DLX5

Summary

DLX5 (distal-less homeobox 5, HGNC:2918) is a protein-coding gene on chromosome 7q21.3, encoding Homeobox protein DLX-5 (P56178). Transcriptional factor involved in bone development.

This gene encodes a member of a homeobox transcription factor gene family similiar to the Drosophila distal-less gene. The encoded protein may play a role in bone development and fracture healing. Mutation in this gene, which is located in a tail-to-tail configuration with another member of the family on the long arm of chromosome 7, may be associated with split-hand/split-foot malformation.

Source: NCBI Gene 1749 — RefSeq curated summary.

At a glance

• Gene–disease (curated): split hand-foot malformation 1 with sensorineural hearing loss (Strong, GenCC) — +2 more curated relationships
• GWAS associations: 5
• Clinical variants (ClinVar): 97 total — 5 pathogenic, 6 likely-pathogenic
• Phenotypes (HPO): 29
• Dosage sensitivity (ClinGen): haploinsufficiency no evidence, triplosensitivity no evidence
• Transcription factor: yes — 41 downstream targets (CollecTRI)
• MANE Select transcript: NM_005221

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:2918
Approved symbol	DLX5
Name	distal-less homeobox 5
Location	7q21.3
Locus type	gene with protein product
Status	Approved
Ensembl gene	ENSG00000105880
Ensembl biotype	protein_coding
OMIM	600028
Entrez	1749

Gene structure

Transcript identifiers

Ensembl transcripts: 3 — 2 protein_coding, 1 protein_coding_CDS_not_defined

ENST00000486603, ENST00000493764, ENST00000648378

RefSeq mRNA: 1 — MANE Select: NM_005221 NM_005221

CCDS: CCDS5647

Canonical transcript exons

ENST00000648378 — 3 exons

Exon	Start	End
ENSE00000706885	97022185	97022369
ENSE00001896696	97024269	97024831
ENSE00003833200	97020396	97021065

Expression profiles

Bgee: expression breadth ubiquitous, 158 present calls, max score 90.54.

FANTOM5 (CAGE): breadth broad, TPM avg 11.4378 / max 1809.1452, expressed in 553 samples.

FANTOM5 promoters (4 alternative TSS)

Promoter ID	TPM avg	Samples expressed
85025	10.0338	462
85024	1.0346	345
85022	0.1937	92
85023	0.1757	87

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
tibia	UBERON:0000979	90.54	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	88.64	gold quality
skin of leg	UBERON:0001511	87.21	gold quality
endometrium	UBERON:0001295	86.83	gold quality
skin of abdomen	UBERON:0001416	86.57	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	85.64	gold quality
zone of skin	UBERON:0000014	84.09	gold quality
calcaneal tendon	UBERON:0003701	81.78	gold quality
placenta	UBERON:0001987	79.44	gold quality
tendon	UBERON:0000043	77.48	gold quality
periodontal ligament	UBERON:0008266	77.40	gold quality
ganglionic eminence	UBERON:0004023	76.10	gold quality
nucleus accumbens	UBERON:0001882	75.45	gold quality
caudate nucleus	UBERON:0001873	75.11	gold quality
putamen	UBERON:0001874	74.77	gold quality
olfactory segment of nasal mucosa	UBERON:0005386	73.51	gold quality
upper leg skin	UBERON:0004262	72.68	gold quality
minor salivary gland	UBERON:0001830	72.25	gold quality
uterus	UBERON:0000995	72.10	gold quality
penis	UBERON:0000989	71.12	gold quality
tendon of biceps brachii	UBERON:0008188	70.98	gold quality
embryo	UBERON:0000922	70.35	gold quality
ventricular zone	UBERON:0003053	70.10	gold quality
endocervix	UBERON:0000458	70.01	gold quality
cingulate cortex	UBERON:0003027	69.95	gold quality
mouth mucosa	UBERON:0003729	69.93	gold quality
cortical plate	UBERON:0005343	69.87	gold quality
anterior cingulate cortex	UBERON:0009835	69.75	gold quality
trabecular bone tissue	UBERON:0002483	69.05	gold quality
prefrontal cortex	UBERON:0000451	68.52	gold quality

Single-cell (SCXA)

Detected in 9 experiment(s), a significant marker in 8.

Experiment	Marker?	Max mean expression
E-HCAD-5	yes	1536.92
E-GEOD-93593	yes	865.90
E-MTAB-10485	yes	648.44
E-MTAB-9388	yes	615.03
E-MTAB-10018	yes	443.43
E-MTAB-10287	yes	240.01
E-CURD-112	yes	15.44
E-MTAB-8894	no	1677.06
E-ANND-3	no	0.00

Regulation

Is transcription factor: yes

Downstream targets (CollecTRI)

41 targets.

Target	Regulation
ACVR1
AKT1
ALPL	Activation
BGLAP	Unknown
BMP2
BMP4
BMPER	Activation
CAMK2A
CD74
COL10A1	Unknown
COL1A1
DKK1
DLX5
DLX6
DPPA4
DSPP	Activation
EPHA7
FGF2
GBX2	Activation
GJA1
GNAS
GSC	Activation
IBSP	Activation
IGFBP3	Unknown
IRS2	Activation
LEFTY2
MAB21L1
MYC	Activation
NPPA
OAP

JASPAR motifs

Motif	Name	Family
MA1476.1	DLX5	NK

JASPAR matrix evidence (PMIDs): PMID:18585359

Upstream regulators (CollecTRI, top): ASCL1, DLX1, DLX2, DLX5, DLX6, EGR4, ELF4, GLI2, MECP2, MEF2C, MSX2, POU5F1, TBX22, TP63

miRNA regulators (miRDB)

58 targeting DLX5, 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-3613-3P	100.00	76.36	7965
HSA-MIR-548AW	99.99	72.57	3559
HSA-MIR-4789-3P	99.99	70.75	2484
HSA-MIR-12136	99.98	72.81	5713
HSA-MIR-4775	99.98	75.00	6394
HSA-LET-7F-2-3P	99.98	70.98	2588
HSA-MIR-1185-1-3P	99.98	71.04	2593
HSA-MIR-1185-2-3P	99.98	71.04	2593
HSA-MIR-590-3P	99.96	74.34	6478
HSA-MIR-545-3P	99.95	70.74	2783
HSA-MIR-767-5P	99.95	70.85	993
HSA-MIR-3143	99.93	71.96	3104
HSA-MIR-124-3P	99.89	73.74	3043
HSA-MIR-506-3P	99.89	73.55	3057
HSA-MIR-9902	99.89	69.15	2250
HSA-MIR-30A-3P	99.87	69.74	2928
HSA-MIR-30D-3P	99.87	69.92	2917
HSA-MIR-30E-3P	99.87	69.68	2942
HSA-MIR-3941	99.86	70.54	2735
HSA-MIR-548AJ-5P	99.78	71.12	3085
HSA-MIR-548F-5P	99.78	71.02	3093
HSA-MIR-548G-5P	99.78	71.12	3085
HSA-MIR-548X-5P	99.78	71.12	3085
HSA-MIR-498-5P	99.76	69.64	1807
HSA-MIR-199A-3P	99.75	70.48	929
HSA-MIR-199B-3P	99.75	70.48	929
HSA-MIR-3129-5P	99.75	70.46	914
HSA-MIR-4699-3P	99.71	70.15	3142
HSA-MIR-3059-5P	99.70	69.93	2491

Functional genomics

ClinGen dosage: haploinsufficiency 0 (no evidence), triplosensitivity 0 (no evidence). ClinGen Gene Dosage Map

Literature-anchored findings (GeneRIF, showing 40)

• Dlxin-1 binds Dlx5 and several additional homeodomain proteins and may regulate the function of Dlx family members in bone formation (PMID:11084035)
• A RING finger protein Praja1 regulates Dlx5-dependent transcription through its ubiquitin ligase activity for the Dlx/Msx-interacting MAGE/Necdin family protein, Dlxin-1. (PMID:11959851)
• DLX5 was confirmed to be imprinted in normal human lymphoblasts and brain tissues by a polymorphic analysis (PMID:12782124)
• DLX5 is a target for MeCP2, linking genomic imprinting and Rett syndrome [review] (PMID:15954098)
• In dental follicle cells, gene expression of runx2, DLX-5, and MSX-2 was unaffected during osteogenic differentiation in vitro. (PMID:16467978)
• high expression of mutated MECP2 in TRD mutation showed bialleic expression of DLX5 suggesting loss of imprinting (PMID:17363207)
• DLX5 and DLX6 are not imprinted in humans and are not likely to be direct targets of MeCP2 modulation. (PMID:17701895)
• Dlx5 can act as an oncogene by cooperating with Akt2 to promote lymphomagenesis (PMID:18316591)
• Activation of placenta-specific transcription factor distal-less homeobox 5 predicts clinical outcome in primary lung cancer patients. (PMID:18413826)
• Results describe the expression of DLX5 and DLX6 in autistic spectrum disorder patients in an attempt to identify potential abnormality of expression. (PMID:19195802)
• The MYC promoter is specifically activated by overexpression of DLX5. (PMID:19497851)
• p63 binds to an enhancer element in the SHFM1 locus and this element controls expression of DLX6 and DLX5 which are important for limb development. (PMID:20808887)
• Data suggest that DLX5 plays a significant role in the pathogenesis of some ovarian cancers by enhancing IRS-2-AKT signaling. (PMID:21045156)
• MDA-MB-231 breast neoplasms did not express DLX5 but the resulting bone/lung metastases did. (PMID:21108812)
• DLX5 is significantly increased in heart tissue from calcific aortic valve patients compared to controls. (PMID:21205918)
• the first intragenic DLX5 mutation in split hand and foot malformation is found; a potential dual role for DLX5 in limb development is suggested (PMID:22121204)
• Cyclic tensile stress may induce differentiation of periodontal ligament stem cells towards mineralized tissue cells by promoting Dlx5 mRNA expression and decreasing Msx2 expression. (PMID:22332551)
• Two patients that have in common a p63-Dlx5/Dlx6 pathway dysregulation. (PMID:22342398)
• The duplicated region harbors only DLX5 and DLX6, which are known for their role in SHFM1. (PMID:23169702)
• The strongest evidence for altered methylation patterns in shiftworkers was observed for DLX5 gene. (PMID:23193016)
• Genome sequencing of the deletion breakpoints showed that the DLX5 and DLX6 genes are disomic but the putative DYNC1I1 exon 15 and 17 enhancers are deleted. (PMID:24459211)
• A novel heterozygous mutation in exon 3 of DLX5 found in the family members with SHFM1 phenotype. (PMID:24496061)
• In cells grown on titanium support, DLX5 and RUNX1 were respectively upregulated (+3.12-fold) and downregulated (-2.14-fold) (PMID:25025858)
• Heterozygous DLX5 nonsense mutation c.G115T(p.E39X) associated with isolated split-hand/foot malformation with reduced penetrance and variable expressivity in two unrelated Polish families. (PMID:25196357)
• Absent expression of the osteoblast-specific maternally imprinted genes, DLX5 and DLX6, causes split hand/split foot malformation type I. (PMID:25332435)
• These data indicate that certain missense mutations diminish the ability of the Dlx5 homeodomain to recognize and bind target DNAs, and they likely destabilize the formation of functional complexes. (PMID:26829219)
• These results indicate activation of DLX5 and RUNX2 via its distal promoter represents a unique feature of GFs, and is important for ECM regulation. Down-regulation of these transcription factors in PAFs could be associated with their property to degrade collagen, which may impact on the process of periodontitis. (PMID:27645561)
• Our data suggest that loss of DLX5, TLX1 and HOXA10 expression in late gestation is required for proper placental differentiation and function. (PMID:28674422)
• As a result of disturbed imprinting, the upregulated DLX5 affects trophoblast proliferation in preeclampsia. (PMID:28904069)
• these findings indicate that, in MSCs, DLX5 is a master regulator of osteogenesis. Furthermore, tanshinone IIA may be valuable for stem cell-based therapies of certain bone diseases. (PMID:28949384)
• Our results in mice suggest that long-range DLX5 enhancer elements located in the human SLC25A13 gene may underlie the sensorineural hearing loss that is sometimes associated with SHFM1. (PMID:29301908)
• Children with biobehavioral reactivity to challenge and were inhibited were found to have decreased DNA methylation of the DLX5 and IGF2 genes at both time points, as compared to non-reactive, disinhibited children. (PMID:30176105)
• Inhibition of STAT5A promotes osteogenesis by DLX5 regulation. (PMID:30429452)
• activation of the DLX5/KDM4B signaling pathway might serve as an intrinsic mechanism that promotes tissue regeneration mediated by dental-derived mesenchymal stem cells. (PMID:30503866)
• Distal-Less Homeobox 5 Is a Therapeutic Target for Attenuating Hypertrophy and Apoptosis of Mesenchymal Progenitor Cells. (PMID:32650430)
• Inhibition of microRNA-27b-3p relieves osteoarthritis pain via regulation of KDM4B-dependent DLX5. (PMID:32856377)
• Dlx5 promotes cancer progression through regulation of CCND1 in oral squamous cell carcinoma (OSCC). (PMID:34283652)
• Activation of bivalent factor DLX5 cooperates with master regulator TP63 to promote squamous cell carcinoma. (PMID:34370013)
• Identification and functional analysis of changes to the ox-LDL-induced microRNA-124-3p/DLX5 axis in vascular smooth muscle cells. (PMID:34705345)
• Sequence variants in DLX5, HOXD13 and 445 kb-microduplication surrounding BTRC cause split-hand/foot malformation in three different families. (PMID:37776184)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	dlx5a	ENSDARG00000042296
mus_musculus	Dlx5	ENSMUSG00000029755
rattus_norvegicus	Dlx5	ENSRNOG00000010905
drosophila_melanogaster	Dll	FBGN0000157
caenorhabditis_elegans		WBGENE00000463

Paralogs (9): DLX6 (ENSG00000006377), DLX3 (ENSG00000064195), DLX4 (ENSG00000108813), NANOG (ENSG00000111704), DLX2 (ENSG00000115844), DLX1 (ENSG00000144355), VENTX (ENSG00000151650), BSX (ENSG00000188909), NANOGP8 (ENSG00000255192)

Protein

Protein identifiers

Homeobox protein DLX-5 — P56178 (reviewed: P56178)

All UniProt accessions (2): P56178, Q53Y73

UniProt curated annotations — full annotation on UniProt →

Function. Transcriptional factor involved in bone development. Acts as an immediate early BMP-responsive transcriptional activator essential for osteoblast differentiation. Stimulates ALPL promoter activity in a RUNX2-independent manner during osteoblast differentiation. Stimulates SP7 promoter activity during osteoblast differentiation. Promotes cell proliferation by up-regulating MYC promoter activity. Involved as a positive regulator of both chondrogenesis and chondrocyte hypertrophy in the endochondral skeleton. Binds to the homeodomain-response element of the ALPL and SP7 promoter. Binds to the MYC promoter. Requires the 5’-TAATTA-3’ consensus sequence for DNA-binding.

Subunit / interactions. Interacts with XRCC6 (Ku70).

Subcellular location. Nucleus.

Post-translational modifications. Phosphorylated. Phosphorylation of Ser-34 and Ser-217 by MAPK14 enhances its transcriptional activity. Phosphorylation by CaMK2 increases its protein stability.

Disease relevance. Split-hand/foot malformation 1 with sensorineural hearing loss, autosomal recessive (SHFM1D) [MIM:220600] A disease characterized by the association of split-hand/foot malformation with deafness. Split-hand/foot malformation is a limb malformation involving the central rays of the autopod and presenting with syndactyly, median clefts of the hands and feet, and aplasia and/or hypoplasia of the phalanges, metacarpals, and metatarsals. Some patients have been found to have intellectual disability, ectodermal and craniofacial findings, and orofacial clefting. The disease is caused by variants affecting the gene represented in this entry.

Similarity. Belongs to the distal-less homeobox family.

Isoforms (2)

UniProt ID	Names	Canonical?
P56178-1	1	yes
P56178-2	2

RefSeq proteins (1): NP_005212* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000047	HTH_motif	Conserved_site
IPR001356	HD	Domain
IPR009057	Homeodomain-like_sf	Homologous_superfamily
IPR017970	Homeobox_CS	Conserved_site
IPR020479	HD_metazoa	Domain
IPR022135	Distal-less_N	Domain
IPR050460	Distal-less_Homeobox_TF	Family

Pfam: PF00046, PF12413

UniProt features (16 total): helix 3, region of interest 3, compositionally biased region 3, sequence variant 2, modified residue 2, chain 1, DNA-binding region 1, splice variant 1

Structure

Experimental structures (PDB)

2 structures.

PDB	Method	Resolution (Å)
4RDU	X-RAY DIFFRACTION	1.85
2DJN	SOLUTION NMR

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P56178-F1	61.56	0.21

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 (2): 34, 217

Function

Pathways and Gene Ontology

Reactome pathways

3 pathways

ID	Pathway
R-HSA-8939902	Regulation of RUNX2 expression and activity
R-HSA-9834899	Specification of the neural plate border
R-HSA-9938206	Developmental Lineage of Mammary Stem Cells

MSigDB gene sets: 278 (showing top): GOBP_OLFACTORY_BULB_INTERNEURON_DIFFERENTIATION, GOBP_EMBRYO_DEVELOPMENT_ENDING_IN_BIRTH_OR_EGG_HATCHING, GOBP_EPITHELIUM_DEVELOPMENT, GOBP_BODY_MORPHOGENESIS, BENPORATH_ES_WITH_H3K27ME3, GOBP_SKELETAL_SYSTEM_DEVELOPMENT, NKX25_02, GOBP_EMBRYONIC_SKELETAL_SYSTEM_DEVELOPMENT, GRAESSMANN_APOPTOSIS_BY_DOXORUBICIN_DN, GOBP_OSTEOBLAST_DIFFERENTIATION, GOBP_NEUROGENESIS, GOBP_REGULATION_OF_WNT_SIGNALING_PATHWAY, GOBP_FOREBRAIN_DEVELOPMENT, GOBP_FOREBRAIN_GENERATION_OF_NEURONS, COUP_01

GO Biological Process (30): skeletal system development (GO:0001501), osteoblast differentiation (GO:0001649), endochondral ossification (GO:0001958), regulation of transcription by RNA polymerase II (GO:0006357), nervous system development (GO:0007399), cell population proliferation (GO:0008283), positive regulation of gene expression (GO:0010628), olfactory bulb interneuron differentiation (GO:0021889), cell differentiation (GO:0030154), embryonic limb morphogenesis (GO:0030326), BMP signaling pathway (GO:0030509), epithelial cell differentiation (GO:0030855), inner ear morphogenesis (GO:0042472), positive regulation of DNA-templated transcription (GO:0045893), positive regulation of transcription by RNA polymerase II (GO:0045944), anatomical structure formation involved in morphogenesis (GO:0048646), embryonic skeletal system development (GO:0048706), positive regulation of epithelial cell proliferation (GO:0050679), roof of mouth development (GO:0060021), olfactory pit development (GO:0060166), face morphogenesis (GO:0060325), positive regulation of canonical Wnt signaling pathway (GO:0090263), interneuron axon guidance (GO:0097376), ossification (GO:0001503), regulation of DNA-templated transcription (GO:0006355), axonogenesis (GO:0007409), axon guidance (GO:0007411), ear development (GO:0043583), head development (GO:0060322), bone morphogenesis (GO:0060349)

GO Molecular Function (7): transcription cis-regulatory region binding (GO:0000976), 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), HMG box domain binding (GO:0071837), sequence-specific double-stranded DNA binding (GO:1990837), DNA binding (GO:0003677)

GO Cellular Component (3): chromatin (GO:0000785), nucleus (GO:0005634), cytoplasm (GO:0005737)

Reactome top-level categories

Rollup of top-3 pathways:

Category	Pathways
Transcriptional regulation by RUNX2	1
Gastrulation	1
Developmental Lineages of the Mammary Gland	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
system development	2
cell differentiation	2
regulation of DNA-templated transcription	2
transcription by RNA polymerase II	2
regulation of transcription by RNA polymerase II	2
anatomical structure development	2
cellular anatomical structure	2
ossification	1
replacement ossification	1
endochondral bone morphogenesis	1
cellular process	1
gene expression	1
regulation of gene expression	1
positive regulation of macromolecule biosynthetic process	1
olfactory bulb development	1
forebrain neuron differentiation	1
cellular developmental process	1
limb morphogenesis	1
embryonic appendage morphogenesis	1
cellular response to BMP stimulus	1
transforming growth factor beta receptor superfamily signaling pathway	1
epithelium development	1
ear morphogenesis	1
embryonic morphogenesis	1
inner ear development	1
DNA-templated transcription	1
positive regulation of RNA biosynthetic process	1
positive regulation of DNA-templated transcription	1
anatomical structure morphogenesis	1
developmental process	1
skeletal system development	1
chordate embryonic development	1
positive regulation of cell population proliferation	1
epithelial cell proliferation	1
regulation of epithelial cell proliferation	1
nose development	1
transcription regulatory region nucleic acid binding	1
sequence-specific double-stranded DNA binding	1
cis-regulatory region sequence-specific DNA binding	1

Protein interactions and networks

STRING

1854 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
DLX5	RUNX2	Q13950	961
DLX5	BGLAP	P02818	896
DLX5	SP7	Q8TDD2	871
DLX5	MAGED1	Q9Y5V3	864
DLX5	WNT3A	P56704	824
DLX5	MECP2	P51608	752
DLX5	MSX2	P35548	735
DLX5	SEM1	Q6ZVN7	725
DLX5	BMP7	P18075	719
DLX5	WNT1	P04628	715
DLX5	GAD1	Q99259	714
DLX5	BMP4	P12644	710
DLX5	LHX6	Q9UPM6	685
DLX5	SLC32A1	Q9H598	676
DLX5	SHH	Q15465	654

IntAct

11 interactions, top by confidence:

A	B	Type	Score
FOXA1	NFIC	psi-mi:“MI:0914”(association)	0.350
FOXC1	NFIX	psi-mi:“MI:0914”(association)	0.350
FOXC2	ZNF536	psi-mi:“MI:0914”(association)	0.350
FOXE1	DDX39A	psi-mi:“MI:0914”(association)	0.350
FOXI2	DDX39A	psi-mi:“MI:0914”(association)	0.350
FOXJ2	TCERG1	psi-mi:“MI:0914”(association)	0.350
FOXO1	HOXC13	psi-mi:“MI:0914”(association)	0.350
RBPJ	SAMD1	psi-mi:“MI:0914”(association)	0.350
TEAD2	DDX39A	psi-mi:“MI:0914”(association)	0.350
PARP1	KPNA3	psi-mi:“MI:0914”(association)	0.350

BioGRID (21): DLX5 (Affinity Capture-MS), DLX5 (Affinity Capture-MS), DLX5 (Affinity Capture-MS), DLX5 (Affinity Capture-MS), DLX5 (Affinity Capture-MS), DLX5 (Affinity Capture-MS), DLX5 (Affinity Capture-MS), DLX5 (Affinity Capture-MS), DLX5 (Affinity Capture-MS), MSX1 (Reconstituted Complex), MSX2 (Reconstituted Complex), DLX2 (Reconstituted Complex), DLX5 (Reconstituted Complex), DLX5 (Reconstituted Complex), DLX5 (Reconstituted Complex)

ESM2 similar proteins: A1L2P5, A8DT10, O08656, O42368, O42370, O93353, O94900, P09022, P09027, P09089, P23682, P31249, P46692, P49639, P50574, P53773, P53774, P53775, P56178, Q01702, Q08820, Q08821, Q1KKS7, Q1KKU6, Q1KKX7, Q1KL10, Q1KL12, Q1KL13, Q28IU6, Q3V5Z9, Q66JW3, Q6B3N0, Q6DCQ1, Q6NVT7, Q8AWZ2, Q8BUR3, Q90423, Q91690, Q91904, Q98875

Diamond homologs: A1YF16, A1YG93, A2RU54, A2T764, A6NCS4, A6NHT5, G5EE18, M0R6D8, O02786, O35767, O42230, O57601, O60479, O70218, P10181, P13297, P15857, P19601, P20009, P23410, P28360, P28361, P28362, P35548, P35993, P40764, P42580, P42581, P43687, P43688, P48031, P50219, P50223, P50574, P50575, P50576, P50577, P52953, P53547, P53770

SIGNOR signaling

21 interactions.

A	Effect	B	Mechanism
DLX5	“up-regulates quantity by expression”	RUNX2	“transcriptional regulation”
AKT	up-regulates	DLX5	phosphorylation
AKT1	up-regulates	DLX5	phosphorylation
DLX5	“up-regulates quantity”	MYC	“transcriptional regulation”
POU5F1	“down-regulates quantity by repression”	DLX5	“transcriptional regulation”
DLX5	“down-regulates activity”	MSX1	binding
DLX5	“down-regulates activity”	MSX2	binding
MSX1	“down-regulates activity”	DLX5	binding
MSX2	“down-regulates activity”	DLX5	binding
MECP2	“down-regulates quantity by repression”	DLX5	“transcriptional regulation”
DLX5	up-regulates	Osteoblast_differentiation
SMAD1/4	up-regulates	DLX5	“transcriptional regulation”
SMAD5/SMAD4	up-regulates	DLX5	“transcriptional regulation”
MAPK14	“up-regulates activity”	DLX5	phosphorylation
SMAD1/5/8/SMAD4	up-regulates	DLX5	“transcriptional regulation”
DLX5	“up-regulates quantity”	SPP1	“transcriptional regulation”
TBX22	“down-regulates quantity by repression”	DLX5	“transcriptional regulation”
DLX5	up-regulates	Neurogenesis

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 18 IntAct physical interaction partners (hypergeometric vs the genome-wide background, BH-FDR, gene-set size 15–500, ranked by fold). A functional readout of the neighbourhood — distinct from this gene’s own memberships above, and biased toward well-studied / hub proteins, so read it as themes rather than proof.

GO biological processes:

GO term	Partners	Fold	FDR
anatomical structure morphogenesis	6	46.4×	2e-07

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	5
Likely pathogenic	6
Uncertain significance	52
Likely benign	17
Benign	9

Top pathogenic / likely-pathogenic (11)

Variant ID	HGVS	Classification
1443159	NM_005221.6(DLX5):c.437del (p.Ser146fs)	Pathogenic
152344	GRCh38/hg38 7q21.3(chr7:96924153-97157268)x1	Pathogenic
156469	NM_005221.6(DLX5):c.115G>T (p.Glu39Ter)	Pathogenic
1807807	GRCh37/hg19 7q21.3(chr7:96264152-96860892)x1	Pathogenic
30021	NM_005221.6(DLX5):c.533A>C (p.Gln178Pro)	Pathogenic
2502307	NM_005221.6(DLX5):c.509T>C (p.Leu170Pro)	Likely pathogenic
2635143	NM_005221.6(DLX5):c.376G>T (p.Glu126Ter)	Likely pathogenic
3030607	NM_005221.6(DLX5):c.541-1G>A	Likely pathogenic
3381995	NM_005221.6(DLX5):c.481T>C (p.Tyr161His)	Likely pathogenic
3893225	NM_005221.6(DLX5):c.512C>T (p.Ala171Val)	Likely pathogenic
4279282	GRCh37/hg19 7q21.3(chr7:96630308-96675313)x1	Likely pathogenic

SpliceAI

696 predictions. Top by Δscore:

Variant	Effect	Δscore
7:97021527:C:CA	donor_gain	1.0000
7:97024264:TGTA:T	donor_loss	1.0000
7:97024265:GTACC:G	donor_loss	1.0000
7:97024266:TA:T	donor_loss	1.0000
7:97024268:CCTGG:C	donor_gain	1.0000
7:97021536:C:CA	donor_gain	0.9900
7:97022370:C:G	acceptor_gain	0.9900
7:97021066:C:CC	acceptor_gain	0.9800
7:97022180:TTTAC:T	donor_loss	0.9800
7:97022181:TTACC:T	donor_loss	0.9800
7:97022182:TACCT:T	donor_loss	0.9800
7:97022183:A:T	donor_loss	0.9800
7:97022184:C:A	donor_loss	0.9800
7:97022370:C:CC	acceptor_gain	0.9800
7:97024267:A:AC	donor_gain	0.9800
7:97024268:C:CC	donor_gain	0.9800
7:97021071:T:C	acceptor_gain	0.9700
7:97021071:T:TC	acceptor_gain	0.9700
7:97022286:AGC:A	acceptor_gain	0.9700
7:97022287:GCT:G	acceptor_gain	0.9700
7:97022369:TCTAA:T	acceptor_gain	0.9700
7:97021063:CAC:C	acceptor_gain	0.9600
7:97021524:ACTC:A	donor_gain	0.9600
7:97021525:CTCC:C	donor_gain	0.9600
7:97022368:CT:C	acceptor_gain	0.9600
7:97021061:TTCAC:T	acceptor_gain	0.9500
7:97022288:CTG:C	acceptor_gain	0.9400
7:97022367:TCT:T	acceptor_gain	0.9400
7:97022368:CTC:C	acceptor_gain	0.9400
7:97022784:A:AC	donor_gain	0.9400

AlphaMissense

1875 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
7:97021026:T:C	K194E	1.000
7:97021027:C:A	K193N	1.000
7:97021027:C:G	K193N	1.000
7:97021028:T:A	K193M	1.000
7:97021029:T:C	K193E	1.000
7:97021033:C:A	K191N	1.000
7:97021033:C:G	K191N	1.000
7:97021034:T:A	K191M	1.000
7:97021035:T:C	K191E	1.000
7:97021037:G:A	S190F	1.000
7:97021038:A:G	S190P	1.000
7:97021039:T:A	R189S	1.000
7:97021039:T:G	R189S	1.000
7:97021040:C:A	R189I	1.000
7:97021040:C:G	R189T	1.000
7:97021041:T:C	R189G	1.000
7:97021042:T:A	K188N	1.000
7:97021042:T:G	K188N	1.000
7:97021045:G:C	N187K	1.000
7:97021045:G:T	N187K	1.000
7:97021046:T:A	N187I	1.000
7:97021046:T:C	N187S	1.000
7:97021046:T:G	N187T	1.000
7:97021047:T:A	N187Y	1.000
7:97021047:T:C	N187D	1.000
7:97021047:T:G	N187H	1.000
7:97021048:C:A	Q186H	1.000
7:97021048:C:G	Q186H	1.000
7:97021049:T:A	Q186L	1.000
7:97021049:T:C	Q186R	1.000

dbSNP variants (sampled 300 via entrez): RS1000284684 (7:97019913 T>C,G), RS1000750720 (7:97025081 GTCTA>G), RS1001677784 (7:97022804 G>A,T), RS1001709036 (7:97022652 C>A,G), RS1002466755 (7:97023760 T>C), RS1002470621 (7:97021756 C>T), RS1002685713 (7:97021763 C>A,G), RS1003088701 (7:97021409 C>G), RS1003225395 (7:97025695 A>G), RS1003528644 (7:97023582 C>CGAAAAAGGAGGACG), RS1003684215 (7:97020303 T>C), RS1004226787 (7:97025955 T>C), RS1004637237 (7:97024184 T>A), RS1004693954 (7:97022694 T>A,G), RS1004823454 (7:97024682 T>C)

Disease associations

OMIM: gene MIM:600028 | disease phenotypes: MIM:183600, MIM:220600

GenCC curated gene-disease

Disease	Classification	Inheritance
split hand-foot malformation 1	Strong	Autosomal dominant
split hand-foot malformation 1 with sensorineural hearing loss	Strong	Autosomal dominant
split hand-foot malformation	Supportive	Autosomal dominant

Mondo (3): split hand-foot malformation 1 (MONDO:0008464), split hand-foot malformation 1 with sensorineural hearing loss (MONDO:0009080), split hand-foot malformation (MONDO:0016576)

Orphanet (2): Isolated split hand-split foot malformation (Orphanet:2440), Split hand-split foot-deafness syndrome (Orphanet:71271)

HPO phenotypes

29 total (29 of 29 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000007	Autosomal recessive inheritance
HP:0000175	Cleft palate
HP:0000365	Hearing impairment
HP:0000377	Abnormal pinna morphology
HP:0000407	Sensorineural hearing impairment
HP:0000526	Aniridia
HP:0001159	Syndactyly
HP:0001171	Split hand
HP:0001182	Tapered finger
HP:0001199	Triphalangeal thumb
HP:0001249	Intellectual disability
HP:0001839	Split foot
HP:0001849	Foot oligodactyly
HP:0002007	Frontal bossing
HP:0002650	Scoliosis
HP:0003510	Severe short stature
HP:0003577	Congenital onset
HP:0003828	Variable expressivity
HP:0003829	Typified by incomplete penetrance
HP:0004050	Absent hand
HP:0004058	Hand monodactyly
HP:0006101	Finger syndactyly
HP:0009380	Finger aplasia
HP:0010055	Broad hallux
HP:0012165	Oligodactyly
HP:0030084	Clinodactyly
HP:0030680	Abnormal cardiovascular system morphology
HP:0100257	Ectrodactyly

GWAS associations

5 associations (top):

Study	Trait	p-value
GCST003429_35	Morning vs. evening chronotype	1.000000e-08
GCST006288_650	Heel bone mineral density	7.000000e-10
GCST006288_756	Heel bone mineral density	2.000000e-06
GCST006979_139	Heel bone mineral density	3.000000e-29
GCST90013406_154	Liver enzyme levels (alkaline phosphatase)	5.000000e-11

EFO canonical traits (2, from GWAS)

EFO ID	Trait name
EFO:0009270	heel bone mineral density
EFO:0004533	alkaline phosphatase measurement

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
C565647	Split-Hand-Foot Malformation With Sensorineural Hearing Loss (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects cotreatment, increases expression	4
methylmercuric chloride	increases expression	3
sodium arsenite	increases expression	2
mercuric bromide	increases expression, affects cotreatment	2
Tunicamycin	decreases expression	2
p-Chloromercuribenzoic Acid	affects cotreatment, increases expression	2
decabromobiphenyl ether	increases expression	1
terbufos	increases methylation	1
trichostatin A	increases expression	1
butyraldehyde	increases expression	1
tetrabromobisphenol A	increases expression	1
tetrachlorodian	increases expression	1
perfluorooctane sulfonic acid	affects 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
2,2’,4,4’-tetrabromodiphenyl ether	increases expression	1
dorsomorphin	affects cotreatment, increases expression	1
bisphenol S	decreases methylation	1
N-(2-(3H-indol-3-yl)ethyl)-9-isopropyl-2-(5-methyl-3-pyridyl)purin-6-amine	decreases expression, decreases reaction	1
Benzo(a)pyrene	affects methylation, increases methylation	1
Cadmium	affects expression	1
Cannabidiol	increases expression	1
Carbamazepine	affects expression	1
DDT	increases expression	1
Dexamethasone	decreases expression	1
Fonofos	increases methylation	1
Estrogens	increases expression	1
Parathion	increases methylation	1
Tetrachlorodibenzodioxin	decreases expression, decreases reaction, affects expression	1
Antirheumatic Agents	increases 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_A0Y9	SEES3-1V human DLX5, clone1	Embryonic stem cell	Male
CVCL_A0Z0	SEES3-1V human DLX5, clone2	Embryonic stem cell	Male
CVCL_A0Z1	SEES3-1V human DLX5, clone3	Embryonic stem cell	Male

Clinical trials (associated diseases)

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