MSX1

Summary

MSX1 (msh homeobox 1, HGNC:7391) is a protein-coding gene on chromosome 4p16.2, encoding Homeobox protein MSX-1 (P28360). Acts as a transcriptional repressor. It is haploinsufficient (ClinGen: sufficient evidence).

This gene encodes a member of the muscle segment homeobox gene family. The encoded protein functions as a transcriptional repressor during embryogenesis through interactions with components of the core transcription complex and other homeoproteins. It may also have roles in limb-pattern formation, craniofacial development, particularly odontogenesis, and tumor growth inhibition. Mutations in this gene, which was once known as homeobox 7, have been associated with nonsyndromic cleft lip with or without cleft palate 5, Witkop syndrome, Wolf-Hirschom syndrome, and autosomoal dominant hypodontia.

Source: NCBI Gene 4487 — RefSeq curated summary.

At a glance

• Gene–disease (curated): tooth agenesis, selective, 1 (Definitive, ClinGen) — +3 more curated relationships
• GWAS associations: 5
• Clinical variants (ClinVar): 124 total — 23 pathogenic, 3 likely-pathogenic
• Phenotypes (HPO): 88
• Dosage sensitivity (ClinGen): haploinsufficiency sufficient evidence, triplosensitivity no evidence
• Transcription factor: yes — 29 downstream targets (CollecTRI)
• MANE Select transcript: NM_002448

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:7391
Approved symbol	MSX1
Name	msh homeobox 1
Location	4p16.2
Locus type	gene with protein product
Status	Approved
Aliases	HYD1, OFC5
Ensembl gene	ENSG00000163132
Ensembl biotype	protein_coding
OMIM	142983
Entrez	4487

Gene structure

Transcript identifiers

Ensembl transcripts: 2 — 1 protein_coding, 1 protein_coding_CDS_not_defined

ENST00000382723, ENST00000468421

RefSeq mRNA: 1 — MANE Select: NM_002448 NM_002448

CCDS: CCDS3378

Canonical transcript exons

ENST00000382723 — 2 exons

Exon	Start	End
ENSE00001493096	4862701	4863936
ENSE00001530899	4859665	4860368

Expression profiles

Bgee: expression breadth ubiquitous, 222 present calls, max score 97.87.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 12.0634 / max 1359.0198, expressed in 1220 samples.

FANTOM5 promoters (1 alternative TSS)

Promoter ID	TPM avg	Samples expressed
46747	12.0634	1220

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
buccal mucosa cell	CL:0002336	97.87	gold quality
choroid plexus epithelium	UBERON:0003911	97.73	gold quality
endocervix	UBERON:0000458	96.18	gold quality
periodontal ligament	UBERON:0008266	96.04	gold quality
saphenous vein	UBERON:0007318	94.88	gold quality
endometrium	UBERON:0001295	93.84	gold quality
oocyte	CL:0000023	91.60	gold quality
vena cava	UBERON:0004087	91.33	gold quality
secondary oocyte	CL:0000655	89.10	gold quality
uterus	UBERON:0000995	89.00	gold quality
urethra	UBERON:0000057	88.11	gold quality
pituitary gland	UBERON:0000007	87.65	gold quality
myometrium	UBERON:0001296	86.60	gold quality
adenohypophysis	UBERON:0002196	86.03	gold quality
subcutaneous adipose tissue	UBERON:0002190	84.80	gold quality
ectocervix	UBERON:0012249	84.80	gold quality
mucosa of paranasal sinus	UBERON:0005030	84.55	gold quality
cervix squamous epithelium	UBERON:0006922	84.03	gold quality
body of uterus	UBERON:0009853	83.89	gold quality
omental fat pad	UBERON:0010414	83.61	gold quality
peritoneum	UBERON:0002358	83.59	gold quality
adipose tissue of abdominal region	UBERON:0007808	83.59	gold quality
adult organism	UBERON:0007023	83.36	gold quality
adipose tissue	UBERON:0001013	83.34	gold quality
mammalian vulva	UBERON:0000997	82.89	gold quality
penis	UBERON:0000989	82.55	gold quality
connective tissue	UBERON:0002384	82.51	gold quality
uterine cervix	UBERON:0000002	82.49	gold quality
pericardium	UBERON:0002407	81.82	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	81.81	gold quality

Single-cell (SCXA)

Detected in 6 experiment(s), a significant marker in 4.

Experiment	Marker?	Max mean expression
E-HCAD-56	yes	2300.47
E-MTAB-10287	yes	679.52
E-MTAB-8271	yes	6.75
E-MTAB-6142	no	5.21
E-MTAB-6678	no	2.42
E-ANND-3	no	0.00

Regulation

Is transcription factor: yes

Downstream targets (CollecTRI)

29 targets.

Target	Regulation
BGLAP	Repression
BMP2	Repression
BMP4	Activation
CALD1	Repression
CDH2	Unknown
CDKN2D	Unknown
CGA	Unknown
DKK1	Repression
DLK1	Activation
FSHB	Repression
GNRH1
GNRHR	Unknown
H1-5
HEY1	Activation
LHB	Repression
MSX1	Unknown
MYOD1	Repression
NOTCH3	Activation
PITX1	Repression
PTCH1	Activation
RUNX2	Repression
S100A4	Activation
SDC1	Unknown
SHH	Activation
TAGLN
TSC1
VDR	Repression
WNT1	Activation
ZHX2	Unknown

JASPAR motifs

Motif	Name	Family
MA0666.1	MSX1	NK
MA0666.2	MSX1	NK
MA0666.3	MSX1	NK

JASPAR matrix evidence (PMIDs): PMID:18585359

Upstream regulators (CollecTRI, top): ACVR1, CTNNB1, FOXA2, FOXE1, HAND2, HOXA2, LHX2, LHX8, LMX1A, MSX1, MSX2, NFKB, OTX2, PAX9, PHOX2B, SMAD4, SMAD9, SP1, USF1

miRNA regulators (miRDB)

67 targeting MSX1, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-5692B	100.00	71.32	2622
HSA-MIR-5692C	100.00	71.32	2622
HSA-MIR-656-3P	100.00	72.15	2788
HSA-MIR-3646	100.00	73.56	5283
HSA-MIR-3163	100.00	77.23	8605
HSA-MIR-1277-5P	100.00	73.95	5056
HSA-MIR-6833-3P	100.00	70.63	3197
HSA-MIR-4282	99.99	75.36	6408
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-607	99.97	73.62	5593
HSA-MIR-302C-5P	99.97	72.56	3642
HSA-MIR-590-3P	99.96	74.34	6478
HSA-MIR-5688	99.96	73.23	4504
HSA-MIR-495-3P	99.96	72.81	4197
HSA-MIR-144-3P	99.94	73.98	2698
HSA-MIR-101-3P	99.94	75.03	2230
HSA-MIR-7-1-3P	99.91	71.53	4384
HSA-MIR-7-2-3P	99.91	71.40	4394
HSA-MIR-6809-3P	99.91	71.45	3814
HSA-MIR-3671	99.90	73.04	3897
HSA-MIR-627-3P	99.90	71.42	3316
HSA-MIR-374A-5P	99.90	71.34	2923
HSA-MIR-4731-5P	99.89	67.23	2537
HSA-MIR-4492	99.87	68.25	3611
HSA-MIR-369-3P	99.85	70.52	2264
HSA-MIR-3121-3P	99.82	71.96	3630
HSA-MIR-577	99.78	69.13	2479

Functional genomics

ClinGen dosage: haploinsufficiency 3 (sufficient evidence), triplosensitivity 0 (no evidence). ClinGen Gene Dosage Map

Literature-anchored findings (GeneRIF, showing 40)

• mutations in MSX1 are responsible for a specific pattern of inherited tooth agenesis. (PMID:12097313)
• might be involved in the genetic control of cuspid malpositions connected with the specific expression of third molar hypodontia (PMID:12490878)
• mutations make a contribution to clefts in South American populations (PMID:12651933)
• positively associated with cleft lip and/or palate with hypodontia outside the cleft region (PMID:12733956)
• MSX1 mutations which may contribute to non-syndromic forms of cleft lip and/or cleft palate are found in 2% of cases of clefting. (PMID:12807959)
• genetic role in odontogenesis and tooth development abnormalities (PMID:12974677)
• Individuals with Huntington disease with MSX1 genotype 3/3 tended to have younger age of onset (PMID:15029481)
• We have identified a novel MSX1 mutation (559 C –> T, resulting in Gln187Stop) in three individuals of one family (PMID:15264286)
• the contribution of MSX1 in the etiology of non-syndromic cleft lip/palate in the Chilean population (PMID:15381719)
• The homeodomain of Msx1 functions as a protein-protein interacting motif rather than a DNA-binding domain and is essential for stabilization, nuclear accumulation, and apoptotic function of wild-type p53. (PMID:15705871)
• PIAS1 is required for the appropriate localization and retention of Msx1 at the nuclear periphery in myoblast cells. (PMID:16600910)
• MSX1 mutations are found in 2% of cases of nonsyndromic cleft lip with or without cleft palate (CL/P) and should be considered for genetic counseling implications, but suggest that the P147Q variant is not pathogenic. (PMID:16868654)
• MSX1 with a novel missense mutation is associated with autosomal recessive oligodontia with associated dental anomalies in Pakistani families (PMID:16932841)
• results are consistent with evidence from other studies in the US and Chile and confirm the importance of the MSX1 genotype in determining the risk of cleft lip with or without palate and cleft palate in Koreans (PMID:17326252)
• muscle segment homeobox 1 (MSX1) microsatellite marker distribution and the relationship between MSX1 gene and the genetic susceptibility of nonsyndromic cleft lip and palate (NSCLP) in Hunan Hans (PMID:17557248)
• gene mutation contributes to tooth agenesis in Iranian individuals (PMID:17559452)
• Specifically required for osteogenesis in the cranial neural crest lineage within the frontal bone primordium of Msx1 transgenic mice. (PMID:17693062)
• MSX1 gene is associated with nonsyndromic cleft lip and palate. (PMID:18070437)
• positive association between CA polymorphism and cleft lip and/or palate in a Colombian group population (PMID:18177186)
• PCR-SSCP analysis and DNA sequencing revealed a novel missense mutation c.662C>A in a highly conserved homeobox sequence of MSX1 and a known polymorphisms c.347C>G which may be responsible for the oligodontia. (PMID:18374898)
• MSX1 mRNA is expressed in GH- and TSH-producing pituitary adenomas and in normal pituitary glands. (PMID:18379900)
• IVS1-2A > G was a novel splicing mutation identified in the MSX-1 gene and it might be responsible for nonsyndromic oligodontia in this family. (PMID:18788550)
• Significant interactions were observed between allele 4 homozygosity of the child with maternal smoking (OR 2.7, 95% CI 1.1-6.6) and with smoking by both parents (OR 4.9, 95% CI 1.4-18.0) in nonsyndromic orofacial clefts. (PMID:18932005)
• sequence of MSX1 gene in 3 unrelated patients with sporadic, non-syndromic oligodontia; homozygotic deletion of 11 nucleotides in the intron near the 5’ splicing site in 2 patients was identified; the deletion may decrease expression of MSX1 protein (PMID:19346736)
• gene polymorphism is associated with hypodontia (PMID:19776500)
• Families with an anterior pattern of tooth agenesis msx1 mutations. (PMID:19816326)
• Mutations in the coding region of the MSX1 gene play little or no role in the development of Parkinson disease. (PMID:19922584)
• YB1/p32 functionally interacts with Msx1 through its N-terminal region and colocalizes with Msx1 at the nuclear periphery (PMID:20004191)
• In both central and peripheral giant cell granulomas of the jaws, MSX1 protein was abundantly expressed by type I multinucleated giant cells and mononucleated stromal cells with vesicular nuclei but type II multinucleated giant cells did not express it. (PMID:20060342)
• Several genes, not just MSX1, in the same region may influence risk of oral clefts. (PMID:20087401)
• Data report expression of both muscle segment homeobox (MSX)1 and MSX2 in the human fetal ovary. (PMID:20506112)
• most significant associations with nonsyndromic cleft lip with or without cleft palate (CL/P) were found for SNPs in MSX1, including several common haplotypes in the MSX1 genes. (PMID:20572854)
• PAX9 and MSX1 gene mutation can cause different phenotypes of tooth agenesis. (PMID:20602873)
• Downregulation of Msx1 and Msx2 gene expression during the narrow window of early embryogenesis may cause an omphalocele by disrupting cellular proliferation and differentiation in the developing body wall. (PMID:20620318)
• Epigenetic control by imprinting in MSX1 gene is associated with nonsyndromic cleft lip/palate. (PMID:20635363)
• The del/del genotype of the c.469+46_56del mutation in the MSX1 gene may be associated with the increased risk of breast cancer in Polish population and may be considered as an early marker in this disease. (PMID:20638926)
• No mutations in the MSX1 gene were found in individuals with maxillary lateral incisor agenesis. (PMID:20660504)
• Msx-1 suppression in ONJ-adjacent periodontal tissue suggested a bisphosphonate-related impairment in cellular differentiation that occurred exclusively jaw remodelling (PMID:20942943)
• Common variants located out of the DNA binding domain of the MSX1 gene can be related to tooth agenesis. (PMID:21111400)
• MSX1 and TGF-beta3 are direct targets of FOXE1. (PMID:21177256)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
mus_musculus	Msx1	ENSMUSG00000048450
rattus_norvegicus	Msx1	ENSRNOG00000078426
drosophila_melanogaster	Dr	FBGN0000492
caenorhabditis_elegans		WBGENE00006881

Paralogs (1): MSX2 (ENSG00000120149)

Protein

Protein identifiers

Homeobox protein MSX-1 — P28360 (reviewed: P28360)

Alternative names: Homeobox protein Hox-7, Msh homeobox 1-like protein

All UniProt accessions (1): P28360

UniProt curated annotations — full annotation on UniProt →

Function. Acts as a transcriptional repressor. Capable of transcription autoinactivation. Binds to the consensus sequence 5’-C/GTAAT-3’ in downstream activin regulatory elements (DARE) in the gene promoter, thereby repressing the transcription of CGA/alpha-GSU and GNRHR. Represses transcription of myoblast differentiation factors. Binds to core enhancer regions in target gene promoters of myoblast differentiation factors with binding specificity facilitated by interaction with PIAS1. Regulates, in a stage-specific manner, a developmental program of gene expression in the fetal tooth bud that controls odontoblast differentiation and proliferation of dental mesenchymal cells. At the bud stage, required for mesenchymal molar tooth bud development via facilitating reciprocal signaling between dental epithelial and mesenchymal cells. May also regulate expression of Wnt antagonists such as DKK2 and SFPR2 in the developing tooth mesenchyme. Required for BMP4 expression in dental mesenchyme cells. Also, in response to BMP4, required for BMP4 expression in neighboring dental epithelial cells. Required for maximal FGF4-induced expression of SDC1 in dental mesenchyme cells. Also in response to SDC1, required for SDC1 expression in neighboring dental epithelial cells. At the early bell stage, acts to drive proliferation of dental mesenchyme cells, however during the late bell stage acts as an homeostatic regulator of the cell cycle. Regulates proliferation and inhibits premature mesenchymal odontogenesis during the bell stage via inhibition of the Wnt signaling component CTNNB1 and subsequent repression of the odontoblast differentiation factors BMP2, BMP4, LEF1, ALPL and BGLAP/OCN. Additionally, required for correct development and fusion of the palatal shelves and embryonic mandibular formation. Plays a role in embryonic bone formation of the middle ear, skull and nasal bones. Required for correct formation and thickness of the nail plate. May play a role in limb-pattern formation.

Subunit / interactions. Interacts with CREBBP/CBP, TBP and SP1; interaction with these transcription activators may inhibit autoinactivation. Interacts (via C-terminus) with PIAS1 (via N-terminus); the interaction is required for the localization of both proteins to the nuclear periphery and specific binding of MSX1 to the core enhancer region in target gene promoters. Interacts with H1-5.

Subcellular location. Nucleus.

Post-translational modifications. Sumoylated by PIAS1, desumoylated by SENP1. Sumoylation of Lys-15 and Lys-133 not required for interaction with H1-5, transcriptional repression, inhibition of myoblast differentiation, or binding to gene promoters.

Disease relevance. Tooth agenesis, selective, 1 (STHAG1) [MIM:106600] A form of selective tooth agenesis, a common anomaly characterized by the congenital absence of one or more teeth. Selective tooth agenesis without associated systemic disorders has sometimes been divided into 2 types: oligodontia, defined as agenesis of 6 or more permanent teeth, and hypodontia, defined as agenesis of less than 6 teeth. The number in both cases does not include absence of third molars (wisdom teeth). STHAG1 can be associated with orofacial cleft in some patients. The disease is caused by variants affecting the gene represented in this entry. MSX1 is deleted in some patients with Wolf-Hirschhorn syndrome (WHS). WHS results from sub-telomeric deletions in the short arm of chromosome 4. Ectodermal dysplasia 3, Witkop type (ECTD3) [MIM:189500] A form of ectodermal dysplasia, a heterogeneous group of disorders due to abnormal development of two or more ectodermal structures such as hair, teeth, nails and sweat glands, with or without any additional clinical sign. Each combination of clinical features represents a different type of ectodermal dysplasia. ECTD3 is characterized by abnormalities largely limited largely to teeth (some of which are missing) and nails (which are poorly formed early in life, especially toenails). This condition is distinguished from anhidrotic ectodermal dysplasia by autosomal dominant inheritance and little involvement of hair and sweat glands. The teeth are not as severely affected. The disease is caused by variants affecting the gene represented in this entry. Non-syndromic orofacial cleft 5 (OFC5) [MIM:608874] A birth defect consisting of cleft lips with or without cleft palate. Cleft lips are associated with cleft palate in two-third of cases. A cleft lip can occur on one or both sides and range in severity from a simple notch in the upper lip to a complete opening in the lip extending into the floor of the nostril and involving the upper gum. The disease is caused by variants affecting the gene represented in this entry.

Similarity. Belongs to the Msh homeobox family.

RefSeq proteins (1): NP_002439* (*=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
IPR050674	Msh_Homeobox_Regulators	Family

Pfam: PF00046

UniProt features (22 total): sequence variant 8, sequence conflict 5, region of interest 3, compositionally biased region 2, cross-link 2, chain 1, DNA-binding region 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P28360-F1	66.06	0.23

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): 15, 133

Function

Pathways and Gene Ontology

Reactome pathways

3 pathways

ID	Pathway
R-HSA-9834899	Specification of the neural plate border
R-HSA-1266738	Developmental Biology
R-HSA-9758941	Gastrulation

MSigDB gene sets: 575 (showing top): MORF_RAGE, CREL_01, MODULE_52, GOBP_POSITIVE_REGULATION_OF_REPRODUCTIVE_PROCESS, GOBP_REGULATION_OF_CELLULAR_RESPONSE_TO_GROWTH_FACTOR_STIMULUS, GOBP_EMBRYO_DEVELOPMENT_ENDING_IN_BIRTH_OR_EGG_HATCHING, GOBP_EPITHELIUM_DEVELOPMENT, GOBP_BODY_MORPHOGENESIS, GOBP_POSITIVE_REGULATION_OF_DNA_DAMAGE_RESPONSE_SIGNAL_TRANSDUCTION_BY_P53_CLASS_MEDIATOR, MORF_FLT1, GOBP_MUSCLE_TISSUE_DEVELOPMENT, BENPORATH_ES_WITH_H3K27ME3, GOBP_CARTILAGE_DEVELOPMENT, GOBP_NEGATIVE_REGULATION_OF_STRIATED_MUSCLE_CELL_DIFFERENTIATION, GOBP_SKELETAL_SYSTEM_DEVELOPMENT

GO Biological Process (59): cell morphogenesis (GO:0000902), in utero embryonic development (GO:0001701), cardiac conduction system development (GO:0003161), epithelial to mesenchymal transition involved in endocardial cushion formation (GO:0003198), regulation of transcription by RNA polymerase II (GO:0006357), transcription by RNA polymerase II (GO:0006366), muscle organ development (GO:0007517), negative regulation of cell population proliferation (GO:0008285), anterior/posterior pattern specification (GO:0009952), mesenchymal cell proliferation (GO:0010463), negative regulation of gene expression (GO:0010629), pituitary gland development (GO:0021983), signal transduction involved in regulation of gene expression (GO:0023019), negative regulation of cell growth (GO:0030308), BMP signaling pathway (GO:0030509), positive regulation of BMP signaling pathway (GO:0030513), midbrain development (GO:0030901), protein localization to nucleus (GO:0034504), embryonic forelimb morphogenesis (GO:0035115), embryonic hindlimb morphogenesis (GO:0035116), embryonic nail plate morphogenesis (GO:0035880), middle ear morphogenesis (GO:0042474), odontogenesis of dentin-containing tooth (GO:0042475), regulation of odontogenesis (GO:0042481), positive regulation of odontogenesis (GO:0042482), negative regulation of apoptotic process (GO:0043066), positive regulation of DNA damage response, signal transduction by p53 class mediator (GO:0043517), nose development (GO:0043584), positive regulation of cell cycle (GO:0045787), embryonic morphogenesis (GO:0048598), inner ear development (GO:0048839), stem cell differentiation (GO:0048863), protein stabilization (GO:0050821), negative regulation of striated muscle cell differentiation (GO:0051154), roof of mouth development (GO:0060021), face morphogenesis (GO:0060325), bone morphogenesis (GO:0060349), cartilage morphogenesis (GO:0060536), mammary gland epithelium development (GO:0061180), cell surface receptor signaling pathway involved in heart development (GO:0061311)

GO Molecular Function (11): transcription cis-regulatory region binding (GO:0000976), RNA polymerase II transcription regulatory region sequence-specific DNA binding (GO:0000977), DNA-binding transcription factor activity, RNA polymerase II-specific (GO:0000981), cis-regulatory region sequence-specific DNA binding (GO:0000987), DNA-binding transcription repressor activity, RNA polymerase II-specific (GO:0001227), DNA-binding transcription activator activity, RNA polymerase II-specific (GO:0001228), p53 binding (GO:0002039), sequence-specific double-stranded DNA binding (GO:1990837), DNA binding (GO:0003677), protein binding (GO:0005515), sequence-specific DNA binding (GO:0043565)

GO Cellular Component (5): chromatin (GO:0000785), nucleus (GO:0005634), nucleoplasm (GO:0005654), transcription regulator complex (GO:0005667), nuclear periphery (GO:0034399)

Reactome top-level categories

Rollup of top-2 pathways:

Category	Pathways
Gastrulation	1
Developmental Biology	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
RNA polymerase II transcription regulatory region sequence-specific DNA binding	3
cellular anatomical structure	3
cell population proliferation	2
negative regulation of cellular process	2
regulation of gene expression	2
embryonic limb morphogenesis	2
transcription cis-regulatory region binding	2
DNA-binding transcription factor activity, RNA polymerase II-specific	2
nuclear lumen	2
anatomical structure morphogenesis	1
chordate embryonic development	1
cardiac muscle tissue development	1
endocardial cushion formation	1
cardiac epithelial to mesenchymal transition	1
regulation of DNA-templated transcription	1
transcription by RNA polymerase II	1
DNA-templated transcription	1
animal organ development	1
muscle structure development	1
regulation of cell population proliferation	1
regionalization	1
gene expression	1
negative regulation of macromolecule biosynthetic process	1
diencephalon development	1
endocrine system development	1
gland development	1
signal transduction	1
regulation of cell growth	1
cell growth	1
negative regulation of growth	1
cellular response to BMP stimulus	1
transforming growth factor beta receptor superfamily signaling pathway	1
BMP signaling pathway	1
regulation of BMP signaling pathway	1
positive regulation of transmembrane receptor protein serine/threonine kinase signaling pathway	1
brain development	1
anatomical structure development	1
protein localization to organelle	1
forelimb morphogenesis	1
hindlimb morphogenesis	1

Protein interactions and networks

STRING

2220 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
MSX1	H1-5	P16401	985
MSX1	PAX9	P55771	982
MSX1	BMP4	P12644	909
MSX1	OSR2	Q8N2R0	862
MSX1	LHX8	Q68G74	848
MSX1	CSRNP1	Q96S65	844
MSX1	TGFB3	P10600	833
MSX1	LEF1	Q9UJU2	820
MSX1	IRF6	O14896	815
MSX1	LMX1A	Q8TE12	799
MSX1	BMP2	P12643	795
MSX1	SHH	Q15465	776
MSX1	FGF8	P55075	767
MSX1	WNT10A	Q9GZT5	761
MSX1	LHX6	Q9UPM6	724

IntAct

10 interactions, top by confidence:

A	B	Type	Score
MSX1	RBPMS	psi-mi:“MI:0915”(physical association)	0.560
GMNN	MSX1	psi-mi:“MI:0407”(direct interaction)	0.440
MSX1	TLE2	psi-mi:“MI:0915”(physical association)	0.370
ING4	MSX1	psi-mi:“MI:0915”(physical association)	0.370
MSX1	NMNAT1	psi-mi:“MI:0915”(physical association)	0.370
MED19	MSX1	psi-mi:“MI:0915”(physical association)	0.370
PTBP3		psi-mi:“MI:0914”(association)	0.350
RBPMS	MSX1	psi-mi:“MI:0915”(physical association)	0.000

BioGRID (31): CREBBP (Phenotypic Suppression), TBP (Phenotypic Suppression), SP1 (Phenotypic Suppression), MSX1 (Affinity Capture-Western), MSX1 (Affinity Capture-Western), MSX1 (Affinity Capture-Western), MSX1 (Two-hybrid), LHX2 (Reconstituted Complex), MSX1 (Reconstituted Complex), MSX1 (Reconstituted Complex), MSX1 (Reconstituted Complex), MSX1 (Reconstituted Complex), MSX1 (Reconstituted Complex), MSX2 (Reconstituted Complex), DLX2 (Reconstituted Complex)

ESM2 similar proteins: A0A1W2PQ73, A1YF16, A1YG93, A2RU54, A5PKG8, O02786, O14813, O15353, O35602, O43638, O57601, P13297, P19419, P28360, P35548, P41969, P42580, P43687, P49640, P50223, P50548, P52946, P52950, P63156, P63157, P70459, P78413, Q03358, Q14549, Q2VL78, Q2VL79, Q2VL82, Q2VL83, Q2VL84, Q2VL85, Q2VL86, Q2VL87, Q2VL88, Q5NSW5, Q61575

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

9 interactions.

A	Effect	B	Mechanism
MSX1	“down-regulates quantity by repression”	MYOD1	“transcriptional regulation”
DLX2	“down-regulates activity”	MSX1	binding
DLX5	“down-regulates activity”	MSX1	binding
MSX1	“down-regulates activity”	DLX2	binding
MSX1	“down-regulates activity”	DLX5	binding
FOXE1	“up-regulates quantity by expression”	MSX1	“transcriptional regulation”
MSX1	“down-regulates activity”	TBP	binding
LHX2	“down-regulates activity”	MSX1	binding
MSX1	“down-regulates activity”	LHX2	binding

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	23
Likely pathogenic	3
Uncertain significance	60
Likely benign	16
Benign	13

Top pathogenic / likely-pathogenic (26)

Variant ID	HGVS	Classification
1064708	NM_002448.3(MSX1):c.576_577insTAG (p.Gln193Ter)	Pathogenic
127273	NM_002448.3(MSX1):c.910_911dup (p.Ter304TyrextTer?)	Pathogenic
1319948	NM_002448.3(MSX1):c.519_525dup (p.Arg176Ter)	Pathogenic
1393580	NM_002448.3(MSX1):c.683dup (p.Arg229fs)	Pathogenic
14879	NM_002448.3(MSX1):c.605G>C (p.Arg202Pro)	Pathogenic
14881	NM_002448.3(MSX1):c.577C>T (p.Gln193Ter)	Pathogenic
14882	NM_002448.3(MSX1):c.623C>A (p.Ser208Ter)	Pathogenic
14884	NM_002448.3(MSX1):c.365G>A (p.Gly122Glu)	Pathogenic
14887	NM_002448.3(MSX1):c.81dup (p.Gly28fs)	Pathogenic
2010901	NM_002448.3(MSX1):c.487dup (p.Ala163fs)	Pathogenic
2424448	NC_000004.11:g.(?4859065)(4864603_?)del	Pathogenic
3242443	NM_002448.3(MSX1):c.739C>T (p.Pro247Ser)	Pathogenic
3242444	NM_002448.3(MSX1):c.466_469+1del	Pathogenic
3246606	NC_000004.11:g.(?4861627)(4862115_?)del	Pathogenic
3246608	NC_000004.11:g.(?4864676)(4960528_?)del	Pathogenic
3253075	NM_002448.3(MSX1):c.469+5G>A	Pathogenic
3646272	NM_002448.3(MSX1):c.668_669del (p.Arg223fs)	Pathogenic
3661406	NM_002448.3(MSX1):c.691_692del (p.Gln231fs)	Pathogenic
3687322	NM_002448.3(MSX1):c.365dup (p.Leu123fs)	Pathogenic
4111440	NM_002448.3(MSX1):c.541_546delinsCTTCA (p.Thr181fs)	Pathogenic
461602	NM_002448.3(MSX1):c.661C>T (p.Gln221Ter)	Pathogenic
4722939	NM_002448.3(MSX1):c.364_365dup (p.Leu123fs)	Pathogenic
845306	NM_002448.3(MSX1):c.655_659del (p.Trp219fs)	Pathogenic
1285193	NM_002448.3(MSX1):c.469+5G>C	Likely pathogenic
3061414	NM_002448.3(MSX1):c.547C>T (p.Gln183Ter)	Likely pathogenic
4820125	NM_002448.3(MSX1):c.469+1G>T	Likely pathogenic

SpliceAI

205 predictions. Top by Δscore:

Variant	Effect	Δscore
4:4860364:GGCCA:G	donor_gain	1.0000
4:4860365:GCCA:G	donor_gain	1.0000
4:4860365:GCCAG:G	donor_gain	1.0000
4:4860369:G:GG	donor_gain	1.0000
4:4862691:C:CA	acceptor_gain	1.0000
4:4862692:G:A	acceptor_gain	1.0000
4:4862697:TCAGG:T	acceptor_loss	1.0000
4:4862699:A:AG	acceptor_gain	1.0000
4:4862699:AG:A	acceptor_gain	1.0000
4:4862700:G:GG	acceptor_gain	1.0000
4:4862700:GG:G	acceptor_gain	1.0000
4:4862700:GGGC:G	acceptor_gain	1.0000
4:4860367:CA:C	donor_gain	0.9900
4:4862699:AGG:A	acceptor_gain	0.9900
4:4862699:AGGGC:A	acceptor_gain	0.9900
4:4862700:GGG:G	acceptor_gain	0.9900
4:4862700:GGGCG:G	acceptor_gain	0.9900
4:4860112:G:GT	donor_gain	0.9800
4:4860366:CCA:C	donor_gain	0.9800
4:4860366:CCAGT:C	donor_loss	0.9800
4:4860368:AG:A	donor_loss	0.9800
4:4860370:T:A	donor_loss	0.9800
4:4860371:G:GT	donor_loss	0.9800
4:4860372:A:AG	donor_gain	0.9800
4:4860372:A:AT	donor_loss	0.9800
4:4860373:G:GG	donor_gain	0.9800
4:4861444:TCTGA:T	donor_gain	0.9200
4:4861394:G:T	donor_gain	0.8900
4:4860366:C:T	donor_gain	0.8800
4:4860396:G:GT	donor_gain	0.8800

AlphaMissense

1925 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
4:4862748:C:A	R173S	1.000
4:4862748:C:T	R173C	1.000
4:4862751:A:G	K174E	1.000
4:4862753:G:C	K174N	1.000
4:4862753:G:T	K174N	1.000
4:4862757:C:G	R176G	1.000
4:4862757:C:T	R176W	1.000
4:4862758:G:A	R176Q	1.000
4:4862764:C:A	P178H	1.000
4:4862766:T:A	F179I	1.000
4:4862766:T:C	F179L	1.000
4:4862766:T:G	F179V	1.000
4:4862767:T:C	F179S	1.000
4:4862767:T:G	F179C	1.000
4:4862768:C:A	F179L	1.000
4:4862768:C:G	F179L	1.000
4:4862770:C:T	T180I	1.000
4:4862780:G:C	Q183H	1.000
4:4862780:G:T	Q183H	1.000
4:4862782:T:A	L184Q	1.000
4:4862782:T:C	L184P	1.000
4:4862785:T:C	L185P	1.000
4:4862787:G:C	A186P	1.000
4:4862791:T:A	L187Q	1.000
4:4862791:T:C	L187P	1.000
4:4862791:T:G	L187R	1.000
4:4862793:G:A	E188K	1.000
4:4862794:A:T	E188V	1.000
4:4862795:G:C	E188D	1.000
4:4862795:G:T	E188D	1.000

dbSNP variants (sampled 300 via entrez): RS10000804 (4:4862572 G>A), RS1000853737 (4:4861904 C>A,T), RS1001391142 (4:4862148 G>A,T), RS10014077 (4:4862503 A>G), RS1001592237 (4:4860676 A>T), RS1001828551 (4:4860022 C>A,G,T), RS1002841304 (4:4859399 A>G), RS1002858351 (4:4859532 G>A,C), RS1003161289 (4:4864175 C>G), RS1003333364 (4:4858674 G>A), RS1003404773 (4:4859654 G>C,T), RS1003755213 (4:4862753 G>A), RS1004316504 (4:4861069 C>A), RS1004501294 (4:4862499 G>A), RS1004689922 (4:4860855 T>A)

Disease associations

OMIM: gene MIM:142983 | disease phenotypes: MIM:189500, MIM:106600, MIM:608874, MIM:123100

GenCC curated gene-disease

Disease	Classification	Inheritance
orofacial cleft 5	Definitive	Autosomal dominant
tooth agenesis, selective, 1	Strong	Autosomal dominant
tooth and nail syndrome	Supportive	Autosomal dominant
tooth agenesis	Supportive	Autosomal dominant

ClinGen Gene-Disease Validity (2)

Expert-panel classifications — Definitive > Strong > Moderate > Limited > Disputed > Refuted.

Disease	Classification	Inheritance
tooth agenesis, selective, 1	Definitive	AD
tooth and nail syndrome	Disputed	AD

Mondo (5): tooth and nail syndrome (MONDO:0008582), tooth agenesis, selective, 1 (MONDO:0007129), orofacial cleft 5 (MONDO:0012142), craniosynostosis (MONDO:0015469), tooth agenesis (MONDO:0005486)

Orphanet (3): Hypodontia-dysplasia of nails syndrome (Orphanet:2228), Oligodontia (Orphanet:99798), Craniosynostosis (Orphanet:1531)

HPO phenotypes

88 total (30 of 88 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000147	Polycystic ovaries
HP:0000164	Abnormality of the dentition
HP:0000175	Cleft palate
HP:0000202	Orofacial cleft
HP:0000204	Cleft upper lip
HP:0000220	Velopharyngeal insufficiency
HP:0000232	Everted lower lip vermilion
HP:0000271	Abnormality of the face
HP:0000327	Hypoplasia of the maxilla
HP:0000389	Chronic otitis media
HP:0000403	Recurrent otitis media
HP:0000405	Conductive hearing impairment
HP:0000419	Abnormal nasal septum morphology
HP:0000668	Hypodontia
HP:0000677	Oligodontia
HP:0000679	Taurodontia
HP:0000684	Delayed eruption of teeth
HP:0000685	Hypoplasia of teeth
HP:0000687	Widely spaced teeth
HP:0000689	Dental malocclusion
HP:0000690	Agenesis of maxillary lateral incisor
HP:0000691	Microdontia
HP:0000696	Delayed eruption of permanent teeth
HP:0000698	Conical tooth
HP:0000708	Atypical behavior
HP:0000750	Delayed speech and language development
HP:0000971	Abnormal sweat gland morphology
HP:0001231	Abnormal fingernail morphology
HP:0001328	Specific learning disability

GWAS associations

5 associations (top):

Study	Trait	p-value
GCST000344_6	Electrocardiographic conduction measures	3.000000e-06
GCST002035_1	Congenital heart disease	3.000000e-10
GCST004166_53	Nonsyndromic cleft lip with cleft palate	2.000000e-08
GCST005038_36	Allergic disease (asthma, hay fever or eczema)	1.000000e-10
GCST006035_15	Breast cancer and/or colorectal cancer	6.000000e-06

EFO canonical traits (3, from GWAS)

EFO ID	Trait name
EFO:0004327	electrocardiography
EFO:0005095	PR segment
EFO:0003959	cleft lip

MeSH disease descriptors (3)

Descriptor	Name	Tree numbers
D003398	Craniosynostoses	C05.116.099.370.894.232; C05.660.207.240; C05.660.906.364; C16.131.621.207.240; C16.131.621.906.364
C563843	Orofacial Cleft 5 (supp.)
C536736	Witkop syndrome (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects expression, decreases expression, affects cotreatment, increases expression	9
trichostatin A	affects cotreatment, increases expression	3
sodium arsenite	decreases expression, decreases reaction, increases expression	3
mercuric bromide	increases expression, affects cotreatment	2
belinostat	increases expression, affects cotreatment	2
Vorinostat	affects cotreatment, increases expression	2
Panobinostat	affects cotreatment, increases expression	2
Acetaminophen	increases expression	2
Benzo(a)pyrene	decreases expression, affects methylation	2
Diethylhexyl Phthalate	decreases expression, increases expression	2
Phenylmercuric Acetate	affects cotreatment, increases expression	2
Tretinoin	increases expression	2
p-Chloromercuribenzoic Acid	affects cotreatment, increases expression	2
aristolochic acid I	increases expression	1
TAK-243	increases sumoylation	1
bisphenol A	increases methylation	1
arsenite	increases methylation	1
sulindac sulfide	decreases expression	1
monoisoamyl-2,3-dimercaptosuccinate	decreases expression, decreases reaction	1
SC 560	decreases expression	1
entinostat	increases expression	1
monomethylarsonous acid	increases expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, increases expression	1
abrine	increases expression	1
dorsomorphin	affects cotreatment, increases expression	1
licochalcone B	increases expression	1
PCI 5002	increases expression, affects cotreatment	1
Temozolomide	increases expression	1
Decitabine	increases expression	1
Troglitazone	increases expression	1

Cellosaurus cell lines

4 cell lines: 2 cancer cell line, 2 embryonic stem cell

First 10 cell lines (id-ordered, not curated):

Cellosaurus	Name	Category	Sex
CVCL_B1GG	Abcam A-549 MSX1 KO 1	Cancer cell line	Male
CVCL_B2P0	Abcam A-549 MSX1 KO 2	Cancer cell line	Male
CVCL_B5QM	WAe009-A-81	Embryonic stem cell	Female
CVCL_QY38	WAe001-A-3	Embryonic stem cell	Male

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT00722436	PHASE4	TERMINATED	Tranexamic Acid for Craniofacial Surgery
NCT02188576	PHASE4	COMPLETED	The Efficacy and Population Pharmacokinetics of Tranexamic Acid for Craniosynostosis Surgery
NCT02229968	PHASE2	ACTIVE_NOT_RECRUITING	Efficacy of Amicar for Children Having Craniofacial Surgery
NCT00912119	PHASE1	COMPLETED	Amicar Pharmacokinetics of Children Having Craniofacial Surgery
NCT01470235	Not specified	UNKNOWN	Hypodontia and Ovarian Cancer
NCT03445026	Not specified	UNKNOWN	Frequency of Hypodontia After Chemotherapy in Childhood Cancer Survivors Study
NCT05771246	Not specified	COMPLETED	Craniofacial Morphology And Sella Turcica Bridging Associated With Third Molar Agenesis.
NCT00077831	Not specified	COMPLETED	Child and Infant Learning Project
NCT00106977	Not specified	COMPLETED	Clinical Study of Muenke Syndrome (FGFR3-Related Craniosynostosis)
NCT00367796	Not specified	COMPLETED	Genetic Analysis of Craniosynostosis, Philadelphia Type
NCT00769847	Not specified	WITHDRAWN	Endoscopic Treatment for Isolated, Single Suture Craniosynostosis
NCT00773643	Not specified	COMPLETED	Osteogenic Profiling of Tissue From Children With Craniosynostosis
NCT01898650	Not specified	COMPLETED	MRI for Non-invasive Evaluation of Brain Stress
NCT02287805	Not specified	COMPLETED	Qualitative and Quantitative Study Which Aims to Determine the Specifics of the Announcement for the Diagnosis of Patients With Craniosynostosis and Their Parents to Better Support Them in Their Care
NCT02561728	Not specified	WITHDRAWN	Hanger Helmet Study
NCT03025763	Not specified	ACTIVE_NOT_RECRUITING	Network Of Clinical Research Studies On Craniosynostosis, Skull Malformations With Premature Fusion Of Skull Bones
NCT03231085	Not specified	COMPLETED	Comparison of the Rate of Preoperative Haemoglobin After Administration of Epoetin Alpha Associated With an Oral Medical Supplementation Versus Intravenous Before Surgery of Craniosynostosis at the Child
NCT04704284	Not specified	COMPLETED	Comparing MRI to CT on Pediatric Craniosynostosis.
NCT05911139	Not specified	ENROLLING_BY_INVITATION	Influence of General Anesthesia on the Dynamic Changes in Brain Damage Markers During and After Craniosynostosis Operations in Infancy
NCT06928727	Not specified	RECRUITING	Ocular Characteristics in Patients With Craniosynostosis