HDX

Summary

HDX (highly divergent homeobox, HGNC:26411) is a protein-coding gene on chromosome Xq21.1, encoding Highly divergent homeobox (Q7Z353).

Predicted to enable DNA-binding transcription factor activity, RNA polymerase II-specific and RNA polymerase II cis-regulatory region sequence-specific DNA binding activity. Predicted to be involved in regulation of transcription by RNA polymerase II. Predicted to be located in chromatin.

Source: NCBI Gene 139324 — RefSeq curated summary.

At a glance

• GWAS associations: 2
• Clinical variants (ClinVar): 142 total
• MANE Select transcript: NM_001177479

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:26411
Approved symbol	HDX
Name	highly divergent homeobox
Location	Xq21.1
Locus type	gene with protein product
Status	Approved
Aliases	FLJ30678
Ensembl gene	ENSG00000165259
Ensembl biotype	protein_coding
OMIM	300994
Entrez	139324

Gene structure

Transcript identifiers

Ensembl transcripts: 15 — 13 protein_coding, 1 protein_coding_CDS_not_defined, 1 retained_intron

ENST00000297977, ENST00000373177, ENST00000449553, ENST00000465509, ENST00000472135, ENST00000506585, ENST00000851223, ENST00000851224, ENST00000851225, ENST00000851226, ENST00000851227, ENST00000933426, ENST00000933427, ENST00000933428, ENST00000951003

RefSeq mRNA: 3 — MANE Select: NM_001177479 NM_001177478, NM_001177479, NM_144657

CCDS: CCDS35342, CCDS55456

Canonical transcript exons

ENST00000373177 — 11 exons

Exon	Start	End
ENSE00001091691	84333759	84333842
ENSE00001091692	84336801	84336880
ENSE00001091693	84326178	84326300
ENSE00001091696	84440532	84440585
ENSE00001091697	84361466	84361612
ENSE00001091699	84344250	84344457
ENSE00001331631	84475251	84475397
ENSE00001459720	84488024	84488132
ENSE00002027855	84317878	84322014
ENSE00003696830	84468472	84469575
ENSE00003737820	84502342	84502453

Expression profiles

Bgee: expression breadth ubiquitous, 162 present calls, max score 85.59.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 5.1858 / max 166.3849, expressed in 1404 samples.

FANTOM5 promoters (2 alternative TSS)

Promoter ID	TPM avg	Samples expressed
199861	4.5471	1356
199862	0.6387	353

Top tissues by expression

245 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	85.59	gold quality
calcaneal tendon	UBERON:0003701	80.03	gold quality
ganglionic eminence	UBERON:0004023	79.32	gold quality
cortical plate	UBERON:0005343	77.12	gold quality
popliteal artery	UBERON:0002250	75.54	gold quality
tibial artery	UBERON:0007610	75.49	gold quality
monocyte	CL:0000576	75.28	gold quality
leukocyte	CL:0000738	74.72	gold quality
ventricular zone	UBERON:0003053	74.54	gold quality
aorta	UBERON:0000947	73.82	gold quality
islet of Langerhans	UBERON:0000006	73.77	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	73.44	gold quality
adrenal tissue	UBERON:0018303	73.21	gold quality
stromal cell of endometrium	CL:0002255	72.48	gold quality
descending thoracic aorta	UBERON:0002345	72.09	gold quality
ascending aorta	UBERON:0001496	71.98	gold quality
thoracic aorta	UBERON:0001515	71.98	gold quality
smooth muscle tissue	UBERON:0001135	71.08	gold quality
left coronary artery	UBERON:0001626	70.90	gold quality
gall bladder	UBERON:0002110	69.96	gold quality
coronary artery	UBERON:0001621	68.96	gold quality
right ovary	UBERON:0002118	68.65	gold quality
ectocervix	UBERON:0012249	68.45	gold quality
left ovary	UBERON:0002119	68.33	gold quality
body of uterus	UBERON:0009853	68.14	gold quality
right coronary artery	UBERON:0001625	67.40	gold quality
endocervix	UBERON:0000458	67.33	gold quality
mucosa of stomach	UBERON:0001199	67.01	gold quality
tibial nerve	UBERON:0001323	66.71	gold quality
prefrontal cortex	UBERON:0000451	66.57	gold quality

Single-cell (SCXA)

Detected in 3 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-GEOD-100618	yes	188.14
E-CURD-10	no	270.25
E-ANND-3	no	4.73

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

196 targeting HDX, 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-5692A	100.00	74.40	6850
HSA-MIR-3163	100.00	77.23	8605
HSA-MIR-4768-5P	100.00	69.49	2861
HSA-MIR-6833-3P	100.00	70.63	3197
HSA-MIR-3646	100.00	73.56	5283
HSA-MIR-340-5P	100.00	72.50	4437
HSA-MIR-1277-5P	100.00	73.95	5056
HSA-MIR-6867-5P	100.00	82.21	3464
HSA-MIR-7110-3P	100.00	73.18	2486
HSA-MIR-4668-3P	100.00	68.74	2635
HSA-MIR-513A-5P	100.00	69.77	2465
HSA-MIR-3185	99.99	68.12	1959
HSA-MIR-548AW	99.99	72.57	3559
HSA-MIR-513B-5P	99.99	69.96	2150
HSA-MIR-3662	99.99	73.82	5684
HSA-MIR-4500	99.99	72.72	2367
HSA-MIR-186-5P	99.99	70.83	3707
HSA-MIR-371B-5P	99.99	75.34	4759
HSA-MIR-548C-3P	99.99	74.01	7587
HSA-MIR-4531	99.99	69.70	3181
HSA-MIR-4775	99.98	75.00	6394
HSA-LET-7B-5P	99.98	72.31	1790
HSA-LET-7G-5P	99.98	72.37	1784
HSA-LET-7I-5P	99.98	72.37	1788
HSA-MIR-4482-3P	99.98	72.50	3147
HSA-MIR-548N	99.98	71.94	4170
HSA-LET-7A-5P	99.98	72.29	1790
HSA-LET-7C-5P	99.98	72.29	1790
HSA-LET-7E-5P	99.98	72.29	1790
HSA-LET-7F-5P	99.98	72.56	1784

Literature-anchored findings (GeneRIF, showing 1)

• HDX negatively regulates EPAS1 expression through a release-of-inhibition mechanism. (PMID:29577908)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	hdx	ENSDARG00000079382
mus_musculus	Hdx	ENSMUSG00000034551
rattus_norvegicus	Hdx	ENSRNOG00000037799
drosophila_melanogaster	acj6	FBGN0000028
caenorhabditis_elegans		WBGENE00006818

Paralogs (17): POU2F2 (ENSG00000028277), POU1F1 (ENSG00000064835), POU4F3 (ENSG00000091010), POU6F2 (ENSG00000106536), POU2F3 (ENSG00000137709), POU2F1 (ENSG00000143190), POU4F2 (ENSG00000151615), POU4F1 (ENSG00000152192), POU6F1 (ENSG00000184271), POU3F2 (ENSG00000184486), POU3F1 (ENSG00000185668), POU3F4 (ENSG00000196767), POU3F3 (ENSG00000198914), CCDC160 (ENSG00000203952), POU5F1 (ENSG00000204531), POU5F1B (ENSG00000212993), POU5F2 (ENSG00000248483)

Protein

Protein identifiers

Highly divergent homeobox — Q7Z353 (reviewed: Q7Z353)

All UniProt accessions (2): E2QRN0, Q7Z353

UniProt curated annotations — full annotation on UniProt →

Subcellular location. Nucleus.

Isoforms (2)

UniProt ID	Names	Canonical?
Q7Z353-1	1	yes
Q7Z353-2	2

RefSeq proteins (3): NP_001170949, NP_001170950, NP_653258 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001356	HD	Domain
IPR009057	Homeodomain-like_sf	Homologous_superfamily
IPR050255	POU_domain_TF	Family

UniProt features (27 total): cross-link 10, region of interest 4, helix 3, compositionally biased region 3, DNA-binding region 2, sequence variant 2, chain 1, splice variant 1, turn 1

Structure

Experimental structures (PDB)

1 structures.

PDB	Method	Resolution (Å)
2DA4	SOLUTION NMR

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q7Z353-F1	56.42	0.23

Functional residue map

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

Post-translational modifications (10): 135, 140, 144, 163, 172, 194, 212, 221, 232, 613

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 108 (showing top): TGCGCANK_UNKNOWN, CREBP1_Q2, CREB_Q4, WTGAAAT_UNKNOWN, E4F1_Q6, AACTTT_UNKNOWN, TGGNNNNNNKCCAR_UNKNOWN, CREBP1CJUN_01, CREB_01, TGACGTCA_ATF3_Q6, GOMF_SEQUENCE_SPECIFIC_DNA_BINDING, CREB_Q2, chrXq21, SREBP_Q3, GSE13522_WT_VS_IFNG_KO_SKING_T_CRUZI_Y_STRAIN_INF_DN

GO Biological Process (1): regulation of transcription by RNA polymerase II (GO:0006357)

GO Molecular Function (4): RNA polymerase II cis-regulatory region sequence-specific DNA binding (GO:0000978), DNA-binding transcription factor activity, RNA polymerase II-specific (GO:0000981), DNA binding (GO:0003677), protein binding (GO:0005515)

GO Cellular Component (2): chromatin (GO:0000785), nucleus (GO:0005634)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
RNA polymerase II transcription regulatory region sequence-specific DNA binding	2
regulation of DNA-templated transcription	1
transcription by RNA polymerase II	1
cis-regulatory region sequence-specific DNA binding	1
chromatin	1
DNA-binding transcription factor activity	1
regulation of transcription by RNA polymerase II	1
nucleic acid binding	1
binding	1
chromosome	1
cellular anatomical structure	1
intracellular membrane-bounded organelle	1

Protein interactions and networks

STRING

398 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
HDX	SMIM1	B2RUZ4	572
HDX	HOMEZ	Q8IX15	394
HDX	TRO	Q12816	364
HDX	KRT86	P78387	336
HDX	PSME3	P61289	325
HDX	DYM	Q7RTS9	313
HDX	GNAS	Q5JWF2	305
HDX	POLE	Q07864	296
HDX	RFX2	P48378	290
HDX	CFAP52	Q8N1V2	284
HDX	PSME2	Q9UL46	276
HDX	GNS	P15586	271
HDX	PAMR1	Q6UXH9	270
HDX	TGIF2LX	Q8IUE1	270
HDX	PSME1	Q06323	269
HDX	TGIF2LY	Q8IUE0	269

IntAct

53 interactions, top by confidence:

A	B	Type	Score
HDX	SUFU	psi-mi:“MI:0915”(physical association)	0.670
SUFU	HDX	psi-mi:“MI:0915”(physical association)	0.670
BOLA2-SMG1P6	HDX	psi-mi:“MI:0915”(physical association)	0.560
POLR1C	HDX	psi-mi:“MI:0915”(physical association)	0.560
HDX	MID2	psi-mi:“MI:0915”(physical association)	0.560
HDX	BOLA1	psi-mi:“MI:0915”(physical association)	0.560
HDX	RTN4IP1	psi-mi:“MI:0915”(physical association)	0.560
HDX	TSGA10	psi-mi:“MI:0915”(physical association)	0.560
CCDC57	HDX	psi-mi:“MI:0915”(physical association)	0.560
HDX	GCC1	psi-mi:“MI:0915”(physical association)	0.560
HDX	LNX1	psi-mi:“MI:0915”(physical association)	0.560
HDX	CTNNA3	psi-mi:“MI:0915”(physical association)	0.560
LMO1	HDX	psi-mi:“MI:0915”(physical association)	0.560
FHL5	HDX	psi-mi:“MI:0915”(physical association)	0.560
HDX	TTC5	psi-mi:“MI:0915”(physical association)	0.560
ZBTB16	HDX	psi-mi:“MI:0915”(physical association)	0.370
Arhgap33	MAP3K7	psi-mi:“MI:0914”(association)	0.350
Arhgap18	KRT86	psi-mi:“MI:0914”(association)	0.350
CTBP1	GSN	psi-mi:“MI:0914”(association)	0.350
MAPT	SHTN1	psi-mi:“MI:0914”(association)	0.350
SCRIB	CHD2	psi-mi:“MI:0914”(association)	0.350
POLR1E	HDX	psi-mi:“MI:0915”(physical association)	0.000
BOLA2-SMG1P6	HDX	psi-mi:“MI:0915”(physical association)	0.000
POLR1C	HDX	psi-mi:“MI:0915”(physical association)	0.000
MID2	HDX	psi-mi:“MI:0915”(physical association)	0.000
BOLA1	HDX	psi-mi:“MI:0915”(physical association)	0.000
TTC5	HDX	psi-mi:“MI:0915”(physical association)	0.000

BioGRID (38): HDX (Affinity Capture-MS), HDX (Affinity Capture-MS), HDX (Affinity Capture-MS), HDX (Affinity Capture-MS), HDX (Two-hybrid), HDX (Two-hybrid), HDX (Two-hybrid), HDX (Two-hybrid), HDX (Two-hybrid), HDX (Two-hybrid), HDX (Two-hybrid), LMO1 (Two-hybrid), BOLA2B (Two-hybrid), POLR1C (Two-hybrid), CCDC57 (Two-hybrid)

ESM2 similar proteins: A0AVK6, A4L9P5, B2GUN4, D2HNW6, D3ZGB1, E1BKK0, E1BP74, E1BZ85, F1LMN3, O14607, O15164, O15550, O70546, O88850, O88904, O94916, Q14B70, Q58CW6, Q58FA4, Q5RJA1, Q5ZKW8, Q64127, Q6B4Z3, Q7Z353, Q7Z3K3, Q84VX4, Q86Z02, Q8BJ34, Q8BZH4, Q8C7R7, Q8HWS3, Q8IXK0, Q8K0L9, Q8N187, Q93073, Q99743, Q99MQ1, Q99PP7, Q9BYH8, Q9ERH7

Diamond homologs: Q14B70, Q5ZKW8, Q7Z353

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	58
Likely benign	3
Benign	6

Top pathogenic / likely-pathogenic (0)

SpliceAI

2332 predictions. Top by Δscore:

Variant	Effect	Δscore
X:84326172:ACCT:A	donor_loss	1.0000
X:84326176:ACC:A	donor_loss	1.0000
X:84326177:C:CT	donor_loss	1.0000
X:84326177:CCTG:C	donor_gain	1.0000
X:84326297:CATT:C	acceptor_gain	1.0000
X:84326299:TT:T	acceptor_gain	1.0000
X:84326300:TC:T	acceptor_loss	1.0000
X:84326301:C:CC	acceptor_gain	1.0000
X:84326302:T:A	acceptor_loss	1.0000
X:84333755:CTA:C	donor_loss	1.0000
X:84333757:A:C	donor_loss	1.0000
X:84333839:TTTT:T	acceptor_gain	1.0000
X:84333840:TTT:T	acceptor_gain	1.0000
X:84333841:TT:T	acceptor_gain	1.0000
X:84333841:TTC:T	acceptor_loss	1.0000
X:84333842:TCT:T	acceptor_loss	1.0000
X:84333843:C:CA	acceptor_loss	1.0000
X:84333843:C:CC	acceptor_gain	1.0000
X:84333849:C:CT	acceptor_gain	1.0000
X:84336795:ACAT:A	donor_loss	1.0000
X:84336797:ATACC:A	donor_loss	1.0000
X:84336798:TA:T	donor_loss	1.0000
X:84336799:A:AC	donor_gain	1.0000
X:84336799:A:AG	donor_loss	1.0000
X:84336800:C:CC	donor_gain	1.0000
X:84336800:CCA:C	donor_gain	1.0000
X:84336876:CTCTT:C	acceptor_gain	1.0000
X:84336878:CTT:C	acceptor_gain	1.0000
X:84336879:TT:T	acceptor_gain	1.0000
X:84336879:TTCTA:T	acceptor_loss	1.0000

AlphaMissense

4544 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
X:84344454:A:G	W486R	1.000
X:84344454:A:T	W486R	1.000
X:84361470:A:T	V483D	1.000
X:84469570:C:A	W51C	1.000
X:84469570:C:G	W51C	1.000
X:84469572:A:G	W51R	1.000
X:84469572:A:T	W51R	1.000
X:84475255:A:T	V48D	1.000
X:84475263:G:C	F45L	1.000
X:84475263:G:T	F45L	1.000
X:84475265:A:G	F45L	1.000
X:84475270:A:G	L43P	1.000
X:84475287:A:C	C37W	1.000
X:84475289:A:G	C37R	1.000
X:84475305:A:C	F31L	1.000
X:84475305:A:T	F31L	1.000
X:84475306:A:C	F31C	1.000
X:84475307:A:G	F31L	1.000
X:84475330:A:G	M23T	1.000
X:84475354:A:G	L15S	1.000
X:84475378:A:G	F7S	1.000
X:84344434:C:A	R492S	0.999
X:84344434:C:G	R492S	0.999
X:84344435:C:G	R492T	0.999
X:84344437:T:A	R491S	0.999
X:84344437:T:G	R491S	0.999
X:84344438:C:G	R491T	0.999
X:84344441:C:G	R490P	0.999
X:84344452:C:A	W486C	0.999
X:84344452:C:G	W486C	0.999

dbSNP variants (sampled 300 via entrez): RS1000004518 (X:84466642 A>C), RS1000012299 (X:84400672 T>A,C), RS1000046092 (X:84473446 G>A), RS1000047111 (X:84405844 A>G), RS1000067807 (X:84459230 C>T), RS1000097273 (X:84353390 G>A), RS1000150821 (X:84490179 T>C), RS1000183713 (X:84339520 G>A), RS1000197765 (X:84343611 G>A), RS1000215885 (X:84483114 C>A,G), RS1000236145 (X:84339950 G>A), RS1000247262 (X:84320238 A>G), RS1000251168 (X:84373242 T>C), RS1000262378 (X:84427996 T>G), RS1000266843 (X:84483611 G>A)

Disease associations

OMIM: gene MIM:300994 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

2 associations (top):

Study	Trait	p-value
GCST008295_8	Number of decayed, missing and filled tooth surfaces or use of dentures	2.000000e-08
GCST008306_22	Dentures	2.000000e-07

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0010078	dentures

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

20 total (human), top 20 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects expression, decreases expression, decreases methylation, increases expression	6
Benzo(a)pyrene	affects methylation, increases expression	2
aristolochic acid I	decreases expression	1
GSK-J4	decreases expression	1
TAK-243	increases sumoylation	1
sodium arsenite	decreases expression	1
ferrous chloride	decreases expression	1
entinostat	decreases expression	1
abrine	increases expression	1
jinfukang	affects cotreatment, decreases expression	1
Sunitinib	decreases expression	1
Acetaminophen	increases expression	1
Air Pollutants	decreases expression, increases abundance	1
Amiodarone	increases expression	1
Cisplatin	affects cotreatment, decreases expression	1
Doxorubicin	decreases expression	1
Thimerosal	increases expression	1
Cyclosporine	increases expression	1
Aflatoxin B1	decreases methylation	1
Particulate Matter	decreases expression, increases abundance	1

Clinical trials (associated diseases)

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