AlphaMissense

2299 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
20:8010270:C:A	W74C	1.000
20:8010270:C:G	W74C	1.000
20:7999779:C:A	W140C	0.999
20:7999779:C:G	W140C	0.999
20:7999781:A:G	W140R	0.999
20:7999781:A:T	W140R	0.999
20:7999840:C:G	R120P	0.999
20:8001508:G:T	P109Q	0.999
20:8001520:A:T	V105D	0.999
20:8001525:G:C	F103L	0.999
20:8001525:G:T	F103L	0.999
20:8001526:A:G	F103S	0.999
20:8001527:A:G	F103L	0.999
20:8010272:A:G	W74R	0.999
20:8010272:A:T	W74R	0.999
20:8010292:C:T	C67Y	0.999
20:8010302:A:G	C64R	0.999
20:8010303:C:A	W63C	0.999
20:8010303:C:G	W63C	0.999
20:8010305:A:G	W63R	0.999
20:8010305:A:T	W63R	0.999
20:8010315:A:C	F59L	0.999
20:8010315:A:T	F59L	0.999
20:8019439:A:G	F59L	0.999
20:8019473:C:A	W47C	0.999
20:8019473:C:G	W47C	0.999
20:8019475:A:G	W47R	0.999
20:8019475:A:T	W47R	0.999
20:7999807:A:G	L131P	0.998
20:7999835:A:C	Y122D	0.998

dbSNP variants (sampled 300 via entrez): RS1000104146 (20:7989422 A>T), RS1000337228 (20:8007822 T>A), RS1000355043 (20:7991726 A>G), RS1000613398 (20:7985237 G>A), RS1000686447 (20:7990277 A>G), RS1000701261 (20:7990082 G>T), RS1000736171 (20:8020553 G>C), RS1000744169 (20:7977128 G>A,C), RS1000788568 (20:8020901 A>T), RS1000798666 (20:7997318 T>C), RS1000870451 (20:7998986 G>C), RS1000993946 (20:7983310 T>A,C), RS1001004695 (20:8003335 C>T), RS1001094435 (20:7977368 AT>A,ATT), RS1001177407 (20:8015236 C>T)

Disease associations

OMIM: gene MIM:616766 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

3 associations (top):

Study	Trait	p-value
GCST003140_3	Chronic kidney disease	6.000000e-06
GCST009363_41	Triglyceride levels x short total sleep time interaction (2df test)	8.000000e-09
GCST009391_1096	Metabolite levels	7.000000e-06

EFO canonical traits (2, from GWAS)

EFO ID	Trait name
EFO:0004530	triglyceride measurement
EFO:0010446	2-hydroxyglutaric acid measurement

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
sodium arsenite	decreases expression, increases abundance	3
potassium chromate(VI)	affects cotreatment, increases expression, decreases expression	2
Cisplatin	increases expression, affects response to substance	2
Tretinoin	decreases expression, increases expression	2
Valproic Acid	affects expression, increases expression	2
FR900359	increases phosphorylation	1
triphenyl phosphate	affects expression	1
arsenite	increases methylation	1
cobaltous chloride	decreases expression	1
butyraldehyde	decreases expression	1
nickel sulfate	decreases expression	1
epigallocatechin gallate	affects cotreatment, increases expression	1
di-n-butylphosphoric acid	affects expression	1
chromium hexavalent ion	affects expression	1
monomethylarsonous acid	decreases expression	1
ICG 001	increases expression	1
abrine	decreases expression	1
Resveratrol	affects cotreatment, increases expression	1
Acetaminophen	increases expression	1
Arsenic	decreases expression, increases abundance	1
Benzo(a)pyrene	increases methylation	1
Cadmium	decreases expression	1
Coumestrol	affects cotreatment, increases expression	1
Dimethyl Sulfoxide	decreases expression	1
Doxorubicin	decreases expression	1
Formaldehyde	decreases expression	1
Isoflavones	affects expression	1
Smoke	decreases expression	1
Tetrachlorodibenzodioxin	increases expression	1
Thiram	decreases expression	1

Clinical trials (associated diseases)

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