HOXD1

Summary

HOXD1 (homeobox D1, HGNC:5132) is a protein-coding gene on chromosome 2q31.1, encoding Homeobox protein Hox-D1 (Q9GZZ0). 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 is a member of the Antp homeobox family and encodes a protein with a homeobox DNA-binding domain. This nuclear protein functions as a sequence-specific transcription factor that is involved in differentiation and limb development. Mutations in this gene have been associated with severe developmental defects on the anterior-posterior (a-p) limb axis.

Source: NCBI Gene 3231 — RefSeq curated summary.

At a glance

• GWAS associations: 15
• Clinical variants (ClinVar): 42 total — 1 pathogenic
• MANE Select transcript: NM_024501

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:5132
Approved symbol	HOXD1
Name	homeobox D1
Location	2q31.1
Locus type	gene with protein product
Status	Approved
Ensembl gene	ENSG00000128645
Ensembl biotype	protein_coding
OMIM	142987
Entrez	3231

Gene structure

Transcript identifiers

Ensembl transcripts: 2 — 2 protein_coding

ENST00000331462, ENST00000876788

RefSeq mRNA: 1 — MANE Select: NM_024501 NM_024501

CCDS: CCDS2271

Canonical transcript exons

ENST00000331462 — 2 exons

Exon	Start	End
ENSE00000882927	176188668	176189453
ENSE00002391549	176189808	176190907

Expression profiles

Bgee: expression breadth ubiquitous, 185 present calls, max score 86.45.

FANTOM5 (CAGE): breadth broad, TPM avg 1.4170 / max 54.2742, expressed in 334 samples.

FANTOM5 promoters (1 alternative TSS)

Promoter ID	TPM avg	Samples expressed
23874	1.4170	334

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
corpus epididymis	UBERON:0004359	86.45	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	86.32	gold quality
metanephric glomerulus	UBERON:0004736	85.57	gold quality
renal glomerulus	UBERON:0000074	85.22	gold quality
C1 segment of cervical spinal cord	UBERON:0006469	83.67	gold quality
secondary oocyte	CL:0000655	83.33	gold quality
spinal cord	UBERON:0002240	82.88	gold quality
dorsal root ganglion	UBERON:0000044	82.02	gold quality
caput epididymis	UBERON:0004358	81.62	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	81.53	silver quality
inferior vagus X ganglion	UBERON:0005363	81.11	gold quality
mucosa of sigmoid colon	UBERON:0004993	80.94	gold quality
seminal vesicle	UBERON:0000998	80.73	gold quality
oocyte	CL:0000023	80.44	gold quality
colonic mucosa	UBERON:0000317	79.82	gold quality
kidney epithelium	UBERON:0004819	79.50	gold quality
inferior olivary complex	UBERON:0002127	78.65	gold quality
trigeminal ganglion	UBERON:0001675	78.33	gold quality
metanephros	UBERON:0000081	77.63	gold quality
nephron tubule	UBERON:0001231	77.45	gold quality
subthalamic nucleus	UBERON:0001906	76.82	gold quality
medulla oblongata	UBERON:0001896	76.08	gold quality
germinal epithelium of ovary	UBERON:0001304	74.91	silver quality
cortex of kidney	UBERON:0001225	74.33	gold quality
ileal mucosa	UBERON:0000331	74.17	gold quality
right uterine tube	UBERON:0001302	73.13	gold quality
mucosa of urinary bladder	UBERON:0001259	72.98	silver quality
visceral pleura	UBERON:0002401	72.86	gold quality
mucosa of transverse colon	UBERON:0004991	72.83	gold quality
substantia nigra	UBERON:0002038	71.09	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	5.31

Regulation

Is transcription factor: yes

Downstream targets (CollecTRI)

7 targets.

Target	Regulation
GPRASP3
ITGB1	Unknown
KRAS
MLH1
MOG
SOCS1
SOS1

JASPAR motifs

Motif	Name	Family
MA2677.1	HOXD1	HOX

JASPAR matrix evidence (PMIDs): PMID:33184220

Upstream regulators (CollecTRI, top): EZH2, RBPJ, THRA

miRNA regulators (miRDB)

77 targeting HOXD1, 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-4262	100.00	73.26	3931
HSA-MIR-4692	100.00	67.32	2066
HSA-MIR-6758-5P	100.00	66.21	1470
HSA-MIR-6856-5P	100.00	65.47	1298
HSA-MIR-181A-5P	99.99	72.96	2995
HSA-MIR-181B-5P	99.99	72.97	2996
HSA-MIR-181C-5P	99.99	72.95	2996
HSA-MIR-181D-5P	99.99	73.04	2997
HSA-MIR-4500	99.99	72.72	2367
HSA-MIR-4514	99.99	67.10	1870
HSA-LET-7A-5P	99.98	72.29	1790
HSA-LET-7B-5P	99.98	72.31	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
HSA-LET-7G-5P	99.98	72.37	1784
HSA-LET-7I-5P	99.98	72.37	1788
HSA-MIR-98-5P	99.98	72.33	1787
HSA-MIR-19A-3P	99.98	75.33	2762
HSA-MIR-19B-3P	99.98	75.44	2754
HSA-LET-7D-5P	99.96	71.76	1632
HSA-MIR-4458	99.96	71.64	1650
HSA-MIR-590-3P	99.96	74.34	6478
HSA-MIR-548AA	99.96	70.64	3753
HSA-MIR-548AP-3P	99.96	70.64	3753
HSA-MIR-548T-3P	99.96	70.64	3753
HSA-MIR-454-3P	99.91	74.01	1925
HSA-MIR-130A-3P	99.90	73.31	1861
HSA-MIR-130B-3P	99.90	73.27	1850
HSA-MIR-301A-3P	99.90	73.15	1839

Literature-anchored findings (GeneRIF, showing 7)

• Single nucleotide polymorphism in HOXD1 is associated with ovarian cancer. (PMID:20852632)
• HOXD1 plays a significant role in endothelial cells functions by regulating the expression of ITGB1. (PMID:21501586)
• Data indicate that median methylation levels of BCAN, HOXD1, KCTD8, KLF11, NXPH1, POU4F1, SIM1, and TCF7L1 were >/=30% higher than in normal samples, representing potential biomarkers for tumor diagnosis. (PMID:22930747)
• HOXD1 functions as a novel tumor suppressor in kidney renal clear cell carcinoma. (PMID:33559901)
• Homeobox-D 1 and FTO form a transcriptional-epigenetic feedback loop to promote head and neck cancer proliferation. (PMID:37655555)
• A pan-cancer analysis of the role of HOXD1, HOXD3, and HOXD4 and validation in renal cell carcinoma. (PMID:37827698)
• HOXD1 inhibits lung adenocarcinoma progression and is regulated by DNA methylation. (PMID:39450540)

Cross-species orthologs

2 orthologs

Organism	Symbol	Gene ID
mus_musculus	Hoxd1	ENSMUSG00000042448
rattus_norvegicus	Hoxd1	ENSRNOG00000001572

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), HOXD3 (ENSG00000128652), HOXD9 (ENSG00000128709), HOXD10 (ENSG00000128710), HOXD11 (ENSG00000128713), 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-D1 — Q9GZZ0 (reviewed: Q9GZZ0)

Alternative names: Homeobox protein Hox-GG

All UniProt accessions (1): Q9GZZ0

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. Acts on the anterior body structures.

Subcellular location. Nucleus.

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

RefSeq proteins (1): NP_078777* (*=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
IPR046327	HXA1/B1/D1	Family

Pfam: PF00046

UniProt features (6 total): chain 1, DNA-binding region 1, region of interest 1, short sequence motif 1, compositionally biased region 1, sequence variant 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9GZZ0-F1	61.63	0.21

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: 110 (showing top): GOBP_EMBRYO_DEVELOPMENT_ENDING_IN_BIRTH_OR_EGG_HATCHING, BENPORATH_ES_WITH_H3K27ME3, GOBP_SKELETAL_SYSTEM_DEVELOPMENT, GOBP_EMBRYONIC_SKELETAL_SYSTEM_DEVELOPMENT, GOBP_NEUROGENESIS, GOBP_SENSORY_PERCEPTION_OF_PAIN, SHIN_B_CELL_LYMPHOMA_CLUSTER_5, GATA1_04, GUO_HEX_TARGETS_UP, NKX25_01, RYTTCCTG_ETS2_B, GOBP_SENSORY_PERCEPTION, GOBP_EMBRYO_DEVELOPMENT, MARTORIATI_MDM4_TARGETS_FETAL_LIVER_UP, GATA_Q6

GO Biological Process (5): regulation of transcription by RNA polymerase II (GO:0006357), sensory perception of pain (GO:0019233), neuron differentiation (GO:0030182), embryonic skeletal system development (GO:0048706), regulation of DNA-templated transcription (GO:0006355)

GO Molecular Function (6): 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), DNA-binding transcription factor activity (GO:0003700), sequence-specific DNA binding (GO:0043565)

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

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
regulation of DNA-templated transcription	2
RNA polymerase II transcription regulatory region sequence-specific DNA binding	2
cellular anatomical structure	2
transcription by RNA polymerase II	1
sensory perception	1
cell differentiation	1
generation of neurons	1
skeletal system development	1
chordate embryonic 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
transcription cis-regulatory region binding	1
transcription regulator activity	1
DNA binding	1
chromosome	1
intracellular membrane-bounded organelle	1
nuclear lumen	1

Protein interactions and networks

STRING

842 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
HOXD1	LNPK	Q9C0E8	830
HOXD1	GTF3C3	Q9Y5Q9	669
HOXD1	MTX2	O75431	657
HOXD1	CHN1	P15882	648
HOXD1	KCNH3	Q9ULD8	607
HOXD1	CC2D1A	Q6P1N0	601
HOXD1	HOXD10	P28358	575
HOXD1	HOXD11	P31277	568
HOXD1	MDK	P21741	548
HOXD1	HOXD12	P35452	520
HOXD1	SATB2	Q9UPW6	450
HOXD1	TXNDC16	Q9P2K2	437
HOXD1	HLA-DPB1	P01916	429
HOXD1	COL5A2	P05997	426
HOXD1	NIPAL2	Q9H841	407

IntAct

3 interactions, top by confidence:

A	B	Type	Score
HOXD1	HOXB1	psi-mi:“MI:0915”(physical association)	0.400
HOXC9	HOXD1	psi-mi:“MI:0915”(physical association)	0.370

BioGRID (4): HOXD1 (Synthetic Lethality), HOXB1 (Affinity Capture-MS), HOXD1 (Affinity Capture-RNA), HOXD1 (Two-hybrid)

ESM2 similar proteins: A1YER7, A1YF08, A1YFD8, A1YFY3, A1YG85, A2D4P8, A2D4R4, A2D5I1, A2D649, A2T6H5, A2T6X6, A2T6Z0, A2T756, A2T7H5, A2T7J2, O35767, O43186, O88470, P06798, P09016, P10284, P10628, P17277, P17483, P18111, P23813, P31260, P31277, P31310, P42582, P43241, P43345, P47902, P52945, P52946, P52947, P52952, P57073, P58012, P70118

Diamond homologs: A1L2P5, A1YER7, A1YFD8, A1YFY3, A1YG01, A2D4P8, A2D4R4, A2D5I1, A2D5K9, A2D5Y4, A2D649, A2T6H5, A2T6X6, A2T6Z0, A2T7J2, A8DT10, A9L937, B0VXK3, O08656, O13074, O42365, O42366, O42367, O42368, O42370, O43364, O43365, O93353, P02831, P06798, P07548, P09016, P09017, P09021, P09022, P09027, P09070, P09638, P0C1T1, P10105

SIGNOR signaling

1 interactions.

A	Effect	B	Mechanism
HOXD1	“up-regulates quantity by expression”	ITGB1	“transcriptional regulation”

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	1
Likely pathogenic	0
Uncertain significance	39
Likely benign	1
Benign	0

Top pathogenic / likely-pathogenic (1)

Variant ID	HGVS	Classification
1695396	Single allele	Pathogenic

SpliceAI

157 predictions. Top by Δscore:

Variant	Effect	Δscore
2:176189449:GAAAG:G	donor_gain	1.0000
2:176189450:AAAG:A	donor_gain	1.0000
2:176189451:AAG:A	donor_gain	1.0000
2:176189451:AAGG:A	donor_loss	1.0000
2:176189452:AG:A	donor_gain	1.0000
2:176189452:AGGT:A	donor_loss	1.0000
2:176189453:GG:G	donor_gain	1.0000
2:176189453:GGTA:G	donor_loss	1.0000
2:176189454:G:GG	donor_gain	1.0000
2:176189804:GCA:G	acceptor_loss	1.0000
2:176189806:A:AG	acceptor_gain	1.0000
2:176189806:AGGCA:A	acceptor_loss	1.0000
2:176189807:G:GG	acceptor_gain	1.0000
2:176189807:GGC:G	acceptor_gain	0.9900
2:176189807:GGCA:G	acceptor_gain	0.9900
2:176189807:GGCAA:G	acceptor_gain	0.9900
2:176189654:G:GT	donor_gain	0.9800
2:176189806:AG:A	acceptor_gain	0.9800
2:176189807:GG:G	acceptor_gain	0.9800
2:176189800:C:CA	acceptor_gain	0.9700
2:176189454:G:T	donor_gain	0.9600
2:176189655:A:T	donor_gain	0.9600
2:176189799:AC:A	acceptor_gain	0.9500
2:176189636:GCAT:G	donor_gain	0.9400
2:176189803:T:TA	acceptor_gain	0.9200
2:176189709:G:GT	donor_gain	0.8900
2:176189800:C:G	acceptor_gain	0.8500
2:176189677:TCCTG:T	donor_loss	0.8200
2:176189678:CCTG:C	donor_loss	0.8200
2:176189679:CTG:C	donor_loss	0.8200

AlphaMissense

2098 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
2:176189861:T:C	F236L	1.000
2:176189862:T:C	F236S	1.000
2:176189862:T:G	F236C	1.000
2:176189863:C:A	F236L	1.000
2:176189863:C:G	F236L	1.000
2:176189877:T:C	L241P	1.000
2:176189886:T:C	L244P	1.000
2:176189897:T:C	F248L	1.000
2:176189898:T:C	F248S	1.000
2:176189899:T:A	F248L	1.000
2:176189899:T:G	F248L	1.000
2:176189943:C:A	A263D	1.000
2:176189981:T:A	W276R	1.000
2:176189981:T:C	W276R	1.000
2:176189983:G:C	W276C	1.000
2:176189983:G:T	W276C	1.000
2:176189984:T:A	F277I	1.000
2:176189984:T:C	F277L	1.000
2:176189984:T:G	F277V	1.000
2:176189985:T:C	F277S	1.000
2:176189985:T:G	F277C	1.000
2:176189986:C:A	F277L	1.000
2:176189986:C:G	F277L	1.000
2:176189989:G:C	Q278H	1.000
2:176189989:G:T	Q278H	1.000
2:176189990:A:G	N279D	1.000
2:176189993:C:A	R280S	1.000
2:176189886:T:A	L244Q	0.999
2:176189889:A:T	E245V	0.999
2:176189890:A:C	E245D	0.999

dbSNP variants (sampled 300 via entrez): RS1000423196 (2:176191128 C>T), RS1001160152 (2:176189462 G>T), RS1002154023 (2:176189146 C>G,T), RS1003114523 (2:176187941 C>T), RS1003160256 (2:176188311 G>A,T), RS1003506594 (2:176188324 C>A,G,T), RS1003557592 (2:176188110 G>GA), RS1004884057 (2:176190227 G>A), RS1005238480 (2:176190605 T>C), RS1006462065 (2:176190328 A>C), RS1006512538 (2:176190701 G>A), RS1006689887 (2:176191168 G>A), RS1006958606 (2:176191356 G>A,T), RS1007782111 (2:176188428 A>G), RS1010473702 (2:176188516 G>A,C,T)

Disease associations

OMIM: gene MIM:142987 | disease phenotypes: MIM:606708

GenCC curated gene-disease

Mondo (1): split hand-foot malformation 5 (MONDO:0011709)

Orphanet (1): Isolated split hand-split foot malformation (Orphanet:2440)

HPO phenotypes

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

GWAS associations

15 associations (top):

Study	Trait	p-value
GCST000802_4	Ovarian cancer	5.000000e-14
GCST002748_3	Epithelial ovarian cancer	9.000000e-14
GCST003996_11	Monobrow	9.000000e-12
GCST005166_2	GIP levels in response to oral glucose tolerance test (120 minutes)	2.000000e-08
GCST006105_6	Eye morphology	9.000000e-07
GCST006107_1	Upper eyelid morphology	2.000000e-07
GCST006107_10	Upper eyelid morphology	4.000000e-06
GCST006107_13	Upper eyelid morphology	1.000000e-07
GCST006107_15	Upper eyelid morphology	4.000000e-09
GCST006107_4	Upper eyelid morphology	9.000000e-08
GCST006107_8	Upper eyelid morphology	7.000000e-09
GCST006661_148	Male-pattern baldness	3.000000e-18
GCST008747_175	Estimated glomerular filtration rate	3.000000e-13
GCST008747_9	Estimated glomerular filtration rate	7.000000e-13
GCST009391_579	Metabolite levels	7.000000e-07

EFO canonical traits (4, from GWAS)

EFO ID	Trait name
EFO:0007906	synophrys measurement
EFO:0004307	glucose tolerance test
EFO:0008464	glucose-dependent insulinotropic peptide measurement
EFO:0010501	indole-3-propionate measurement

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
C564674	Split-Hand-Foot Malformation 5 (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Benzo(a)pyrene	affects methylation, decreases expression, increases expression, increases methylation	3
Cyclosporine	decreases expression	3
Silicon Dioxide	increases expression, decreases expression	2
Tetrachlorodibenzodioxin	decreases expression	2
Tretinoin	increases expression	2
FR900359	decreases phosphorylation	1
dicrotophos	increases expression	1
methylmercuric chloride	increases expression	1
propionaldehyde	increases expression	1
bisphenol A	affects expression	1
titanium dioxide	decreases expression	1
trichostatin A	affects expression, decreases reaction	1
arsenite	increases methylation	1
tris(1,3-dichloro-2-propyl)phosphate	decreases expression	1
butyraldehyde	increases expression	1
tetrabromobisphenol A	increases expression	1
ferrous chloride	decreases expression	1
resorcinol	increases expression	1
pentanal	increases expression	1
CGP 52608	affects binding, increases reaction	1
entinostat	increases expression	1
Resveratrol	affects cotreatment, decreases expression	1
Leflunomide	decreases expression	1
Ethanol	decreases expression	1
Aldehydes	increases expression	1
Ampicillin	increases expression	1
Arsenic	affects methylation	1
Azathioprine	decreases expression	1
Copper	affects binding, decreases expression	1
Disulfiram	affects binding, 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_A3A5	SEES3-1V human HOXD1, clone1	Embryonic stem cell	Male
CVCL_A3A6	SEES3-1V human HOXD1, clone2	Embryonic stem cell	Male
CVCL_A3A7	SEES3-1V human HOXD1, clone3	Embryonic stem cell	Male

Clinical trials (associated diseases)

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