ESX1

Summary

ESX1 (ESX homeobox 1, HGNC:14865) is a protein-coding gene on chromosome Xq22.2, encoding Homeobox protein ESX1 (Q8N693). May coordinately regulate cell cycle progression and transcription during spermatogenesis.

This gene encodes a dual-function 65 kDa protein that undergoes proteolytic cleavage to produce a 45 kDa N-terminal fragment with a paired-like homeodomain and a 20 kDa C-terminal fragment with a proline-rich domain. The C-terminal fragment localizes to the cytoplasm while the N-terminal fragment localizes exclusively to the nucleus. In contrast to human, the mouse homolog has a novel PN/PF motif in the C-terminus and is paternally imprinted in placental tissue. This gene likely plays a role in placental development and spermatogenesis.

Source: NCBI Gene 80712 — RefSeq curated summary.

At a glance

• Clinical variants (ClinVar): 79 total — 1 pathogenic, 2 likely-pathogenic
• MANE Select transcript: NM_153448

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:14865
Approved symbol	ESX1
Name	ESX homeobox 1
Location	Xq22.2
Locus type	gene with protein product
Status	Approved
Aliases	ESXR1
Ensembl gene	ENSG00000123576
Ensembl biotype	protein_coding
OMIM	300154
Entrez	80712

Gene structure

Transcript identifiers

Ensembl transcripts: 1 — 1 protein_coding

ENST00000372588

RefSeq mRNA: 1 — MANE Select: NM_153448 NM_153448

CCDS: CCDS14516

Canonical transcript exons

ENST00000372588 — 4 exons

Exon	Start	End
ENSE00000840326	104254154	104254577
ENSE00000840327	104252783	104252828
ENSE00001458161	104250038	104250896
ENSE00001458163	104254768	104254933

Expression profiles

Bgee: expression breadth broad, 23 present calls, max score 81.24.

FANTOM5 (CAGE): breadth tissue_specific, TPM avg 0.1428 / max 69.8515, expressed in 38 samples.

FANTOM5 promoters (2 alternative TSS)

Promoter ID	TPM avg	Samples expressed
200036	0.1058	27
200037	0.0370	16

Top tissues by expression

244 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	81.24	gold quality
right testis	UBERON:0004534	75.55	gold quality
left testis	UBERON:0004533	73.77	gold quality
testis	UBERON:0000473	73.45	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	71.09	gold quality
adult organism	UBERON:0007023	63.42	gold quality
lower lobe of lung	UBERON:0008949	54.22	silver quality
epithelium of nasopharynx	UBERON:0001951	53.07	gold quality
colonic epithelium	UBERON:0000397	49.55	gold quality
sperm	CL:0000019	43.92	silver quality
skeletal muscle tissue of rectus abdominis	UBERON:0004511	43.37	gold quality
secondary oocyte	CL:0000655	42.57	gold quality
pharyngeal mucosa	UBERON:0000355	42.45	gold quality
vastus lateralis	UBERON:0001379	41.41	gold quality
quadriceps femoris	UBERON:0001377	41.37	gold quality
superficial temporal artery	UBERON:0001614	41.33	gold quality
skin of hip	UBERON:0001554	41.23	silver quality
inferior vagus X ganglion	UBERON:0005363	41.12	gold quality
palpebral conjunctiva	UBERON:0001812	41.10	gold quality
subthalamic nucleus	UBERON:0001906	41.03	gold quality
mucosa of paranasal sinus	UBERON:0005030	40.98	gold quality
amniotic fluid	UBERON:0000173	40.69	gold quality
jejunal mucosa	UBERON:0000399	40.59	gold quality
biceps brachii	UBERON:0001507	40.57	gold quality
myocardium	UBERON:0002349	40.45	gold quality
gingival epithelium	UBERON:0001949	40.43	gold quality
germinal epithelium of ovary	UBERON:0001304	40.33	gold quality
esophagus squamous epithelium	UBERON:0006920	40.29	gold quality
skeletal muscle tissue of biceps brachii	UBERON:0004502	40.27	gold quality
dorsal plus ventral thalamus	UBERON:0001897	40.22	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	no	0.65

Regulation

Is transcription factor: yes

Downstream targets (CollecTRI)

2 targets.

Target	Regulation
KRAS	Repression
PTPRVP

JASPAR motifs

Motif	Name	Family
MA0644.1	ESX1	Paired-related HD factors
MA0644.2	ESX1	Paired-related HD factors
MA0644.3	ESX1	Paired-related HD factors

JASPAR matrix evidence (PMIDs): PMID:18585359

Upstream regulators (CollecTRI, top): DLX3, SMAD6

miRNA regulators (miRDB)

13 targeting ESX1, 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-5696	99.98	72.36	4487
HSA-MIR-3148	99.97	75.06	6478
HSA-MIR-548AR-3P	99.85	71.26	3889
HSA-MIR-548AZ-3P	99.82	70.56	3549
HSA-MIR-548BC	99.82	70.61	3524
HSA-MIR-548E-3P	99.82	70.59	3514
HSA-MIR-548F-3P	99.82	70.59	3540
HSA-MIR-548A-3P	99.76	70.58	3524
HSA-MIR-548G-3P	99.48	68.67	2159
HSA-MIR-6868-5P	99.06	65.69	1284
HSA-MIR-4511	98.32	67.97	1500
HSA-MIR-3126-3P	97.17	66.51	468
HSA-MIR-7108-5P	96.42	66.17	598

Literature-anchored findings (GeneRIF, showing 8)

• proteolytic processing of ESXR1 plays a role in concerted regulation of the cell cycle and transcription in human cells (PMID:15235584)
• ESX1L is expressed during all stages of placental development and is localized to sparse areas of trophoblast in terminal villi in association with cytotrophoblastic cells (PMID:15601583)
• In FGR-affected placentae, ESX1L levels were lower than in gestation-matched controls, indicating a potential role for the ESX1L gene within the growth control mechanism of the fetus, through its effect on placental function. (PMID:16613891)
• ESX1 emerges as a potentially reliable molecular marker of residual spermatogenesis in azoospermic men (PMID:20356899)
• ESX1 mRNA level decreases as the severity of spermatogenic defects increase in non-obstructive azoospermic men. (PMID:25316452)
• Could analysis of testis-specific genes, as biomarkers in seminal plasma, predict presence of focal spermatogenesis in non-obstructive azoospermia? (PMID:31793700)
• Association of ESX1 gene variants with non-obstructive azoospermia in Chinese males. (PMID:33633269)
• ESX1 gene as a potential candidate responsible for male infertility in nonobstructive azoospermia. (PMID:37783880)

Cross-species orthologs

2 orthologs

Organism	Symbol	Gene ID
mus_musculus	Esx1	ENSMUSG00000023443
rattus_norvegicus	AABR07040695.1	ENSRNOG00000048011

Paralogs (50): ARX (ENSG00000004848), PAX6 (ENSG00000007372), PAX7 (ENSG00000009709), ALX4 (ENSG00000052850), GSC2 (ENSG00000063515), PITX1 (ENSG00000069011), PAX2 (ENSG00000075891), RHOXF1 (ENSG00000101883), CRX (ENSG00000105392), EVX1 (ENSG00000106038), PAX4 (ENSG00000106331), NOBOX (ENSG00000106410), PITX3 (ENSG00000107859), PHOX2B (ENSG00000109132), OTX1 (ENSG00000115507), PRRX1 (ENSG00000116132), VSX2 (ENSG00000119614), PAX8 (ENSG00000125618), PAX1 (ENSG00000125813), RHOXF2 (ENSG00000131721), GSC (ENSG00000133937), RAX (ENSG00000134438), PAX3 (ENSG00000135903), ALX3 (ENSG00000156150), HESX1 (ENSG00000163666), PITX2 (ENSG00000164093), UNCX (ENSG00000164853), PHOX2A (ENSG00000165462), OTX2 (ENSG00000165588), DRGX (ENSG00000165606), PRRX2 (ENSG00000167157), SHOX2 (ENSG00000168779), OTP (ENSG00000171540), RAX2 (ENSG00000173976), EVX2 (ENSG00000174279), PROP1 (ENSG00000175325), ISX (ENSG00000175329), ALX1 (ENSG00000180318), MIXL1 (ENSG00000185155), SHOX (ENSG00000185960)

Protein

Protein identifiers

Homeobox protein ESX1 — Q8N693 (reviewed: Q8N693)

Alternative names: Extraembryonic, spermatogenesis, homeobox 1

All UniProt accessions (1): Q8N693

UniProt curated annotations — full annotation on UniProt →

Function. May coordinately regulate cell cycle progression and transcription during spermatogenesis. Inhibits degradation of polyubiquitinated cyclin A and cyclin B1 and thereby arrests the cell cycle at early M phase. ESXR1-N acts as a transcriptional repressor. Binds to the sequence 5’-TAATGTTATTA-3’ which is present within the first intron of the KRAS gene and inhibits its expression. ESXR1-C has the ability to inhibit cyclin turnover.

Subcellular location. Cytoplasm. Nucleus.

Tissue specificity. Expressed in placenta and testis. Expressed in testicular germ cell tumors.

Post-translational modifications. Undergoes proteolytic cleavage; produces a 45 kDa N-terminal homeodomain-containing fragment (ESXR1-N) and a 20 kDa C-terminal fragment (ESXR1-C).

RefSeq proteins (1): NP_703149* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001356	HD	Domain
IPR009057	Homeodomain-like_sf	Homologous_superfamily
IPR013847	POU	Domain
IPR017970	Homeobox_CS	Conserved_site
IPR050649	Paired_Homeobox_TFs	Family

Pfam: PF00046

UniProt features (30 total): repeat 15, region of interest 4, chain 3, compositionally biased region 3, sequence conflict 2, DNA-binding region 1, short sequence motif 1, sequence variant 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q8N693-F1	62.35	0.15

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 35 (showing top): BENPORATH_ES_WITH_H3K27ME3, GOBP_NEUROGENESIS, GOBP_REGULATION_OF_CELL_CYCLE, MARTIN_VIRAL_GPCR_SIGNALING_DN, CONRAD_GERMLINE_STEM_CELL, GOCC_NUCLEAR_SPECK, GOCC_NUCLEAR_BODY, GOCC_RIBONUCLEOPROTEIN_GRANULE, GOMF_SEQUENCE_SPECIFIC_DNA_BINDING, MEISSNER_BRAIN_HCP_WITH_H3K27ME3, HATADA_METHYLATED_IN_LUNG_CANCER_UP, chrXq22, GOBP_NEGATIVE_REGULATION_OF_TRANSCRIPTION_BY_RNA_POLYMERASE_II, GOBP_NEGATIVE_REGULATION_OF_NUCLEOBASE_CONTAINING_COMPOUND_METABOLIC_PROCESS, WANG_MLL_TARGETS

GO Biological Process (6): negative regulation of transcription by RNA polymerase II (GO:0000122), regulation of transcription by RNA polymerase II (GO:0006357), negative regulation of DNA-templated transcription (GO:0045892), neuron development (GO:0048666), regulation of cell cycle (GO:0051726), regulation of DNA-templated transcription (GO:0006355)

GO Molecular Function (6): RNA polymerase II transcription regulatory region sequence-specific DNA binding (GO:0000977), DNA-binding transcription factor activity, RNA polymerase II-specific (GO:0000981), DNA-binding transcription repressor activity, RNA polymerase II-specific (GO:0001227), sequence-specific DNA binding (GO:0043565), sequence-specific double-stranded DNA binding (GO:1990837), DNA binding (GO:0003677)

GO Cellular Component (4): chromatin (GO:0000785), nucleus (GO:0005634), cytoplasm (GO:0005737), nuclear speck (GO:0016607)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
regulation of transcription by RNA polymerase II	2
transcription by RNA polymerase II	2
regulation of DNA-templated transcription	2
DNA-templated transcription	2
RNA polymerase II transcription regulatory region sequence-specific DNA binding	2
cellular anatomical structure	2
negative regulation of DNA-templated transcription	1
negative regulation of RNA biosynthetic process	1
neuron differentiation	1
cell development	1
cell cycle	1
regulation of cellular process	1
regulation of gene expression	1
regulation of RNA biosynthetic process	1
transcription cis-regulatory region binding	1
chromatin	1
DNA-binding transcription factor activity	1
negative regulation of transcription by RNA polymerase II	1
DNA-binding transcription factor activity, RNA polymerase II-specific	1
DNA-binding transcription repressor activity	1
DNA binding	1
double-stranded DNA binding	1
sequence-specific DNA binding	1
nucleic acid binding	1
chromosome	1
intracellular membrane-bounded organelle	1
intracellular anatomical structure	1
nuclear ribonucleoprotein granule	1

Protein interactions and networks

STRING

1538 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
ESX1	PDE6B	P35913	869
ESX1	LHX4	Q969G2	823
ESX1	POU1F1	P28069	783
ESX1	LHX3	Q9UBR4	774
ESX1	ELF3	P78545	771
ESX1	SOX3	P35714	718
ESX1	SOX2	P48431	684
ESX1	PROKR2	Q8NFJ6	647
ESX1	GHRHR	Q02643	578
ESX1	POU5F1	P31359	575
ESX1	TBX19	O60806	554
ESX1	CGAS	Q8N884	549
ESX1	RD3	Q7Z3Z2	519
ESX1	ANOS1	P23352	489
ESX1	CALCOCO2	Q13137	484

IntAct

8 interactions, top by confidence:

A	B	Type	Score
	ESX1	psi-mi:“MI:0915”(physical association)	0.520
ESX1		psi-mi:“MI:0915”(physical association)	0.520
ESX1	Dlg4	psi-mi:“MI:0407”(direct interaction)	0.440
TRAP1	ESX1	psi-mi:“MI:0915”(physical association)	0.370
ESX1	EXOC2	psi-mi:“MI:0915”(physical association)	0.370
ESX1		psi-mi:“MI:0914”(association)	0.350

BioGRID (6): ESX1 (Affinity Capture-MS), ESX1 (Co-fractionation), ESX1 (Co-fractionation), ESX1 (Affinity Capture-RNA), EXOC2 (Two-hybrid), TRAP1 (Two-hybrid)

ESM2 similar proteins: A0A087WUL8, A0A0J9YWL9, A0A0J9YY54, A0A0U1RQI7, A6NJ88, A6QL64, B4DH59, D3ZVV1, E9Q6E9, F1LWT0, O04492, O88799, P0DKJ7, P0DKJ8, P0DKL2, P0DPF3, P18583, P53353, Q08AG5, Q0P6D6, Q2EG98, Q3BBV2, Q4ZJZ1, Q5HY64, Q5JPF3, Q5QGU6, Q5TAG4, Q5TI25, Q5XHX6, Q6P3W6, Q6P902, Q6XPR3, Q6ZQX7, Q86T75, Q86VE3, Q86VQ3, Q8N2N9, Q8N660, Q8N693, Q96EQ9

Diamond homologs: A0A1W2PPK0, A0A1W2PPM1, A1A546, A1YEY5, A1YFI3, A1YG57, A1YGA2, A2T733, A2T777, A2T7P4, A6NFQ7, G5EC89, L8E946, O14813, O15499, O35690, O42250, O42356, O42357, O42477, O70137, O73917, O75360, O95076, O97670, P0DMV5, P26367, P26630, P29454, P41935, P47237, P47238, P53544, P53545, P53546, P54366, P55813, P55864, P56915, P56916

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	1
Likely pathogenic	2
Uncertain significance	54
Likely benign	15
Benign	2

Top pathogenic / likely-pathogenic (3)

Variant ID	HGVS	Classification
1706520	GRCh37/hg19 Xq21.1-28(chrX:77670699-155233731)x1	Pathogenic
1526837	GRCh37/hg19 Xq22.2-22.3(chrX:103046942-104214535)	Likely pathogenic
2690946	NM_153448.4(ESX1):c.1094C>G (p.Pro365Arg)	Likely pathogenic

SpliceAI

372 predictions. Top by Δscore:

Variant	Effect	Δscore
X:104251617:T:TA	donor_gain	1.0000
X:104252830:T:C	acceptor_gain	1.0000
X:104254147:CACTT:C	donor_loss	1.0000
X:104254148:ACTT:A	donor_loss	1.0000
X:104254149:CTTA:C	donor_loss	1.0000
X:104254150:TTAC:T	donor_loss	1.0000
X:104254151:TA:T	donor_loss	1.0000
X:104254152:A:AC	donor_gain	1.0000
X:104254152:A:AG	donor_loss	1.0000
X:104254153:C:CG	donor_gain	1.0000
X:104254153:CCG:C	donor_gain	1.0000
X:104254153:CCGCG:C	donor_gain	1.0000
X:104254776:T:TA	donor_gain	1.0000
X:104250892:CAAAC:C	acceptor_gain	0.9900
X:104250894:AACC:A	acceptor_loss	0.9900
X:104250897:CTT:C	acceptor_loss	0.9900
X:104250900:C:CT	acceptor_gain	0.9900
X:104251618:C:A	donor_gain	0.9900
X:104252830:T:TC	acceptor_gain	0.9900
X:104254152:AC:A	donor_gain	0.9900
X:104254152:ACCG:A	donor_gain	0.9900
X:104254153:CC:C	donor_gain	0.9900
X:104254153:CCGC:C	donor_gain	0.9900
X:104254777:C:A	donor_gain	0.9900
X:104250894:AAC:A	acceptor_gain	0.9800
X:104250895:AC:A	acceptor_gain	0.9800
X:104250896:CC:C	acceptor_gain	0.9800
X:104250897:C:CC	acceptor_gain	0.9800
X:104250897:C:T	acceptor_gain	0.9800
X:104250901:A:T	acceptor_gain	0.9800

AlphaMissense

2614 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
X:104250888:A:C	F187L	0.999
X:104250888:A:T	F187L	0.999
X:104250890:A:G	F187L	0.999
X:104254222:G:C	F146L	0.999
X:104254222:G:T	F146L	0.999
X:104254224:A:G	F146L	0.999
X:104250889:A:G	F187S	0.998
X:104254186:G:C	F158L	0.998
X:104254186:G:T	F158L	0.998
X:104254188:A:G	F158L	0.998
X:104250876:T:A	R191S	0.997
X:104250876:T:G	R191S	0.997
X:104250879:T:A	R190S	0.997
X:104250879:T:G	R190S	0.997
X:104250891:C:A	W186C	0.997
X:104250891:C:G	W186C	0.997
X:104250893:A:G	W186R	0.997
X:104250893:A:T	W186R	0.997
X:104254199:A:G	L154P	0.997
X:104254223:A:C	F146C	0.997
X:104254223:A:G	F146S	0.997
X:104250880:C:A	R190I	0.996
X:104250880:C:G	R190T	0.996
X:104250884:T:C	N189D	0.996
X:104254172:T:C	Y163C	0.996
X:104254208:A:G	L151P	0.996
X:104250870:C:A	K193N	0.995
X:104250870:C:G	K193N	0.995
X:104250877:C:G	R191T	0.995
X:104250883:T:C	N189S	0.995

dbSNP variants (sampled 300 via entrez): RS1000400132 (X:104255795 C>T), RS1000703516 (X:104253453 T>C), RS1001115927 (X:104253870 T>C), RS1002103890 (X:104252397 T>C), RS1003156087 (X:104250256 T>C), RS1004245810 (X:104256513 T>A,G), RS1004618930 (X:104255890 C>A,G), RS1006231366 (X:104252359 C>T), RS1006633442 (X:104251999 T>C,G), RS1007734351 (X:104251916 G>C), RS1009462543 (X:104253429 C>A), RS1010446 (X:104251066 C>A,G,T), RS1011178582 (X:104251264 T>C), RS1011976475 (X:104250207 A>T), RS1012334049 (X:104249847 G>A)

Disease associations

OMIM: gene MIM:300154 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (1): Male infertility with azoospermia or oligozoospermia due to single gene mutation (Orphanet:399805)

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

9 total (human), top 9 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects expression, increases methylation	2
sodium arsenite	decreases expression	1
butyraldehyde	increases expression	1
pentanal	increases expression	1
entinostat	increases expression	1
(+)-JQ1 compound	decreases expression	1
Arsenic Trioxide	increases expression	1
Benzo(a)pyrene	affects methylation, increases methylation	1
Dust	decreases expression	1

Cellosaurus cell lines

3 cell lines: 3 embryonic stem cell

First 10 cell lines (id-ordered, not curated):

Cellosaurus	Name	Category	Sex
CVCL_A1L9	SEES3-1V human ESX1, clone1	Embryonic stem cell	Male
CVCL_A1M0	SEES3-1V human ESX1, clone2	Embryonic stem cell	Male
CVCL_A1M1	SEES3-1V human ESX1, clone3	Embryonic stem cell	Male

Clinical trials (associated diseases)

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