HOXD4

Summary

HOXD4 (homeobox D4, HGNC:5138) is a protein-coding gene on chromosome 2q31.1, encoding Homeobox protein Hox-D4 (P09016). Sequence-specific transcription factor which is part of a developmental regulatory system that provides cells with specific positional identities on the anterior-posterior axis.

This gene belongs to the homeobox family of genes. The homeobox genes encode a highly conserved family of transcription factors that play an important role in morphogenesis in all multicellular organisms. Mammals possess four similar homeobox gene clusters, HOXA, HOXB, HOXC and HOXD, located on different chromosomes, consisting of 9 to 11 genes arranged in tandem. This gene is one of several homeobox HOXD genes located at 2q31-2q37 chromosome regions. Deletions that removed the entire HOXD gene cluster or 5’ end of this cluster have been associated with severe limb and genital abnormalities. The protein encoded by this gene may play a role in determining positional values in developing limb buds. Alternatively spliced variants have been described but their full length nature has not been determined.

Source: NCBI Gene 3233 — RefSeq curated summary.

At a glance

• GWAS associations: 5
• Clinical variants (ClinVar): 30 total
• MANE Select transcript: NM_014621

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:5138
Approved symbol	HOXD4
Name	homeobox D4
Location	2q31.1
Locus type	gene with protein product
Status	Approved
Ensembl gene	ENSG00000170166
Ensembl biotype	protein_coding
OMIM	142981
Entrez	3233

Gene structure

Transcript identifiers

Ensembl transcripts: 1 — 1 protein_coding

ENST00000306324

RefSeq mRNA: 1 — MANE Select: NM_014621 NM_014621

CCDS: CCDS2269

Canonical transcript exons

ENST00000306324 — 2 exons

Exon	Start	End
ENSE00001133149	176152608	176153226
ENSE00001133159	176151550	176152066

Expression profiles

Bgee: expression breadth ubiquitous, 127 present calls, max score 91.15.

FANTOM5 (CAGE): breadth tissue_specific, TPM avg 0.4178 / max 20.2666, expressed in 157 samples.

FANTOM5 promoters (3 alternative TSS)

Promoter ID	TPM avg	Samples expressed
23863	0.2136	105
23864	0.1462	77
23865	0.0580	23

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
body of uterus	UBERON:0009853	91.15	gold quality
right uterine tube	UBERON:0001302	90.31	gold quality
corpus epididymis	UBERON:0004359	90.00	gold quality
metanephros cortex	UBERON:0010533	87.79	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	87.26	gold quality
right ovary	UBERON:0002118	86.98	gold quality
left ovary	UBERON:0002119	85.95	gold quality
left uterine tube	UBERON:0001303	83.15	gold quality
cauda epididymis	UBERON:0004360	82.93	gold quality
adult mammalian kidney	UBERON:0000082	81.69	gold quality
left adrenal gland cortex	UBERON:0035825	81.51	gold quality
right adrenal gland cortex	UBERON:0035827	81.43	gold quality
caput epididymis	UBERON:0004358	81.31	gold quality
left adrenal gland	UBERON:0001234	81.20	gold quality
cortex of kidney	UBERON:0001225	81.18	gold quality
right adrenal gland	UBERON:0001233	81.03	gold quality
metanephros	UBERON:0000081	80.37	gold quality
transverse colon	UBERON:0001157	79.39	gold quality
smooth muscle tissue	UBERON:0001135	79.30	gold quality
adrenal cortex	UBERON:0001235	78.91	gold quality
ovary	UBERON:0000992	78.59	gold quality
adrenal gland	UBERON:0002369	78.13	gold quality
hindlimb stylopod muscle	UBERON:0004252	77.78	gold quality
endocervix	UBERON:0000458	76.92	gold quality
mucosa of transverse colon	UBERON:0004991	76.80	gold quality
small intestine Peyer’s patch	UBERON:0003454	76.08	gold quality
stromal cell of endometrium	CL:0002255	76.07	gold quality
myometrium	UBERON:0001296	76.01	gold quality
spleen	UBERON:0002106	75.89	gold quality
muscle layer of sigmoid colon	UBERON:0035805	75.68	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	no	2.58

Regulation

Is transcription factor: yes

Downstream targets (CollecTRI)

6 targets.

Target	Regulation
FGFR1
HOXD4
HOXD9	Activation
KRT27
ME3
TTF1

JASPAR motifs

Motif	Name	Family
MA1507.1	HOXD4	HOX
MA1507.2	HOXD4	HOX

JASPAR matrix evidence (PMIDs): PMID:9079695

Upstream regulators (CollecTRI, top): HOXC8, HOXD4, PAX6, RARA, RARB, YY1

miRNA regulators (miRDB)

10 targeting HOXD4, 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-5692B	100.00	71.32	2622
HSA-MIR-5692C	100.00	71.32	2622
HSA-MIR-1976	99.74	65.48	1127
HSA-MIR-6727-3P	99.49	65.92	1333
HSA-MIR-4441	99.49	66.56	3216
HSA-MIR-4722-3P	99.35	65.22	1099
HSA-MIR-4726-3P	98.49	63.89	1385
HSA-MIR-4769-3P	97.95	68.17	1002
HSA-MIR-6817-5P	97.95	67.86	1026
HSA-MIR-4797-3P	97.48	67.14	989

Literature-anchored findings (GeneRIF, showing 4)

• microRNA-10a (miR-10a) targets a homologous DNA region in the promoter region of the hoxd4 gene and represses its expression at the transcriptional level (PMID:19232136)
• The results suggest that genetic polymorphisms in HOXD4 may not be a major contributor to the observed variability in peak BMD in the lumbar spine and the hip in Chinese men and women (PMID:20686522)
• identified heterozygous HOXD4 loss-of-function mutations in three subjects with spinal extradural arachnoid cyst (SEDAC) (PMID:26545093)
• A pan-cancer analysis of the role of HOXD1, HOXD3, and HOXD4 and validation in renal cell carcinoma. (PMID:37827698)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	hoxd4a	ENSDARG00000059276
mus_musculus	Hoxd4	ENSMUSG00000101174
rattus_norvegicus	Hoxd4	ENSRNOG00000001578

Paralogs (42): HOXA11 (ENSG00000005073), HOXC8 (ENSG00000037965), HOXA1 (ENSG00000105991), HOXA2 (ENSG00000105996), HOXA3 (ENSG00000105997), HOXA5 (ENSG00000106004), HOXA6 (ENSG00000106006), HOXA13 (ENSG00000106031), TLX1 (ENSG00000107807), HOXB6 (ENSG00000108511), TLX2 (ENSG00000115297), HOXB8 (ENSG00000120068), HOXB5 (ENSG00000120075), HOXB3 (ENSG00000120093), HOXB1 (ENSG00000120094), HOXA7 (ENSG00000122592), HOXC13 (ENSG00000123364), HOXC11 (ENSG00000123388), HOXC12 (ENSG00000123407), HOXD1 (ENSG00000128645), HOXD3 (ENSG00000128652), HOXD9 (ENSG00000128709), HOXD10 (ENSG00000128710), HOXD11 (ENSG00000128713), HOXD13 (ENSG00000128714), PDX1 (ENSG00000139515), HOXB13 (ENSG00000159184), TLX3 (ENSG00000164438), HOXD12 (ENSG00000170178), HOXB9 (ENSG00000170689), HOXC5 (ENSG00000172789), HOXB2 (ENSG00000173917), HOXD8 (ENSG00000175879), GSX2 (ENSG00000180613), HOXC9 (ENSG00000180806), HOXC10 (ENSG00000180818), HOXB4 (ENSG00000182742), HOXA4 (ENSG00000197576), HOXC6 (ENSG00000197757), HOXC4 (ENSG00000198353)

Protein

Protein identifiers

Homeobox protein Hox-D4 — P09016 (reviewed: P09016)

Alternative names: Homeobox protein HHO.C13, Homeobox protein Hox-4B, Homeobox protein Hox-5.1

All UniProt accessions (1): P09016

UniProt curated annotations — full annotation on UniProt →

Function. Sequence-specific transcription factor which is part of a developmental regulatory system that provides cells with specific positional identities on the anterior-posterior axis.

Subunit / interactions. Forms a DNA-binding heterodimer with transcription factor PBX1.

Subcellular location. Nucleus.

Similarity. Belongs to the Antp homeobox family. Deformed subfamily.

RefSeq proteins (1): NP_055436* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001356	HD	Domain
IPR001827	Homeobox_Antennapedia_CS	Conserved_site
IPR009057	Homeodomain-like_sf	Homologous_superfamily
IPR017970	Homeobox_CS	Conserved_site
IPR017995	Homeobox_antennapedia	Family
IPR020479	HD_metazoa	Domain
IPR050609	Antp_homeobox_Deformed_sf	Family

Pfam: PF00046

UniProt features (10 total): compositionally biased region 3, region of interest 2, chain 1, DNA-binding region 1, short sequence motif 1, sequence variant 1, sequence conflict 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P09016-F1	66.73	0.26

Function

Pathways and Gene Ontology

Reactome pathways

1 pathways

ID	Pathway
R-HSA-5617472	Activation of anterior HOX genes in hindbrain development during early embryogenesis

MSigDB gene sets: 144 (showing top): GSE45365_CTRL_VS_MCMV_INFECTION_NK_CELL_DN, MORF_RAGE, MYAATNNNNNNNGGC_UNKNOWN, GOBP_EMBRYO_DEVELOPMENT_ENDING_IN_BIRTH_OR_EGG_HATCHING, MORF_FLT1, BENPORATH_ES_WITH_H3K27ME3, MORF_MSH3, GOBP_SKELETAL_SYSTEM_DEVELOPMENT, GOBP_EMBRYONIC_SKELETAL_SYSTEM_DEVELOPMENT, GOBP_EMBRYONIC_SKELETAL_SYSTEM_MORPHOGENESIS, MORF_BRCA1, MORF_ATRX, MORF_ESR1, GGCNKCCATNK_UNKNOWN, MORF_RAD51L3

GO Biological Process (6): anterior/posterior pattern specification (GO:0009952), positive regulation of transcription by RNA polymerase II (GO:0045944), embryonic organ development (GO:0048568), embryonic skeletal system morphogenesis (GO:0048704), stem cell differentiation (GO:0048863), regulation of DNA-templated transcription (GO:0006355)

GO Molecular Function (8): RNA polymerase II transcription regulatory region sequence-specific DNA binding (GO:0000977), 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 transcription activator activity, RNA polymerase II-specific (GO:0001228), sequence-specific double-stranded DNA binding (GO:1990837), DNA binding (GO:0003677), DNA-binding transcription factor activity (GO:0003700), protein binding (GO:0005515)

GO Cellular Component (4): chromatin (GO:0000785), nucleoplasm (GO:0005654), cell junction (GO:0030054), nucleus (GO:0005634)

Reactome top-level categories

Rollup of top-1 pathways:

Category	Pathways
Activation of HOX genes during differentiation	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
RNA polymerase II transcription regulatory region sequence-specific DNA binding	3
cellular anatomical structure	3
regulation of transcription by RNA polymerase II	2
transcription cis-regulatory region binding	2
regionalization	1
transcription by RNA polymerase II	1
positive regulation of DNA-templated transcription	1
embryo development	1
animal organ development	1
embryonic organ morphogenesis	1
skeletal system morphogenesis	1
embryonic skeletal system development	1
cell differentiation	1
DNA-templated transcription	1
regulation of gene expression	1
regulation of RNA biosynthetic process	1
cis-regulatory region sequence-specific DNA binding	1
chromatin	1
DNA-binding transcription factor activity	1
DNA-binding transcription factor activity, RNA polymerase II-specific	1
DNA-binding transcription activator activity	1
positive regulation of transcription by RNA polymerase II	1
double-stranded DNA binding	1
sequence-specific DNA binding	1
nucleic acid binding	1
regulation of DNA-templated transcription	1
transcription regulator activity	1
binding	1
chromosome	1
nuclear lumen	1
intracellular membrane-bounded organelle	1

Protein interactions and networks

STRING

833 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
HOXD4	HOXD13	P35453	565
HOXD4	RARB	P10826	545
HOXD4	ISL1	P20663	482
HOXD4	SUZ12	Q15022	475
HOXD4	PAX1	P15863	462
HOXD4	FGF8	P55075	459
HOXD4	FOXG1	P55315	438
HOXD4	EZH2	Q15910	412
HOXD4	TBX1	O43435	389
HOXD4	RARS1	P54136	354
HOXD4	DLX2	Q07687	354
HOXD4	PDGFRB	P09619	353
HOXD4	KDM7A	Q6ZMT4	353
HOXD4	EGR2	P11161	351
HOXD4	SEPTIN5	Q99719	351

IntAct

25 interactions, top by confidence:

A	B	Type	Score
HOXD4	PBX4	psi-mi:“MI:0915”(physical association)	0.560
HOXD4	FANCL	psi-mi:“MI:0915”(physical association)	0.560
HOXD4	ANKRD17	psi-mi:“MI:0914”(association)	0.530
HOXD4	PCYOX1	psi-mi:“MI:0915”(physical association)	0.400
HOXD4	HOXB13	psi-mi:“MI:0915”(physical association)	0.370
HOXD4	ZMYND11	psi-mi:“MI:0915”(physical association)	0.370
HOXD4	RNPS1	psi-mi:“MI:0915”(physical association)	0.370
HOXD4	ASB8	psi-mi:“MI:0915”(physical association)	0.370
HOXD4	TIGD4	psi-mi:“MI:0915”(physical association)	0.370
HOXD4	ZBTB32	psi-mi:“MI:0915”(physical association)	0.370
HOXD4	CNOT7	psi-mi:“MI:0915”(physical association)	0.370
ETV4	HOXD4	psi-mi:“MI:0915”(physical association)	0.370
HNRNPAB	HOXD4	psi-mi:“MI:0915”(physical association)	0.370
HOXD4	RXRG	psi-mi:“MI:0915”(physical association)	0.370
HOXD4	ZSCAN18	psi-mi:“MI:0915”(physical association)	0.370
HOXD4	SNAI1	psi-mi:“MI:0915”(physical association)	0.370
HOXD4	DEDD	psi-mi:“MI:0915”(physical association)	0.370
HOXD4	ANKRD17	psi-mi:“MI:0914”(association)	0.350
HOXA5	AHCYL1	psi-mi:“MI:0914”(association)	0.350
HOXD4	ANKHD1-EIF4EBP3	psi-mi:“MI:0914”(association)	0.350
PBX4	HOXD4	psi-mi:“MI:0915”(physical association)	0.000
FANCL	HOXD4	psi-mi:“MI:0915”(physical association)	0.000

BioGRID (28): ANKHD1 (Affinity Capture-MS), ACTBL2 (Affinity Capture-MS), ANKRD17 (Affinity Capture-MS), HOXD4 (Two-hybrid), HOXD4 (Two-hybrid), PCYOX1 (Proximity Label-MS), HOXD4 (Reconstituted Complex), HOXD4 (Reconstituted Complex), HOXD4 (Affinity Capture-MS), ANKRD17 (Affinity Capture-MS), ANKHD1 (Affinity Capture-MS), ACTBL2 (Affinity Capture-MS), HOXD4 (Affinity Capture-MS), HOXD4 (Two-hybrid), HOXD4 (Two-hybrid)

ESM2 similar proteins: A1YER7, A1YF08, A1YFD8, A1YFY3, A1YG01, A1YG85, A2D4P8, A2D4R4, A2D5I1, A2D649, A2T6H5, A2T6X6, A2T6Z0, A2T748, A2T756, A2T7H5, A2T7J2, P06798, P09016, P09017, P09023, P09024, P10284, P10628, P13378, P14653, P17277, P17483, P17509, P18111, P18864, P23463, P23813, P31259, P31275, P31276, P31277, P31310, P47902, P50207

Diamond homologs: A1L2P5, A1YER7, A1YF08, A1YFD8, A1YFY3, A1YG85, A2D4P8, A2D5I1, A2D5K9, A2D5Y4, A2T6X6, A2T756, A8DT10, A9L937, B0VXK3, O13074, O42365, O42367, O42368, O42370, O43364, O43365, O57374, O93353, P02830, P02831, P06798, P09013, P09014, P09016, P09019, P09020, P09021, P09026, P09027, P09067, P09070, P09074, P09079, P09080

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	27
Likely benign	1
Benign	2

Top pathogenic / likely-pathogenic (0)

SpliceAI

336 predictions. Top by Δscore:

Variant	Effect	Δscore
2:176152606:A:AG	acceptor_gain	1.0000
2:176152606:A:T	acceptor_loss	1.0000
2:176152606:AGT:A	acceptor_gain	1.0000
2:176152607:G:GG	acceptor_gain	1.0000
2:176152607:G:GT	acceptor_gain	1.0000
2:176152607:GT:G	acceptor_gain	1.0000
2:176152607:GTG:G	acceptor_gain	1.0000
2:176152607:GTGA:G	acceptor_gain	1.0000
2:176152607:GTGAA:G	acceptor_gain	1.0000
2:176152065:GG:G	donor_gain	0.9900
2:176152065:GGGT:G	donor_loss	0.9900
2:176152066:GG:G	donor_gain	0.9900
2:176152067:G:GC	donor_loss	0.9900
2:176152067:G:GG	donor_gain	0.9900
2:176152067:GT:G	donor_loss	0.9900
2:176152068:T:G	donor_loss	0.9900
2:176152598:T:TA	acceptor_gain	0.9900
2:176152603:C:A	acceptor_gain	0.9900
2:176152603:C:CA	acceptor_gain	0.9900
2:176152598:T:A	acceptor_loss	0.9700
2:176152062:TTCGG:T	donor_gain	0.9500
2:176152593:T:TA	acceptor_gain	0.9400
2:176152052:TGC:T	donor_gain	0.9300
2:176152063:TCGG:T	donor_gain	0.9300
2:176152608:T:TA	acceptor_gain	0.9100
2:176152942:G:GT	donor_gain	0.9000
2:176152048:A:T	donor_gain	0.8900
2:176152053:GCA:G	donor_gain	0.8900
2:176152054:CAC:C	donor_gain	0.8900
2:176152840:A:AG	donor_gain	0.8800

AlphaMissense

1629 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
2:176152033:T:G	Y134D	1.000
2:176152039:T:A	W136R	1.000
2:176152039:T:C	W136R	1.000
2:176152041:G:C	W136C	1.000
2:176152041:G:T	W136C	1.000
2:176152043:T:C	M137T	1.000
2:176152646:C:G	R158G	1.000
2:176152653:C:A	A160D	1.000
2:176152655:T:A	Y161N	1.000
2:176152655:T:C	Y161H	1.000
2:176152655:T:G	Y161D	1.000
2:176152656:A:G	Y161C	1.000
2:176152669:A:C	Q165H	1.000
2:176152669:A:T	Q165H	1.000
2:176152674:T:C	L167P	1.000
2:176152680:T:A	L169Q	1.000
2:176152680:T:C	L169P	1.000
2:176152680:T:G	L169R	1.000
2:176152682:G:A	E170K	1.000
2:176152683:A:C	E170A	1.000
2:176152683:A:T	E170V	1.000
2:176152684:A:C	E170D	1.000
2:176152684:A:T	E170D	1.000
2:176152686:A:T	K171I	1.000
2:176152687:A:C	K171N	1.000
2:176152687:A:T	K171N	1.000
2:176152688:G:A	E172K	1.000
2:176152691:T:A	F173I	1.000
2:176152691:T:C	F173L	1.000
2:176152691:T:G	F173V	1.000

dbSNP variants (sampled 300 via entrez): RS1000334284 (2:176150841 T>A), RS1000430812 (2:176150499 A>T), RS1000476286 (2:176152468 G>C), RS1001625388 (2:176152379 A>G), RS1001915559 (2:176153285 T>C), RS1002364696 (2:176153647 T>A), RS1002563049 (2:176150941 A>G), RS1002616905 (2:176151164 C>G), RS1003692417 (2:176153684 C>G), RS1004192765 (2:176153278 G>A,T), RS1006597299 (2:176152220 G>A), RS1006795605 (2:176152566 G>T), RS1007565042 (2:176150901 C>A,T), RS1008207990 (2:176151143 A>G), RS1008809756 (2:176150197 C>G,T)

Disease associations

OMIM: gene MIM:142981 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

5 associations (top):

Study	Trait	p-value
GCST003225_16	Pelvic organ prolapse (moderate/severe)	9.000000e-06
GCST005051_8	Obstructive sleep apnea trait (apnea hypopnea index)	1.000000e-06
GCST005051_9	Obstructive sleep apnea trait (apnea hypopnea index)	4.000000e-07
GCST006661_148	Male-pattern baldness	3.000000e-18
GCST007876_9	Estimated glomerular filtration rate	1.000000e-14

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0007817	sleep apnea measurement

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

27 total (human), top 27 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
bisphenol A	decreases methylation	1
ascorbate-2-phosphate	affects binding, affects cotreatment, increases expression	1
sodium arsenite	decreases expression	1
4-(2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl)-1-propenyl)benzoic acid	affects cotreatment, increases expression	1
CGP 52608	affects binding, increases reaction	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, increases expression	1
Chir 99021	affects cotreatment, increases expression, affects binding	1
belinostat	increases expression	1
XAV939	affects binding, affects cotreatment, increases expression	1
LDN 193189	affects cotreatment, increases expression	1
3-(4-pyridyl)-1H-indole	affects cotreatment, increases expression	1
Vorinostat	increases expression	1
Acetaminophen	decreases expression	1
Amphotericin B	decreases expression	1
Ascorbic Acid	affects binding, affects cotreatment, increases expression	1
Benzo(a)pyrene	affects methylation, decreases methylation	1
Caffeine	decreases phosphorylation	1
Hydrocortisone	affects cotreatment, increases expression	1
Indomethacin	decreases expression	1
Nickel	decreases expression	1
Tretinoin	increases expression	1
Triclosan	increases expression	1
Valproic Acid	decreases methylation	1
Aflatoxin B1	decreases methylation	1
Asbestos, Crocidolite	decreases methylation	1
Asbestos, Amosite	decreases methylation	1
Antirheumatic Agents	increases expression	1

Clinical trials (associated diseases)

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