DLX3

Summary

DLX3 (distal-less homeobox 3, HGNC:2916) is a protein-coding gene on chromosome 17q21.33, encoding Homeobox protein DLX-3 (O60479). Transcriptional activator.

Many vertebrate homeo box-containing genes have been identified on the basis of their sequence similarity with Drosophila developmental genes. Members of the Dlx gene family contain a homeobox that is related to that of Distal-less (Dll), a gene expressed in the head and limbs of the developing fruit fly. The Distal-less (Dlx) family of genes comprises at least 6 different members, DLX1-DLX6. Trichodentoosseous syndrome (TDO), an autosomal dominant condition, has been correlated with DLX3 gene mutation. This gene is located in a tail-to-tail configuration with another member of the gene family on the long arm of chromosome 17. Mutations in this gene have been associated with the autosomal dominant conditions trichodentoosseous syndrome and amelogenesis imperfecta with taurodontism.

Source: NCBI Gene 1747 — RefSeq curated summary.

At a glance

• Gene–disease (curated): tricho-dento-osseous syndrome (Strong, GenCC) — +1 more curated relationship
• GWAS associations: 1
• Clinical variants (ClinVar): 214 total — 2 pathogenic, 4 likely-pathogenic
• Phenotypes (HPO): 21
• Transcription factor: yes — 22 downstream targets (CollecTRI)
• MANE Select transcript: NM_005220

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:2916
Approved symbol	DLX3
Name	distal-less homeobox 3
Location	17q21.33
Locus type	gene with protein product
Status	Approved
Ensembl gene	ENSG00000064195
Ensembl biotype	protein_coding
OMIM	600525
Entrez	1747

Gene structure

Transcript identifiers

Ensembl transcripts: 2 — 2 protein_coding

ENST00000434704, ENST00000512495

RefSeq mRNA: 1 — MANE Select: NM_005220 NM_005220

CCDS: CCDS11556

Canonical transcript exons

ENST00000434704 — 3 exons

Exon	Start	End
ENSE00001781529	49993400	49993590
ENSE00002024502	49994674	49995224
ENSE00002031897	49990005	49991864

Expression profiles

Bgee: expression breadth ubiquitous, 133 present calls, max score 91.74.

FANTOM5 (CAGE): breadth broad, TPM avg 5.6637 / max 408.8213, expressed in 496 samples.

FANTOM5 promoters (4 alternative TSS)

Promoter ID	TPM avg	Samples expressed
166840	5.4766	486
166838	0.0801	49
166839	0.0604	26
166837	0.0466	18

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
skin of leg	UBERON:0001511	91.74	gold quality
skin of abdomen	UBERON:0001416	90.38	gold quality
zone of skin	UBERON:0000014	89.31	gold quality
upper arm skin	UBERON:0004263	86.39	silver quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	80.42	silver quality
placenta	UBERON:0001987	78.20	gold quality
gingiva	UBERON:0001828	76.06	gold quality
gingival epithelium	UBERON:0001949	74.75	silver quality
upper leg skin	UBERON:0004262	72.93	gold quality
buccal mucosa cell	CL:0002336	72.08	gold quality
popliteal artery	UBERON:0002250	69.52	gold quality
tibial artery	UBERON:0007610	69.51	gold quality
lower esophagus mucosa	UBERON:0035834	67.92	gold quality
esophagus mucosa	UBERON:0002469	67.16	gold quality
skin of hip	UBERON:0001554	66.94	gold quality
tibia	UBERON:0000979	66.71	silver quality
mammalian vulva	UBERON:0000997	63.82	silver quality
nipple	UBERON:0002030	63.08	gold quality
pancreatic ductal cell	CL:0002079	61.72	silver quality
aorta	UBERON:0000947	61.41	gold quality
left lobe of thyroid gland	UBERON:0001120	61.41	gold quality
right lobe of thyroid gland	UBERON:0001119	61.11	gold quality
esophagus squamous epithelium	UBERON:0006920	60.39	gold quality
layer of synovial tissue	UBERON:0007616	60.27	gold quality
synovial joint	UBERON:0002217	59.93	gold quality
thyroid gland	UBERON:0002046	59.92	gold quality
vagina	UBERON:0000996	59.73	gold quality
decidua	UBERON:0002450	58.79	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	57.83	gold quality
trabecular bone tissue	UBERON:0002483	56.79	silver quality

Single-cell (SCXA)

Detected in 2 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-ANND-3	yes	7.46
E-MTAB-8060	no	212.39

Regulation

Is transcription factor: yes

Downstream targets (CollecTRI)

22 targets.

Target	Regulation
ACVR1
AKT1
BGLAP
BMP2
BMP4	Unknown
CGA	Activation
DES
DLX3
DLX4	Unknown
DSPP
ESX1	Unknown
HSD3B1
KLK4	Unknown
MAPT	Unknown
MMP9
NPPA
OAP
PAX2	Unknown
PAX8	Unknown
PGF
RUNX2	Activation
SUMO1

Upstream regulators (CollecTRI, top): CEBPB, DLX3, GLI2, HR, SMAD1, SMAD4, SMAD5, SMAD6

miRNA regulators (miRDB)

137 targeting DLX3, 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-190A-3P	100.00	80.35	5520
HSA-MIR-5011-5P	100.00	83.46	5820
HSA-MIR-9-5P	100.00	72.28	2361
HSA-MIR-6798-5P	100.00	65.77	699
HSA-MIR-4481	100.00	66.42	1669
HSA-MIR-340-5P	100.00	72.50	4437
HSA-MIR-6133	100.00	66.48	2064
HSA-MIR-12118	100.00	65.88	1270
HSA-MIR-4510	100.00	66.60	2050
HSA-MIR-6127	100.00	66.76	2188
HSA-MIR-6129	100.00	66.46	2080
HSA-MIR-6130	100.00	66.69	2012
HSA-MIR-19A-3P	99.98	75.33	2762
HSA-MIR-19B-3P	99.98	75.44	2754
HSA-MIR-4745-5P	99.98	65.95	1028
HSA-MIR-3173-3P	99.98	66.49	1217
HSA-MIR-6891-5P	99.98	66.53	1372
HSA-MIR-7152-3P	99.97	67.47	849
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-3658	99.96	73.87	4379
HSA-MIR-3143	99.93	71.96	3104
HSA-MIR-1305	99.91	71.43	3443
HSA-MIR-4648	99.91	67.00	710
HSA-MIR-124-3P	99.89	73.74	3043
HSA-MIR-506-3P	99.89	73.55	3057
HSA-MIR-4496	99.88	68.89	2236
HSA-MIR-4447	99.85	67.81	2900
HSA-MIR-4728-5P	99.85	69.39	4718

Literature-anchored findings (GeneRIF, showing 40)

• results suggest that a serine residue in the homeodomain of the mouse Dlx3 protein can be directly phosphorylated by a protein kinase C-dependent pathway, which affects the DNA binding activity of Dlx3. (PMID:11343707)
• AP-2 gamma and Dlx 3, together with an additional transcription factor(s) that are conserved between humans and mice, are required for trophoblast-specific expression of 3 beta-HSD VI. (PMID:11773066)
• Genomic structure and functional control of the Dlx3-7 bigene cluster (PMID:11792834)
• Overexpression of C/EBP beta was sufficient to increase basal expression of a Dlx3 reporter gene in a dose-dependent manner. (PMID:14670999)
• results suggest that DLX3 gene is important in bone formation and/or homeostasis of the appendicular skeleton (PMID:15454107)
• This is the first report of a mutation within the homeodomain of DLX3. (PMID:15666299)
• p63 and Dlx play central roles in embryonic patterning and regulation of different developmental processes, and their mutations have been associated with ectodermal dysplasias [review] (PMID:16187309)
• mutation has positive effects on bone density throughout life (PMID:16301156)
• DLX-3 gene expression was increased in dental follicle cells during osteogenic differentiation. (PMID:16467978)
• Smad6 appears to functionally interact with Dlx3, altering the ability of Dlx3 to bind target gene promoters. (PMID:16687405)
• gene defect of trichodentoosseous syndrome has been localized only in the DLX3 gene (PMID:17559453)
• Results show that differential DLX3 methylation could be a new epigenetic marker for genotypic B-cell leukemia subgroup with high-risk features. (PMID:17611665)
• Carboxy-terminus of the DLX3 protein is critical in determining its function during development in hair, tooth, and bone. (PMID:18203197)
• The identified mutation was c.561_562delCT mutation in the DLX3 gene. This study clearly showed that the c.561_562delCT mutation had not only enamel defects, but also other clinical phenotypes resembling those of TDO syndrome. (PMID:18362318)
• DLX3(TDO) has a dominant negative effect on DLX3(WT) transcriptional activity (PMID:18492670)
• Dlx3 triggers p63 protein degradation by a proteasome-dependent pathway. (PMID:19282665)
• Enamel hardness with 2-bp del in DLX3 was about 53% normal enamel hardness. Mutant enamel thickness was about 50% normal thickness. Calcium level in enamel with 2-bp del was slightly decreased; magnesium level was slightly increased, compared to normal. (PMID:19608154)
• A genetic investigation revealed a de-novo mutation in the DLX3 gene on chromosome 17q21. (PMID:20151948)
• Nuclear expression for DLX3 was observed in villous cytotrophoblasts, syncytiotrophoblast and extravillous cytotrophoblast in the proximal regions of the cytotrophoblast cell columns in first trimester placental tissues. (PMID:20542333)
• DLX3 homeodomain mutations cause tricho-dento-osseous syndrome with novel phenotypes (PMID:21252474)
• SUMOylation of DLX3 by SUMO1 promotes its transcriptional activity. (PMID:21268066)
• In cells expressing equal amounts of mutant and wild-type DLX3, deltaNp63alpha protein level was efficiently regulated, implying that heterozygosity at the DLX3 locus protects tricho-dento-osseous patients from severe p63-associated skin defects. (PMID:21520071)
• DLX3 acts upstream of syncytin, 3beta-hydroxysteroid dehydrogenase, and the human gonadotropin beta-subunit to play a regulatory role in villous cytotrophoblast differentiation. (PMID:21802725)
• DLX3 stimulates osteogenic differentiation via BMP2 dependent pathway. (PMID:22107079)
• Increased DLX3 expression in idiopathic fetal growth restricion (FGR) may contribute to trophoblast dysfunction observed in FGR. (PMID:22113468)
• DLX3 orchestrates the expression of multiple regulators of trophoblast differentiation and that expression of these regulatory genes is abnormal in fetal growth restriction. (PMID:23831639)
• In conclusion, results of our study suggest that the NOTCH-signaling pathway, which is activated during the osteogenic differentiation of DFCs. (PMID:24321094)
• Results suggest that Dlx3 is a novel target of PKA, and that PKA mediates BMP signaling during osteoblast differentiation, at least in part, by phosphorylating Dlx3 and modulating its stability and function. (PMID:24924519)
• rs2278163 SNP of DLX3 might be associated with dental caries susceptibility in Japanese children. T and C alleles of rs2278163 SNP may potentially be involved in caries susceptibility and caries protection respectively. (PMID:25247779)
• genetic analysis revealed a novel de novo missense mutation c.533A>G (p.Q178R) in the conserved homeodomain of the DLX3 gene. This DLX3 mutation is the sixth causative mutation for TDO to be identified so far. (PMID:26104267)
• Data establish the DLX3-p53 interplay as a major regulatory axis in epidermal differentiation and suggest that DLX3 is a modulator of skin carcinogenesis. (PMID:26522723)
• ER-alpha regulates the osteoblast differentiation through modulation of Dlx3 expression and/or interaction with Dlx3. (PMID:26674964)
• we identified a recurrent 2-bp deletion in the DLX3 gene in a new family and described their mild clinical phenotype related to the DLX3 mutation. (PMID:26762616)
• We showed that the supplementation of the osteogenic differentiation medium with PTHrP inhibited the alkaline phosphatase activity and the expression of the transcription factor DLX3, but the depletion of PTHrP did not support the differentiation of DFCs.We showed that SUFU (Suppressor Of Fused Homolog) was not regulated during the osteogenic differentiation in DFCs (PMID:27368119)
• Our research of DLX3 mutation protecting aging-related bone loss opens the possibility of its therapeutic potential in bone regeneration and bone loss disease. (PMID:27924851)
• Identify a novel cis-acting sequence (-369 to -320) at the placental growth factor promoter, which was critical for mediating the basal and DLX3/GCM1-dependent PGF promoter activities. (PMID:27996093)
• Novel de novo mutation of DLX3 significantly decreases the proliferation rate and inhibits the odontogenic differentiation and mineralization of hDPCs, suggesting that this novel mutation of DLX3 can influence the dentinogenesis in TDO syndrome. (PMID:28135572)
• DLX3 expression specifically modulates regulatory networks such as Wnt signaling, phosphatase activity and cell adhesion. (PMID:28186503)
• our studies demonstrate that DLX3 physically interacts with GCM1 and inhibits its transactivation activity, suggesting that DLX3 and GCM1 may form a complex to functionally regulate placental cell function through modulation of target gene expression. (PMID:28515447)
• DLX3 regulates bone marrow mesenchymal stem cell proliferation through H19/miR-675 axis. (PMID:28963438)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	dlx3b	ENSDARG00000014626
mus_musculus	Dlx3	ENSMUSG00000001510
rattus_norvegicus	Dlx3	ENSRNOG00000004278
drosophila_melanogaster	Dll	FBGN0000157
caenorhabditis_elegans		WBGENE00000463

Paralogs (9): DLX6 (ENSG00000006377), DLX5 (ENSG00000105880), DLX4 (ENSG00000108813), NANOG (ENSG00000111704), DLX2 (ENSG00000115844), DLX1 (ENSG00000144355), VENTX (ENSG00000151650), BSX (ENSG00000188909), NANOGP8 (ENSG00000255192)

Protein

Protein identifiers

Homeobox protein DLX-3 — O60479 (reviewed: O60479)

All UniProt accessions (2): O60479, F8VXG1

UniProt curated annotations — full annotation on UniProt →

Function. Transcriptional activator. Activates transcription of GNRHR, via binding to the downstream activin regulatory element (DARE) in the gene promoter.

Subunit / interactions. Heterodimer with MEIS1. Interacts with IPO7; the interaction facilitates nuclear translocation of DLX3 in dental papilla cells.

Subcellular location. Nucleus. Cytoplasm.

Disease relevance. Trichodentoosseous syndrome (TDO) [MIM:190320] An autosomal dominant disease characterized by curly kinky hair at birth, enamel hypoplasia, taurodontism, thickening of cortical bones and variable expression of craniofacial morphology. The disease is caused by variants affecting the gene represented in this entry. Amelogenesis imperfecta 4 (AI4) [MIM:104510] An autosomal dominant defect of enamel formation associated with enlarged pulp chambers. Enamel is thin, teeth are small and widely spaced. The disease is caused by variants affecting the gene represented in this entry.

Similarity. Belongs to the distal-less homeobox family.

RefSeq proteins (1): NP_005211* (*=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 (15 total): compositionally biased region 4, helix 3, region of interest 3, turn 2, chain 1, DNA-binding region 1, strand 1

Structure

Experimental structures (PDB)

1 structures.

PDB	Method	Resolution (Å)
4XRS	X-RAY DIFFRACTION	3.5

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-O60479-F1	60.87	0.21

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 209 (showing top): GOBP_MORPHOGENESIS_OF_AN_EPITHELIUM, FXR_IR1_Q6, GOBP_EMBRYO_DEVELOPMENT_ENDING_IN_BIRTH_OR_EGG_HATCHING, GOBP_EPITHELIUM_DEVELOPMENT, BENPORATH_ES_WITH_H3K27ME3, GOBP_EPIDERMIS_MORPHOGENESIS, GOBP_SKELETAL_SYSTEM_DEVELOPMENT, GOBP_EMBRYONIC_SKELETAL_SYSTEM_DEVELOPMENT, GOBP_NEUROGENESIS, SP1_Q2_01, GTGCCTT_MIR506, GOBP_EPIDERMAL_CELL_DIFFERENTIATION, MARTINEZ_RB1_TARGETS_UP, GOBP_ANIMAL_ORGAN_MORPHOGENESIS, GGGCATT_MIR365

GO Biological Process (17): blood vessel development (GO:0001568), placenta development (GO:0001890), regulation of transcription by RNA polymerase II (GO:0006357), gene expression (GO:0010467), Wnt signaling pathway (GO:0016055), BMP signaling pathway (GO:0030509), epithelial cell differentiation (GO:0030855), hair follicle morphogenesis (GO:0031069), hair cell differentiation (GO:0035315), odontogenesis of dentin-containing tooth (GO:0042475), positive regulation of transcription by RNA polymerase II (GO:0045944), embryonic skeletal system development (GO:0048706), hair follicle cell proliferation (GO:0071335), odontoblast differentiation (GO:0071895), hair follicle development (GO:0001942), regulation of DNA-templated transcription (GO:0006355), hair cycle (GO:0042633)

GO Molecular Function (9): 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), DNA binding (GO:0003677), chromatin binding (GO:0003682), DNA-binding transcription factor activity (GO:0003700), sequence-specific double-stranded DNA binding (GO:1990837), protein binding (GO:0005515)

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

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
RNA polymerase II transcription regulatory region sequence-specific DNA binding	3
anatomical structure development	2
regulation of DNA-templated transcription	2
transcription by RNA polymerase II	2
hair cycle process	2
regulation of transcription by RNA polymerase II	2
binding	2
cellular anatomical structure	2
vasculature development	1
animal organ development	1
macromolecule biosynthetic process	1
cell surface receptor signaling pathway	1
cellular response to BMP stimulus	1
transforming growth factor beta receptor superfamily signaling pathway	1
cell differentiation	1
epithelium development	1
hair follicle development	1
anatomical structure morphogenesis	1
epidermis morphogenesis	1
epidermal cell differentiation	1
neuron differentiation	1
odontogenesis	1
positive regulation of DNA-templated transcription	1
skeletal system development	1
chordate embryonic development	1
cell population proliferation	1
neuroepithelial cell differentiation	1
skin epidermis development	1
DNA-templated transcription	1
regulation of gene expression	1
regulation of RNA biosynthetic process	1
molting cycle	1
transcription regulatory region nucleic acid binding	1
sequence-specific double-stranded DNA binding	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

Protein interactions and networks

STRING

1326 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
DLX3	RUNX2	Q13950	792
DLX3	BGLAP	P02818	787
DLX3	SACK1H	Q6ZRV2	693
DLX3	ENAM	Q9NRM1	681
DLX3	SP7	Q8TDD2	669
DLX3	COL10A1	Q03692	632
DLX3	IBSP	P21815	626
DLX3	AMTN	Q6UX39	613
DLX3	BMP7	P18075	610
DLX3	FOXN1	O15353	591
DLX3	MMP20	O60882	568
DLX3	MEIS1	O00470	559
DLX3	SMAD6	O43541	556
DLX3	SLC24A4	Q8NFF2	549
DLX3	TMEM108	Q6UXF1	547

IntAct

51 interactions, top by confidence:

A	B	Type	Score
BANP	DLX3	psi-mi:“MI:0915”(physical association)	0.560
DLX3	POU4F2	psi-mi:“MI:0915”(physical association)	0.560
DLX3	APBB2	psi-mi:“MI:0915”(physical association)	0.560
CASP6	DLX3	psi-mi:“MI:0915”(physical association)	0.560
DLX3	DCTN1	psi-mi:“MI:0915”(physical association)	0.560
DLX3		psi-mi:“MI:0915”(physical association)	0.560
DLX3	FGFR3	psi-mi:“MI:0915”(physical association)	0.560
LAMP2	DLX3	psi-mi:“MI:0915”(physical association)	0.560
UBQLN1	DLX3	psi-mi:“MI:0915”(physical association)	0.560
PRPF40A	DLX3	psi-mi:“MI:0915”(physical association)	0.560
DLX3	SNCA	psi-mi:“MI:0915”(physical association)	0.560
DLX3	HTT	psi-mi:“MI:0915”(physical association)	0.560
DLX3	ATXN1	psi-mi:“MI:0915”(physical association)	0.560

BioGRID (5): DLX3 (Two-hybrid), POU4F2 (Two-hybrid), DLX3 (Two-hybrid), TDP2 (Two-hybrid), TBL1X (Two-hybrid)

ESM2 similar proteins: A0A8V0YY16, A1YER7, A1YFD8, A1YFY3, A1YG01, A2D4R4, A2D649, A2T6H5, A2T6X6, A2T6Z0, A2T7J2, A8MTJ6, D3Z120, O08656, O43186, O43248, O54751, O60479, P02831, P09016, P09017, P09022, P09023, P09027, P10628, P14653, P17509, P17919, P18864, P31249, P31259, P31270, P31311, P31313, P49639, P50577, P56178, P78411, Q08624, Q08DG7

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

4 interactions.

A	Effect	B	Mechanism
DLX3	“up-regulates quantity by expression”	RUNX2	“transcriptional regulation”
PRKCA	unknown	DLX3	phosphorylation
PRKCA	“down-regulates activity”	DLX3	phosphorylation
PRKCA	“up-regulates activity”	DLX3	phosphorylation

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	2
Likely pathogenic	4
Uncertain significance	105
Likely benign	54
Benign	36

Top pathogenic / likely-pathogenic (6)

Variant ID	HGVS	Classification
430609	NM_005220.3(DLX3):c.476G>T (p.Arg159Leu)	Pathogenic
9072	NM_005220.3(DLX3):c.571_574del (p.Gly191fs)	Pathogenic
2445428	NM_005220.3(DLX3):c.537C>A (p.Asn179Lys)	Likely pathogenic
373912	NM_005220.3(DLX3):c.574dup (p.Glu192fs)	Likely pathogenic
3900721	NM_005220.3(DLX3):c.535A>C (p.Asn179His)	Likely pathogenic
430607	NM_005220.3(DLX3):c.574del (p.Glu192fs)	Likely pathogenic

SpliceAI

589 predictions. Top by Δscore:

Variant	Effect	Δscore
17:49991860:TTCAC:T	acceptor_gain	1.0000
17:49991862:CAC:C	acceptor_gain	1.0000
17:49991865:C:CC	acceptor_gain	1.0000
17:49991865:CTGG:C	acceptor_loss	1.0000
17:49991866:T:C	acceptor_loss	1.0000
17:49991871:C:CT	acceptor_gain	1.0000
17:49991871:C:T	acceptor_gain	1.0000
17:49991872:A:T	acceptor_gain	1.0000
17:49993398:A:T	donor_loss	1.0000
17:49993399:C:CA	donor_loss	1.0000
17:49993606:C:CT	acceptor_gain	1.0000
17:49993607:G:T	acceptor_gain	1.0000
17:49991861:TCAC:T	acceptor_gain	0.9900
17:49991862:CACC:C	acceptor_gain	0.9900
17:49991863:AC:A	acceptor_gain	0.9900
17:49991864:CC:C	acceptor_gain	0.9900
17:49991993:T:TA	donor_gain	0.9900
17:49992001:C:CA	donor_gain	0.9900
17:49993398:A:AC	donor_gain	0.9900
17:49993399:C:CC	donor_gain	0.9900
17:49993589:CA:C	acceptor_gain	0.9900
17:49993591:C:CC	acceptor_gain	0.9900
17:49993601:C:CT	acceptor_gain	0.9900
17:49993603:C:CT	acceptor_gain	0.9900
17:49994668:CCTCA:C	donor_loss	0.9900
17:49994669:CTCAC:C	donor_loss	0.9900
17:49994670:TCACC:T	donor_loss	0.9900
17:49994671:CACC:C	donor_loss	0.9900
17:49994673:CC:C	donor_loss	0.9900
17:49991861:TCACC:T	acceptor_gain	0.9800

AlphaMissense

1847 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
17:49991823:T:A	K186N	1.000
17:49991823:T:G	K186N	1.000
17:49991825:T:C	K186E	1.000
17:49991826:C:A	K185N	1.000
17:49991826:C:G	K185N	1.000
17:49991827:T:A	K185M	1.000
17:49991828:T:C	K185E	1.000
17:49991832:C:A	K183N	1.000
17:49991832:C:G	K183N	1.000
17:49991833:T:A	K183M	1.000
17:49991834:T:C	K183E	1.000
17:49991834:T:G	K183Q	1.000
17:49991836:G:A	S182F	1.000
17:49991837:A:G	S182P	1.000
17:49991839:C:A	R181L	1.000
17:49991839:C:G	R181P	1.000
17:49991839:C:T	R181H	1.000
17:49991840:G:A	R181C	1.000
17:49991840:G:C	R181G	1.000
17:49991840:G:T	R181S	1.000
17:49991842:C:G	R180P	1.000
17:49991843:G:C	R180G	1.000
17:49991843:G:T	R180S	1.000
17:49991844:G:C	N179K	1.000
17:49991844:G:T	N179K	1.000
17:49991845:T:A	N179I	1.000
17:49991845:T:C	N179S	1.000
17:49991845:T:G	N179T	1.000
17:49991846:T:A	N179Y	1.000
17:49991846:T:C	N179D	1.000

dbSNP variants (sampled 300 via entrez): RS1000829295 (17:49990846 G>A), RS1000949171 (17:49996617 C>G), RS1000962689 (17:49993928 A>C), RS1000981663 (17:49996833 C>A,T), RS1001115736 (17:49990550 C>A,G), RS1001296669 (17:49994639 G>A,T), RS1001684146 (17:49994471 G>A), RS1001851721 (17:49990030 T>C), RS1002072783 (17:49996174 G>A), RS1002104134 (17:49996449 T>C), RS1002282858 (17:49990168 A>G), RS1003566541 (17:49997079 T>C), RS1004173821 (17:49989863 C>G), RS1004228387 (17:49995079 C>A,G,T), RS1004528303 (17:49994453 C>A,G,T)

Disease associations

OMIM: gene MIM:600525 | disease phenotypes: MIM:104510, MIM:190320, MIM:150699, MIM:104500

GenCC curated gene-disease

Disease	Classification	Inheritance
hypomaturation-hypoplastic amelogenesis imperfecta with taurodontism	Strong	Autosomal dominant
tricho-dento-osseous syndrome	Strong	Autosomal dominant

Mondo (4): hypomaturation-hypoplastic amelogenesis imperfecta with taurodontism (MONDO:0007093), tricho-dento-osseous syndrome (MONDO:0008592), uterine corpus leiomyoma (MONDO:0007886), amelogenesis imperfecta (MONDO:0019507)

Orphanet (3): Hypomaturation-hypoplastic amelogenesis imperfecta with taurodontism (Orphanet:100034), Tricho-dento-osseous syndrome (Orphanet:3352), Amelogenesis imperfecta (Orphanet:88661)

HPO phenotypes

21 total (22 of 21 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000264	Abnormal mastoid morphology
HP:0000268	Dolichocephaly
HP:0000679	Taurodontia
HP:0000687	Widely spaced teeth
HP:0000691	Microdontia
HP:0000705	Amelogenesis imperfecta
HP:0001595	Abnormal hair morphology
HP:0001597	Abnormal nail morphology
HP:0001808	Fragile nails
HP:0002007	Frontal bossing
HP:0006285	Enamel hypomineralization
HP:0006286	Yellow-brown discoloration of the teeth
HP:0006297	Enamel hypoplasia
HP:0006485	Agenesis of incisor
HP:0009722	Dental enamel pits
HP:0011001	Increased bone mineral density
HP:0011362	Abnormal hair quantity
HP:0030312	Obliteration of the calvarial diploe
HP:0030758	Periapical tooth abscess
HP:0040019	Finger clinodactyly
HP:0000131	Uterine leiomyoma

GWAS associations

1 associations (top):

Study	Trait	p-value
GCST008462_10	Plasma factor V levels in venous thrombosis (conditioned on rs6027)	4.000000e-07

MeSH disease descriptors (3)

Descriptor	Name	Tree numbers
D000567	Amelogenesis Imperfecta	C07.650.800.295.250; C07.793.700.295.250; C16.131.850.800.295.250
C566293	Amelogenesis Imperfecta, Type IV (supp.)
C536549	Tricho-dento-osseous syndrome (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

29 total (human), top 29 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	increases expression, affects expression, affects cotreatment	5
trichostatin A	increases expression, affects cotreatment	3
mercuric bromide	increases expression, affects cotreatment	2
Panobinostat	affects cotreatment, increases expression	2
Benzo(a)pyrene	affects methylation, increases methylation	2
Phenylmercuric Acetate	affects cotreatment, increases expression	2
p-Chloromercuribenzoic Acid	affects cotreatment, increases expression	2
sodium arsenate	decreases expression, increases abundance	1
2-methyl-4-isothiazolin-3-one	increases expression	1
sulforaphane	decreases expression	1
sodium arsenite	increases expression	1
butyraldehyde	increases expression	1
S-(1,2-dichlorovinyl)cysteine	decreases expression, affects response to substance, increases expression, affects cotreatment	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
dorsomorphin	affects cotreatment, increases expression	1
Resveratrol	affects cotreatment, decreases expression	1
Arsenic Trioxide	decreases expression	1
Vorinostat	increases expression, affects cotreatment	1
Acetaminophen	decreases expression	1
Arsenic	decreases expression, increases abundance	1
Estradiol	affects cotreatment, decreases expression	1
Lipopolysaccharides	decreases expression, affects response to substance, increases expression, affects cotreatment	1
Plant Extracts	affects cotreatment, decreases expression	1
Smoke	decreases expression	1
Tetrachlorodibenzodioxin	increases expression	1
Cyclosporine	decreases methylation	1
Lactic Acid	decreases expression	1
Particulate Matter	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_A0Y3	SEES3-1V human DLX3, clone1	Embryonic stem cell	Male
CVCL_A0Y4	SEES3-1V human DLX3, clone2	Embryonic stem cell	Male
CVCL_A0Y5	SEES3-1V human DLX3, clone3	Embryonic stem cell	Male

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT00159328	PHASE4	COMPLETED	Efficacy Study of Magnetic Resonance (MR) Guided Focused Ultrasound in the Treatment of Large Fibroids
NCT00180739	PHASE4	WITHDRAWN	Safety Trial of Magnetic Resonance (MR) Guided Focused Ultrasound Surgery (FUS) in Women With Uterine Fibroids Wishing to Pursue Pregnancy in the Future
NCT00628901	PHASE4	COMPLETED	A Prospective Study Comparing Contour SE™ Microspheres to Embosphere® Microspheres for Treating Symptomatic Uterine Fibroids With Uterine Fibroid Embolization (UFE)
NCT00995878	PHASE4	COMPLETED	The FIRSTT: Comparing MRgFUS(MR-guided Focused Ultrasound) Versus UAE (Uterine Artery Embolization)for Uterine Fibroids.
NCT01239641	PHASE4	UNKNOWN	High Intensity Focused Ultrasound Ablation Virus Myomectomy to Treat Uterine Fibroids
NCT01388907	PHASE4	COMPLETED	Efficacity Assessment of PREVADH® in Adhesion Prevention in Gynaecologic Surgery
NCT01555073	PHASE4	TERMINATED	Preemptive Analgesia Following Uterine Artery Embolization
NCT01738724	PHASE4	TERMINATED	Study of the Efficacy of Dienogest in the Treatment of Uterine Leiomyomas When Compared to Desogestrel and Goserelin
NCT02293447	PHASE4	COMPLETED	Intra-arterial Lidocaine for Pain Control Post Uterine Fibroid Embolization
NCT02440750	PHASE4	UNKNOWN	Endometrial Preparation Before Operative Hysteroscopy in Premenopausal Women
NCT02470741	PHASE4	COMPLETED	Pilot of Letrozole for Uterine Myomas
NCT03210324	PHASE4	TERMINATED	A Study on the Mifepristone Tablets in the Treatment of Symptomatic Uterine Fibroids With Safety and Efficacy
NCT03317795	PHASE4	COMPLETED	Treatment of Heavy Menstrual Bleeding in Women With Uterine Fibroids
NCT03500367	PHASE4	UNKNOWN	Efficacy and Safety of Rapamycin (Sirolimus) in the Treatment of Symptomatic Uterine Fibroids and Leiomyomatosis
NCT03886220	PHASE4	COMPLETED	A Study to Evaluate the Safety and Efficacy of Elagolix for the Management of Heavy Menstrual Bleeding Associated With Uterine Fibroids in Premenopausal Women
NCT04132349	PHASE4	TERMINATED	Ulipristal Acetate in Symptomatic Uterine Fibroid
NCT04832906	PHASE4	COMPLETED	UA Versus UAE in Treatment of Fibroids
NCT06143631	PHASE4	RECRUITING	Prescription of Letrozole for Uterine Myoma
NCT00152256	PHASE3	COMPLETED	A Study to Evaluate of the Safety and Effectiveness of Asoprisnil in Treating Women With Uterine Fibroids
NCT00156156	PHASE3	COMPLETED	Study of Asoprisnil in the Treatment of Uterine Fibroids.
NCT00156208	PHASE3	COMPLETED	Safety of Treatment of Uterine Fibroids With Asoprisnil
NCT00295217	PHASE3	COMPLETED	MR Guided Focused Ultrasound Surgery in the Treatment of Uterine Fibroids: Software V4.2 Validation
NCT00365989	PHASE3	COMPLETED	MR Guided Focused Ultrasound Treatment of Uterine Fibroids With Enhanced Sonication
NCT00702702	PHASE3	TERMINATED	Safety and Efficacy of Proellex in Pre-menopausal Anemic Women With Symptomatic Uterine Fibroids
NCT00735553	PHASE3	TERMINATED	Evaluating the Safety and Efficacy of Proellex® (CDB-4124) in Premenopausal Women With Symptomatic Uterine Fibroids
NCT00737282	PHASE3	TERMINATED	Multicenter Study Evaluating the Safety of Proellex® in Premenopausal Women With Uterine Fibroids
NCT00785356	PHASE3	TERMINATED	Safety and Efficacy of Proellex in Pre-Menopausal Anemic Women With Symptomatic Uterine Fibroids
NCT00853567	PHASE3	TERMINATED	Evaluating the Safety and Efficacy of Proellex® in Premenopausal Women With Symptomatic Uterine Fibroids
NCT00874302	PHASE3	WITHDRAWN	Safety and Efficacy of 25 and 50 mg Doses of Proellex® in Treating the Recurrence of Uterine Fibroid Symptoms
NCT01064960	PHASE3	COMPLETED	Therapeutic MRI-HIFU Ablation of Uterine Fibroids in a 3T MRI Scanner
NCT01069120	PHASE3	TERMINATED	Safety of 25 and 50 mg Proellex® in the Treatment of Women With Symptomatic Uterine Fibroids
NCT01141062	PHASE3	COMPLETED	Therapeutic MRI Guided High Intensity Focused Ultrasound Ablation of Uterine Fibroids
NCT01156857	PHASE3	COMPLETED	PGL4001 Efficacy Assessment in Reduction of Symptoms Due to Uterine Leiomyomata
NCT01252069	PHASE3	COMPLETED	PGL4001 Efficacy Assessment in Reduction of Symptoms Due to Uterine Leiomyomata (PEARLIII-extension Study)
NCT01629563	PHASE3	COMPLETED	PGL4001 Efficacy Assessment in Reduction of Symptoms Due to Uterine Leiomyomata
NCT01642472	PHASE3	COMPLETED	PGL4001 Efficacy Assessment in Reduction of Symptoms Due to Uterine Leiomyomata
NCT01715597	PHASE3	COMPLETED	Study on the Effect of Intravenous Ascorbic Acid on Intraoperative Blood Loss in Women With Uterine Myoma
NCT02425878	PHASE3	TERMINATED	Ulipristal Acetate 10 mg and Asisted Reproduction
NCT02654054	PHASE3	COMPLETED	Efficacy and Safety of Elagolix in Combination With Estradiol/Norethindrone Acetate for the Management of Heavy Menstrual Bleeding Associated With Uterine Fibroids in Premenopausal Women
NCT02655224	PHASE3	COMPLETED	A Placebo-Controlled, Phase 3 Study of Relugolix (TAK-385) 40 mg in the Treatment of Pain Symptoms Associated With Uterine Fibroids