HOXD11

Summary

HOXD11 (homeobox D11, HGNC:5134) is a protein-coding gene on chromosome 2q31.1, encoding Homeobox protein Hox-D11 (P31277). 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 in a cluster on chromosome 2. Deletions that remove the entire HOXD gene cluster or the 5’ end of this cluster have been associated with severe limb and genital abnormalities. The product of the mouse Hoxd11 gene plays a role in forelimb morphogenesis.

Source: NCBI Gene 3237 — RefSeq curated summary.

At a glance

• GWAS associations: 14
• Clinical variants (ClinVar): 74 total — 1 pathogenic
• MANE Select transcript: NM_021192

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:5134
Approved symbol	HOXD11
Name	homeobox D11
Location	2q31.1
Locus type	gene with protein product
Status	Approved
Ensembl gene	ENSG00000128713
Ensembl biotype	protein_coding
OMIM	142986
Entrez	3237

Gene structure

Transcript identifiers

Ensembl transcripts: 2 — 1 protein_coding, 1 protein_coding_CDS_not_defined

ENST00000249504, ENST00000498438

RefSeq mRNA: 1 — MANE Select: NM_021192 NM_021192

CCDS: CCDS2265

Canonical transcript exons

ENST00000249504 — 2 exons

Exon	Start	End
ENSE00000882910	176107280	176108136
ENSE00001825051	176108907	176109754

Expression profiles

Bgee: expression breadth broad, 75 present calls, max score 85.24.

FANTOM5 (CAGE): breadth broad, TPM avg 3.8242 / max 138.4432, expressed in 313 samples.

FANTOM5 promoters (6 alternative TSS)

Promoter ID	TPM avg	Samples expressed
23823	2.0503	215
23822	1.0029	186
23827	0.4221	91
23828	0.1762	73
23829	0.0909	47
23826	0.0818	33

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
body of uterus	UBERON:0009853	85.24	gold quality
stromal cell of endometrium	CL:0002255	84.46	gold quality
cervix squamous epithelium	UBERON:0006922	82.89	gold quality
calcaneal tendon	UBERON:0003701	81.36	gold quality
urethra	UBERON:0000057	80.49	gold quality
myometrium	UBERON:0001296	80.38	gold quality
muscle layer of sigmoid colon	UBERON:0035805	80.18	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	79.88	silver quality
metanephros cortex	UBERON:0010533	79.02	gold quality
vagina	UBERON:0000996	78.67	gold quality
uterus	UBERON:0000995	78.36	gold quality
ectocervix	UBERON:0012249	76.55	gold quality
endometrium	UBERON:0001295	76.10	gold quality
decidua	UBERON:0002450	75.11	silver quality
uterine cervix	UBERON:0000002	73.85	gold quality
prostate gland	UBERON:0002367	73.12	gold quality
tendon	UBERON:0000043	73.04	gold quality
triceps brachii	UBERON:0001509	72.85	gold quality
gluteal muscle	UBERON:0002000	72.71	gold quality
renal medulla	UBERON:0000362	71.78	silver quality
mammalian vulva	UBERON:0000997	70.96	silver quality
metanephros	UBERON:0000081	70.22	gold quality
adult mammalian kidney	UBERON:0000082	70.19	gold quality
kidney	UBERON:0002113	68.96	gold quality
cardia of stomach	UBERON:0001162	68.59	gold quality
vena cava	UBERON:0004087	68.43	gold quality
saphenous vein	UBERON:0007318	68.40	gold quality
nipple	UBERON:0002030	68.39	gold quality
inferior vagus X ganglion	UBERON:0005363	68.33	gold quality
subthalamic nucleus	UBERON:0001906	68.23	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	3.77

Regulation

Is transcription factor: yes

Downstream targets (CollecTRI)

4 targets.

Target	Regulation
HOXC5
HOXD9
ITGA8
SHH	Activation

JASPAR motifs

Motif	Name	Family
MA0908.1	HOXD11	HOX
MA0908.2	HOXD11	HOX

JASPAR matrix evidence (PMIDs): PMID:18585359

Upstream regulators (CollecTRI, top): POU2F1, SMAD2, SMAD3

miRNA regulators (miRDB)

16 targeting HOXD11, 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-4747-5P	100.00	67.90	2681
HSA-MIR-5196-5P	100.00	67.98	2761
HSA-MIR-4533	100.00	69.48	2758
HSA-MIR-3692-3P	99.98	70.27	2139
HSA-MIR-4446-5P	99.72	69.19	2544
HSA-MIR-3202	99.66	67.70	2737
HSA-MIR-3679-3P	99.64	69.88	1599
HSA-MIR-548AV-5P	99.60	70.84	2107
HSA-MIR-548K	99.60	70.84	2107
HSA-MIR-186-3P	99.51	66.24	1685
HSA-MIR-8054	99.48	70.81	2084
HSA-MIR-6814-5P	99.03	66.68	1273
HSA-MIR-3127-3P	98.94	67.34	1055
HSA-MIR-6756-3P	98.94	66.79	1104
HSA-MIR-6501-3P	98.71	67.45	1480
HSA-MIR-6826-3P	98.19	66.32	1153

Literature-anchored findings (GeneRIF, showing 9)

• The HOXD11 gene is fused to the NUP98 gene in acute myeloid leukemia with t(2;11)(q31;p15). (PMID:11782354)
• Our findings do not support the hypothesis that mutations in the HOXD11 coding regions are involved in the pathogenesis of human non-syndromal congenital renal parenchymal malformations. (PMID:19255789)
• data show no significant difference in HOXD11, HOXD12 & HOXD13 genotype frequencies between the autism spectrum disorder & healthy controls, but one SNP in promoter region of HOXD11 was observed in only 4 patients with ASD (PMID:19540081)
• In human embryonic stem cell (hESCs)differentiation, a 1.8kb region between HOXD11 and HOXD12 (D11.12) that is associated with PcG proteins was discovered, it shows alteration in nuclease sensitivity as hESCs differentiate. (PMID:20085705)
• POU2F1 activity regulates HOXD10 and HOXD11 gene expression in head and neck squamous cell carcinoma, promoting a proliferative and invasive phenotype. (PMID:25301728)
• Knock down of the dickkopf WNT signaling pathway inhibitor 2 (DKK2) resulted in a significant suppression of HOXD10, HOXD11 and HOXD13 while over-expression of DKK2 and stimulation with factors of the WNT signaling pathway. (PMID:27363011)
• High expression of HOXD11 is associated with laryngeal squamous cell carcinoma. (PMID:27658780)
• miR-138-5p-mediated HOXD11 promotes cell invasion and metastasis by activating the FN1/MMP2/MMP9 pathway and predicts poor prognosis in penile squamous cell carcinoma. (PMID:36151071)
• Inhibition of HOXD11 promotes cartilage degradation and induces osteoarthritis development. (PMID:38308324)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
danio_rerio	hoxd11a	ENSDARG00000059267
danio_rerio	hoxc11b	ENSDARG00000102631
mus_musculus	Hoxd11	ENSMUSG00000042499
rattus_norvegicus	Hoxd11	ENSRNOG00000069591

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), HOXD13 (ENSG00000128714), PDX1 (ENSG00000139515), HOXB13 (ENSG00000159184), TLX3 (ENSG00000164438), HOXD4 (ENSG00000170166), 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-D11 — P31277 (reviewed: P31277)

Alternative names: Homeobox protein Hox-4F

All UniProt accessions (1): P31277

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.

Subcellular location. Nucleus.

Similarity. Belongs to the Abd-B homeobox family.

RefSeq proteins (1): NP_067015* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001356	HD	Domain
IPR009057	Homeodomain-like_sf	Homologous_superfamily
IPR017970	Homeobox_CS	Conserved_site
IPR020479	HD_metazoa	Domain
IPR021918	DUF3528	Domain

Pfam: PF00046, PF12045

UniProt features (7 total): compositionally biased region 2, chain 1, DNA-binding region 1, region of interest 1, sequence variant 1, sequence conflict 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P31277-F1	60.30	0.20

Function

Pathways and Gene Ontology

Reactome pathways

1 pathways

ID	Pathway
R-HSA-9830674	Formation of the ureteric bud

MSigDB gene sets: 130 (showing top): GOBP_MORPHOGENESIS_OF_AN_EPITHELIUM, GOBP_EMBRYO_DEVELOPMENT_ENDING_IN_BIRTH_OR_EGG_HATCHING, GOBP_EPITHELIUM_DEVELOPMENT, GOBP_SKELETAL_SYSTEM_DEVELOPMENT, GOBP_EMBRYONIC_SKELETAL_SYSTEM_DEVELOPMENT, GOBP_EMBRYONIC_SKELETAL_SYSTEM_MORPHOGENESIS, GOBP_KIDNEY_EPITHELIUM_DEVELOPMENT, GGAMTNNNNNTCCY_UNKNOWN, GOBP_DORSAL_VENTRAL_PATTERN_FORMATION, GOBP_ANIMAL_ORGAN_MORPHOGENESIS, GOBP_EMBRYONIC_ORGAN_MORPHOGENESIS, GOBP_NEPHRON_EPITHELIUM_DEVELOPMENT, GOBP_RENAL_TUBULE_DEVELOPMENT, MODULE_206, GOBP_MESONEPHRIC_TUBULE_MORPHOGENESIS

GO Biological Process (5): branching involved in ureteric bud morphogenesis (GO:0001658), regulation of transcription by RNA polymerase II (GO:0006357), dorsal/ventral pattern formation (GO:0009953), embryonic skeletal joint morphogenesis (GO:0060272), regulation of DNA-templated transcription (GO:0006355)

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), sequence-specific double-stranded DNA binding (GO:1990837), DNA binding (GO:0003677)

GO Cellular Component (3): chromatin (GO:0000785), nucleus (GO:0005634), nucleoplasm (GO:0005654)

Reactome top-level categories

Rollup of top-1 pathways:

Category	Pathways
Kidney development	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
RNA polymerase II transcription regulatory region sequence-specific DNA binding	2
cellular anatomical structure	2
branching morphogenesis of an epithelial tube	1
ureteric bud morphogenesis	1
regulation of DNA-templated transcription	1
transcription by RNA polymerase II	1
regionalization	1
embryonic skeletal system morphogenesis	1
embryonic skeletal joint development	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
regulation of transcription by RNA polymerase II	1
double-stranded DNA binding	1
sequence-specific DNA binding	1
nucleic acid binding	1
chromosome	1
intracellular membrane-bounded organelle	1
nuclear lumen	1

Protein interactions and networks

STRING

792 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
HOXD11	SHH	Q15465	734
HOXD11	GLI3	P10071	644
HOXD11	PRRX1	P54821	623
HOXD11	NUP98	P52948	623
HOXD11	SIX2	Q9NPC8	621
HOXD11	EVX2	Q03828	608
HOXD11	HOXD13	P35453	593
HOXD11	HOXD10	P28358	576
HOXD11	SALL1	Q9NSC2	570
HOXD11	SUZ12	Q15022	569
HOXD11	HOXD1	Q9GZZ0	568
HOXD11	SHOX	O15266	536
HOXD11	DDX10	Q13206	534
HOXD11	ZP2	Q05996	520
HOXD11	PAX2	Q02962	507

IntAct

5 interactions, top by confidence:

A	B	Type	Score
S100A2	PLEKHG3	psi-mi:“MI:0914”(association)	0.350
S100P	PLEKHG3	psi-mi:“MI:0914”(association)	0.350
HOXD11	LYPLA1	psi-mi:“MI:0914”(association)	0.350
PAX9	BCL9	psi-mi:“MI:2364”(proximity)	0.270

BioGRID (13): HOXD11 (Affinity Capture-RNA), HOXD11 (Reconstituted Complex), HOXD11 (Affinity Capture-MS), PRKD1 (Affinity Capture-MS), HOXD11 (Affinity Capture-MS), LYPLA1 (Affinity Capture-MS), HOXD11 (Affinity Capture-MS), MAN2C1 (Affinity Capture-MS), HOXD11 (Proximity Label-MS), HOXD11 (Affinity Capture-MS), HOXD11 (Proximity Label-MS), HOXD11 (Proximity Label-MS), HOXD11 (Proximity Label-MS)

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: A1YFT7, A2D5V0, A2D635, A2T6F8, A2T7D1, A2T7H7, B5DFK3, O42502, O42503, O42506, O43248, P09013, P09014, P09023, P09025, P09067, P09079, P09087, P09631, P09632, P09633, P10179, P14838, P15861, P17481, P17482, P17509, P18863, P18866, P20615, P23459, P23813, P24340, P24341, P24342, P28356, P28357, P28358, P28359, P31257

SIGNOR signaling

3 interactions.

A	Effect	B	Mechanism
POU2F1	“up-regulates quantity by expression”	HOXD11	“transcriptional regulation”
HMGB1	“up-regulates activity”	HOXD11	binding
HOXD11	“up-regulates activity”	MEIS1	binding

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	1
Likely pathogenic	0
Uncertain significance	67
Likely benign	3
Benign	2

Top pathogenic / likely-pathogenic (1)

Variant ID	HGVS	Classification
2423203	NC_000002.11:g.(?176957619)(176973870_?)del	Pathogenic

SpliceAI

98 predictions. Top by Δscore:

Variant	Effect	Δscore
2:176108134:CAG:C	donor_loss	1.0000
2:176108136:GGTA:G	donor_loss	1.0000
2:176108137:G:T	donor_loss	1.0000
2:176108904:CA:C	acceptor_loss	1.0000
2:176108905:A:AG	acceptor_gain	1.0000
2:176108905:AG:A	acceptor_loss	1.0000
2:176108905:AGTT:A	acceptor_gain	1.0000
2:176108906:G:GG	acceptor_gain	1.0000
2:176108906:GT:G	acceptor_gain	1.0000
2:176108906:GTT:G	acceptor_gain	1.0000
2:176108906:GTTG:G	acceptor_gain	1.0000
2:176108906:GTTGC:G	acceptor_gain	1.0000
2:176108133:GCAG:G	donor_gain	0.9900
2:176108137:G:GG	donor_gain	0.9900
2:176108897:T:TA	acceptor_gain	0.9900
2:176108901:TTGCA:T	acceptor_gain	0.9800
2:176108902:T:TA	acceptor_gain	0.9800
2:176108902:TGCAG:T	acceptor_gain	0.9800
2:176108903:GCAG:G	acceptor_gain	0.9800
2:176108904:CAG:C	acceptor_gain	0.9800
2:176108905:AGTTG:A	acceptor_gain	0.9800
2:176108906:G:T	acceptor_gain	0.9800
2:176109114:A:AG	donor_gain	0.9700
2:176109115:G:GG	donor_gain	0.9700
2:176108136:GGT:G	donor_gain	0.9500
2:176108132:CGCAG:C	donor_gain	0.9400
2:176108133:GCAGG:G	donor_gain	0.9400
2:176108134:CAGGT:C	donor_gain	0.9400
2:176108135:AG:A	donor_gain	0.9400
2:176108137:G:GA	donor_gain	0.9400

AlphaMissense

2186 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
2:176108933:C:A	R270S	1.000
2:176108933:C:T	R270C	1.000
2:176108940:C:A	P272H	1.000
2:176108942:T:A	Y273N	1.000
2:176108942:T:C	Y273H	1.000
2:176108942:T:G	Y273D	1.000
2:176108943:A:G	Y273C	1.000
2:176108946:C:T	T274I	1.000
2:176108948:A:G	K275E	1.000
2:176108950:G:C	K275N	1.000
2:176108950:G:T	K275N	1.000
2:176108955:A:C	Q277P	1.000
2:176108955:A:G	Q277R	1.000
2:176108956:G:C	Q277H	1.000
2:176108956:G:T	Q277H	1.000
2:176108957:A:T	I278F	1.000
2:176108958:T:A	I278N	1.000
2:176108958:T:G	I278S	1.000
2:176108961:G:C	R279P	1.000
2:176108963:G:A	E280K	1.000
2:176108965:A:C	E280D	1.000
2:176108965:A:T	E280D	1.000
2:176108967:T:A	L281Q	1.000
2:176108967:T:C	L281P	1.000
2:176108967:T:G	L281R	1.000
2:176108969:G:A	E282K	1.000
2:176108970:A:C	E282A	1.000
2:176108970:A:G	E282G	1.000
2:176108970:A:T	E282V	1.000
2:176108971:A:C	E282D	1.000

dbSNP variants (sampled 300 via entrez): RS1000193489 (2:176114518 T>C), RS1000374466 (2:176108138 T>G), RS1000419816 (2:176108730 C>G,T), RS1000512049 (2:176110181 G>C), RS1000580695 (2:176109113 C>G), RS1000945047 (2:176110375 A>G), RS1001687785 (2:176113962 T>C), RS1001720766 (2:176109059 A>C,G,T), RS1001911703 (2:176114954 C>T), RS1001926822 (2:176108306 G>A,C), RS1002078187 (2:176108623 G>A), RS1002379096 (2:176108644 C>A), RS1002454641 (2:176110108 T>C,G), RS1002716714 (2:176107734 C>A,T), RS1002764239 (2:176112445 G>A)

Disease associations

OMIM: gene MIM:142986 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

14 associations (top):

Study	Trait	p-value
GCST004604_81	Hematocrit	3.000000e-09
GCST005748_3	Digit length ratio (right hand)	6.000000e-09
GCST005749_5	Digit length ratio (left hand)	6.000000e-07
GCST005749_6	Digit length ratio (left hand)	1.000000e-07
GCST005750_4	Digit length ratio	1.000000e-10
GCST006661_148	Male-pattern baldness	3.000000e-18
GCST006979_45	Heel bone mineral density	6.000000e-17
GCST007877_2	Creatinine levels	1.000000e-08
GCST010083_95	Hemoglobin levels	1.000000e-19
GCST90000025_828	Appendicular lean mass	8.000000e-14
GCST90002383_194	Hematocrit	3.000000e-31
GCST90002384_238	Hemoglobin	2.000000e-25
GCST90002403_120	Red blood cell count	5.000000e-26
GCST90014033_18	Haemorrhoidal disease	1.000000e-17

EFO canonical traits (6, from GWAS)

EFO ID	Trait name
EFO:0004348	hematocrit
EFO:0004841	digit length ratio
EFO:0009270	heel bone mineral density
EFO:0004509	hemoglobin measurement
EFO:0004980	appendicular lean mass
EFO:0004305	erythrocyte count

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

23 total (human), top 23 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Benzo(a)pyrene	affects methylation, decreases expression, increases methylation	2
pirinixic acid	affects binding, increases activity, increases expression	1
arsenite	increases methylation	1
S-(1,2-dichlorovinyl)cysteine	affects response to substance, increases expression	1
exemestane	increases expression	1
entinostat	increases expression	1
jinfukang	affects cotreatment, decreases expression	1
(+)-JQ1 compound	decreases expression	1
Resveratrol	affects cotreatment, decreases expression	1
Temozolomide	increases expression	1
Acetaminophen	decreases expression	1
Cisplatin	affects cotreatment, decreases expression	1
Drugs, Chinese Herbal	increases expression	1
Lipopolysaccharides	increases expression, affects response to substance	1
Naphthoquinones	increases expression	1
Plant Extracts	affects cotreatment, decreases expression	1
Dihydrotestosterone	increases expression	1
Tunicamycin	decreases expression	1
Aflatoxin B1	decreases methylation	1
Asbestos, Serpentine	decreases methylation	1
Asbestos, Crocidolite	decreases methylation	1
Asbestos, Amosite	decreases methylation	1
Okadaic Acid	decreases expression	1

Clinical trials (associated diseases)

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