MSX2

Summary

MSX2 (msh homeobox 2, HGNC:7392) is a protein-coding gene on chromosome 5q35.2, encoding Homeobox protein MSX-2 (P35548). Acts as a transcriptional regulator in bone development.

This gene encodes a member of the muscle segment homeobox gene family. The encoded protein is a transcriptional repressor whose normal activity may establish a balance between survival and apoptosis of neural crest-derived cells required for proper craniofacial morphogenesis. The encoded protein may also have a role in promoting cell growth under certain conditions and may be an important target for the RAS signaling pathways. Mutations in this gene are associated with parietal foramina 1 and craniosynostosis type 2.

Source: NCBI Gene 4488 — RefSeq curated summary.

At a glance

• Gene–disease (curated): parietal foramina (Definitive, ClinGen) — +3 more curated relationships
• GWAS associations: 13
• Clinical variants (ClinVar): 271 total — 10 pathogenic, 4 likely-pathogenic
• Phenotypes (HPO): 45
• Dosage sensitivity (ClinGen): haploinsufficiency little evidence, triplosensitivity no evidence
• Transcription factor: yes — 49 downstream targets (CollecTRI)
• MANE Select transcript: NM_002449

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:7392
Approved symbol	MSX2
Name	msh homeobox 2
Location	5q35.2
Locus type	gene with protein product
Status	Approved
Aliases	CRS2, FPP, HOX8, MSH, PFM
Ensembl gene	ENSG00000120149
Ensembl biotype	protein_coding
OMIM	123101
Entrez	4488

Gene structure

Transcript identifiers

Ensembl transcripts: 2 — 2 protein_coding

ENST00000239243, ENST00000507785

RefSeq mRNA: 2 — MANE Select: NM_002449 NM_001363626, NM_002449

CCDS: CCDS4392, CCDS87348

Canonical transcript exons

ENST00000239243 — 2 exons

Exon	Start	End
ENSE00000812922	174724582	174725038
ENSE00001197342	174729159	174730896

Expression profiles

Bgee: expression breadth ubiquitous, 175 present calls, max score 87.04.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 7.5078 / max 278.5025, expressed in 965 samples.

FANTOM5 promoters (5 alternative TSS)

Promoter ID	TPM avg	Samples expressed
60341	4.7804	868
60342	2.3176	518
60343	0.2926	158
60345	0.0609	28
60344	0.0562	22

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
placenta	UBERON:0001987	87.04	gold quality
endometrium epithelium	UBERON:0004811	86.46	gold quality
secondary oocyte	CL:0000655	85.44	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	85.34	gold quality
oocyte	CL:0000023	83.99	gold quality
mammary duct	UBERON:0001765	81.81	gold quality
urinary bladder	UBERON:0001255	81.39	gold quality
epithelium of mammary gland	UBERON:0003244	81.15	gold quality
tibial artery	UBERON:0007610	79.56	gold quality
popliteal artery	UBERON:0002250	79.55	gold quality
endometrium	UBERON:0001295	78.36	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	76.60	gold quality
mucosa of urinary bladder	UBERON:0001259	73.82	gold quality
skin of abdomen	UBERON:0001416	71.92	gold quality
aorta	UBERON:0000947	71.60	gold quality
hindlimb stylopod muscle	UBERON:0004252	71.41	gold quality
skin of leg	UBERON:0001511	71.33	gold quality
zone of skin	UBERON:0000014	70.62	gold quality
thoracic mammary gland	UBERON:0005200	69.16	gold quality
mammary gland	UBERON:0001911	69.08	gold quality
right testis	UBERON:0004534	68.59	gold quality
C1 segment of cervical spinal cord	UBERON:0006469	68.52	gold quality
right hemisphere of cerebellum	UBERON:0014890	68.34	gold quality
testis	UBERON:0000473	67.64	gold quality
gastrocnemius	UBERON:0001388	67.64	gold quality
spinal cord	UBERON:0002240	67.41	gold quality
muscle of leg	UBERON:0001383	67.25	gold quality
uterus	UBERON:0000995	67.23	gold quality
apex of heart	UBERON:0002098	66.95	gold quality
left testis	UBERON:0004533	66.89	gold quality

Single-cell (SCXA)

Detected in 6 experiment(s), a significant marker in 5.

Experiment	Marker?	Max mean expression
E-MTAB-10018	yes	566.04
E-MTAB-6701	yes	116.72
E-MTAB-10287	yes	48.14
E-ANND-3	yes	9.82
E-MTAB-9388	yes	8.48
E-MTAB-8060	no	558.01

Regulation

Is transcription factor: yes

Downstream targets (CollecTRI)

49 targets.

Target	Regulation
ABCG2	Unknown
ALPL	Unknown
AMELX	Repression
ATOH7	Repression
BCL2	Repression
BGLAP	Repression
BMP4	Repression
CALD1	Repression
CCND1	Unknown
CDH2	Repression
COL10A1	Activation
COL1A1	Repression
COL2A1	Repression
DKK1	Repression
DLX2	Unknown
DLX5	Repression
DSPP	Repression
EFNA5	Repression
ENPP1	Activation
EPHA7	Repression
GNAS
GNRH1
GPNMB
IBSP	Unknown
IHH	Activation
LAMA3	Unknown
LRP5	Repression
MSX1	Unknown
MYOD1	Repression
NKX3-1	Activation

JASPAR motifs

Motif	Name	Family
MA0708.1	MSX2	NK
MA0708.2	MSX2	NK
MA0708.3	MSX2	NK

JASPAR matrix evidence (PMIDs): PMID:18585360

Upstream regulators (CollecTRI, top): BMP2, CTNNB1, DLX2, ESR1, FOXC1, GLI2, HR, LEF1, LHX2, LHX8, NR1I2, PAX3, RBPJ, SMAD1, SMAD4, TBX22, YY1

Functional genomics

ClinGen dosage: haploinsufficiency 1 (little evidence), triplosensitivity 0 (no evidence). ClinGen Gene Dosage Map

Literature-anchored findings (GeneRIF, showing 40)

• Bone sialoprotein expression is additionally regulated by the homeodomain factor Msx2, another regulator of osteoblast-associated genes. (PMID:12750290)
• Results suggest that Msx2 plays a central role in preventing ligaments and tendons from mineralizing, in part by suppressing Runx2/Osf2 transcriptional activity. (PMID:15060165)
• Results suggest that MSX2 exerts repressive effects on the gemcitabine-induced apoptotic pathway in pancreatic cancer cells. (PMID:16425399)
• In dental follicle cells, gene expression of runx2, DLX-5, and MSX-2 was unaffected during osteogenic differentiation in vitro. (PMID:16467978)
• This provides genetic evidence that Twist1, Msx2 and Efna4 function together in boundary formation and the pathogenesis of coronal synostosis. (PMID:16540516)
• MSX2 homeobox mutation in a family with foramina parietalia permagna, headache, and vascular anomaly. (PMID:16642368)
• Specifically required for osteogenesis in the cranial neural crest lineage within the frontal bone primordium of Msx1 transgenic mice. (PMID:17693062)
• vascular Bmp Msx2 Wnt signaling and oxidative stress have roles in arterial calcification [review] (PMID:18056036)
• Msx2 expression may represent a useful prognostic marker in inverted papilloma. (PMID:18187185)
• MSX2 polymorphisms are associated with ankylosing spondylitis in Japanese but not in Taiwanese population. (PMID:18299954)
• These data indicate that MSX2 plays a crucial role in pancreatic cancer development by inducing changes consistent with epithelial to mesenchymal transition through enhanced expression of Twist 1. (PMID:18349132)
• the primary function of MSX2 in suture closure is the induction of cell proliferation and suture maintenance, and the mutation results in an increased susceptibility of both wild type and mutant MSX2 to proteasomal degradation (PMID:18786927)
• In this review, Msx2 is shown to function as a transcriptional enhancer downstream of fibroblast growth factor 2 in calvarial pre-osteoblastic cells. (PMID:19147956)
• These results imply a new mechanism for osteogenic differentiation of vascular smooth muscle cellss in which Notch/RBP-Jk signaling directly induces Msx2(msh homeobox 2) gene expression . (PMID:19407244)
• MSX2 activates NOTCH3-signaling in leukemic T-cells. (PMID:19835636)
• TNF-alpha directly induces MSX2 expression through the NF-kappaB pathway, which in turn induces expression of alkaline phosphatase, a key molecule in mineralization, in VSMCs. (PMID:20004646)
• MSX2 plays a pivotal role in the development of intraductal papillary mucinous neoplasm (IPMN) through growth stimulation of tumor cells, and its expression was identified as an independent predictive factor for malignancy of benign branch duct-IPMN (PMID:20107842)
• Data reveal a selective upregulation of MSX2 expression in human fetal ovary in response to BMP4, suggesting this gene may act as a downstream effector of BMP-induced apoptosis in the ovary. (PMID:20506112)
• 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)
• Data suggest that increased Msx2 expression results in improved outcome for breast cancer patients, possibly by increasing the likelihood of tumour cell death by apoptosis. (PMID:20682066)
• Maternal Msx2 C386T gene polymorphisms were associated with fetal neural tube defects in Han Chinese women in Shanxi Province. (PMID:21362336)
• The detailed regulatory mechanism of ABCG2 expression by MSX2 in pancreatic cancer cells was investigated. (PMID:21465479)
• Notch1 intracellular domain.RBPJk complex enhances the BMP2-induced Msx2 gene expression by cooperating with Smad1 and suggest that Notch signaling makes vascular SMC responsive to BMP2 and promotes vascular calcification. (PMID:21471203)
• The sensitivity of MSX2 expression level for cholangiocarcinoma was much higher than that of cytology. (PMID:21498730)
• findings indicate MSX2 is a direct downstream transcriptional target of beta-catenin/TCF and has a key contributing role in the cancer phenotype of OEAs carrying WNT/beta-catenin pathway defects (PMID:21499300)
• activation of RAGE not only inhibits myocardin-dependent SMC gene expression, but also induces osteogenic differentiation of vascular SMC through Notch/Msx2 induction (PMID:21512281)
• MSX2 may be an important regulator of melanoma cell invasion and survival. Cytoplasmic expression of the protein was identified as biomarker for good prognosis in malignant melanoma. (PMID:21730974)
• 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)
• PKC signaling modulates osteoblast differentiation, at least in part, through the regulation of Msx2. (PMID:22633971)
• The pathogenic effect of the microduplications can best be explained by a misregulation of spatiotemporal MSX2 expression patterns in cleidocranial dysplasia. (PMID:22717651)
• Msx2 and topo II-alpha may play an important role in the occurrence and development of sinonasal inverted papilloma. (PMID:22730815)
• These data confirm that missense mutations altering the proline at codon 148 of MSX2 cause dominantly inherited craniosynostosis. (PMID:23949913)
• SLUG and MSX2, transcription factors involved in epithelial-mesenchymal transitions, essential features of gastrulation in development and tumor progression, are important mediators of BMP4-induced differentiation in human embryonic stem cells. (PMID:24549638)
• This is the first report of an eye development defect due to an increase in the MSX2 copy number in a human being. (PMID:24666290)
• The MSX2 destabilizes the pluripotency circuitry through direct binding to the SOX2 promoter, while MSX2 controls mesendoderm lineage commitment by simultaneous suppression of SOX2 and induction of NODAL expression. (PMID:26427715)
• MSX2 protein expression is downregulated in placental villi from Pre-Eclampsia. (PMID:27088357)
• MSX2 played a crucial role in the progression of colorectal cancer and may be a potential novel prognostic factor (PMID:28286778)
• p19(INK4d) plays an active role during human tooth development along with MSX1 and MSX2 (PMID:28933666)
• MSX2 might be a new drug resistance related gene in pancreatic cancer cells by up-regulation of MRP2 expression. (PMID:29860758)
• The extent of calcification correlated positively with the flow velocity, as did the mRNA and protein levels of TGF-beta1, BMP2, and MSX2. These findings indicate that TGF-beta1/BMP2 signaling is involved in valve calcification induced by abnormal mechanical stimulation. (PMID:30341511)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
mus_musculus	Msx2	ENSMUSG00000021469
rattus_norvegicus	Msx2	ENSRNOG00000018355
drosophila_melanogaster	Dr	FBGN0000492
caenorhabditis_elegans		WBGENE00006881

Paralogs (1): MSX1 (ENSG00000163132)

Protein

Protein identifiers

Homeobox protein MSX-2 — P35548 (reviewed: P35548)

Alternative names: Homeobox protein Hox-8

All UniProt accessions (2): P35548, D6RIS4

UniProt curated annotations — full annotation on UniProt →

Function. Acts as a transcriptional regulator in bone development. Represses the ALPL promoter activity and antagonizes the stimulatory effect of DLX5 on ALPL expression during osteoblast differentiation. Probable morphogenetic role. May play a role in limb-pattern formation. In osteoblasts, suppresses transcription driven by the osteocalcin FGF response element (OCFRE). Binds to the homeodomain-response element of the ALPL promoter.

Subunit / interactions. Interacts with MINT. Interacts with XRCC6 (Ku70) and XRCC5 (Ku80).

Subcellular location. Nucleus.

Disease relevance. Parietal foramina 1 (PFM1) [MIM:168500] Autosomal dominant disease characterized by oval defects of the parietal bones caused by deficient ossification around the parietal notch, which is normally obliterated during the fifth fetal month. The disease is caused by variants affecting the gene represented in this entry. Parietal foramina with cleidocranial dysplasia (PFMCCD) [MIM:168550] Combines skull defects in the form of enlarged parietal foramina and deficient ossification of the clavicles. The disease is caused by variants affecting the gene represented in this entry. Craniosynostosis 2 (CRS2) [MIM:604757] A primary abnormality of skull growth involving premature fusion of one or more cranial sutures. The growth velocity of the skull often cannot match that of the developing brain resulting in an abnormal head shape and, in some cases, increased intracranial pressure, which must be treated promptly to avoid permanent neurodevelopmental disability. CRS2 is characterized by either fronto-orbital recession, or frontal bossing, or turribrachycephaly, or cloverleaf skull. Associated features include severe headache, high incidence of visual problems (myopia or hyperopia), and short first metatarsals. Intelligence is normal. The disease is caused by variants affecting the gene represented in this entry.

Similarity. Belongs to the Msh homeobox family.

RefSeq proteins (2): NP_001350555, NP_002440* (*=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 (23 total): sequence conflict 10, sequence variant 6, region of interest 2, compositionally biased region 2, chain 1, DNA-binding region 1, mutagenesis site 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P35548-F1	68.77	0.25

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Mutagenesis-validated functional residues (1):

Position	Phenotype
147	does not bind dna but still suppresses ocfre activation.

Function

Pathways and Gene Ontology

Reactome pathways

5 pathways

ID	Pathway
R-HSA-8939902	Regulation of RUNX2 expression and activity
R-HSA-212436	Generic Transcription Pathway
R-HSA-73857	RNA Polymerase II Transcription
R-HSA-74160	Gene expression (Transcription)
R-HSA-8878166	Transcriptional regulation by RUNX2

MSigDB gene sets: 443 (showing top): GSE18804_SPLEEN_MACROPHAGE_VS_BRAIN_TUMORAL_MACROPHAGE_UP, GSE45365_NK_CELL_VS_CD11B_DC_UP, GOBP_CARDIAC_CHAMBER_DEVELOPMENT, GOBP_MORPHOGENESIS_OF_AN_EPITHELIUM, RRAGTTGT_UNKNOWN, GOBP_POSITIVE_REGULATION_OF_REPRODUCTIVE_PROCESS, GOBP_REGULATION_OF_CELLULAR_RESPONSE_TO_GROWTH_FACTOR_STIMULUS, GOBP_EPITHELIUM_DEVELOPMENT, GOBP_REGULATION_OF_FAT_CELL_DIFFERENTIATION, GOBP_MAMMARY_GLAND_MORPHOGENESIS, BROWNE_HCMV_INFECTION_6HR_DN, GOBP_BONE_TRABECULA_MORPHOGENESIS, GOBP_MUSCLE_TISSUE_DEVELOPMENT, BENPORATH_ES_WITH_H3K27ME3, GOBP_CARDIAC_SEPTUM_DEVELOPMENT

GO Biological Process (50): negative regulation of transcription by RNA polymerase II (GO:0000122), osteoblast differentiation (GO:0001649), chondrocyte development (GO:0002063), osteoblast development (GO:0002076), outflow tract septum morphogenesis (GO:0003148), cardiac conduction system development (GO:0003161), epithelial to mesenchymal transition involved in endocardial cushion formation (GO:0003198), endochondral bone growth (GO:0003416), regulation of transcription by RNA polymerase II (GO:0006357), negative regulation of cell population proliferation (GO:0008285), anterior/posterior pattern specification (GO:0009952), signal transduction involved in regulation of gene expression (GO:0023019), BMP signaling pathway (GO:0030509), positive regulation of BMP signaling pathway (GO:0030513), embryonic forelimb morphogenesis (GO:0035115), embryonic hindlimb morphogenesis (GO:0035116), wound healing, spreading of epidermal cells (GO:0035313), embryonic nail plate morphogenesis (GO:0035880), negative regulation of apoptotic process (GO:0043066), negative regulation of fat cell differentiation (GO:0045599), negative regulation of keratinocyte differentiation (GO:0045617), positive regulation of osteoblast differentiation (GO:0045669), negative regulation of DNA-templated transcription (GO:0045892), embryonic morphogenesis (GO:0048598), stem cell differentiation (GO:0048863), positive regulation of timing of catagen (GO:0051795), bone trabecula formation (GO:0060346), cranial suture morphogenesis (GO:0060363), frontal suture morphogenesis (GO:0060364), branching involved in mammary gland duct morphogenesis (GO:0060444), cell surface receptor signaling pathway involved in heart development (GO:0061311), enamel mineralization (GO:0070166), cellular response to estradiol stimulus (GO:0071392), activation of meiosis (GO:0090427), mesenchymal cell apoptotic process (GO:0097152), positive regulation of mesenchymal cell apoptotic process (GO:2001055), ossification (GO:0001503), outflow tract morphogenesis (GO:0003151), regulation of DNA-templated transcription (GO:0006355), heart development (GO:0007507)

GO Molecular Function (9): transcription cis-regulatory region binding (GO:0000976), RNA polymerase II transcription regulatory region sequence-specific DNA binding (GO:0000977), 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 repressor activity, RNA polymerase II-specific (GO:0001227), sequence-specific DNA binding (GO:0043565), sequence-specific double-stranded DNA binding (GO:1990837), DNA binding (GO:0003677), protein binding (GO:0005515)

GO Cellular Component (5): chromatin (GO:0000785), nucleus (GO:0005634), transcription regulator complex (GO:0005667), cytosol (GO:0005829), nuclear speck (GO:0016607)

Reactome top-level categories

Rollup of top-4 pathways:

Category	Pathways
Transcriptional regulation by RUNX2	1
RNA Polymerase II Transcription	1
Gene expression (Transcription)	1
Generic Transcription Pathway	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
regulation of transcription by RNA polymerase II	2
transcription by RNA polymerase II	2
cell development	2
embryonic limb morphogenesis	2
cellular anatomical structure	2
negative regulation of DNA-templated transcription	1
ossification	1
cell differentiation	1
chondrocyte differentiation	1
osteoblast differentiation	1
outflow tract morphogenesis	1
cardiac septum morphogenesis	1
cardiac muscle tissue development	1
endocardial cushion formation	1
cardiac epithelial to mesenchymal transition	1
bone growth	1
regulation of DNA-templated transcription	1
cell population proliferation	1
regulation of cell population proliferation	1
negative regulation of cellular process	1
regionalization	1
signal transduction	1
regulation of gene expression	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
forelimb morphogenesis	1
hindlimb morphogenesis	1
wound healing, spreading of cells	1
nail development	1
embryonic digit morphogenesis	1
embryonic morphogenesis	1
apoptotic process	1
regulation of apoptotic process	1
negative regulation of programmed cell death	1
fat cell differentiation	1
negative regulation of cell differentiation	1

Protein interactions and networks

STRING

1986 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
MSX2	RUNX2	Q13950	976
MSX2	TWIST1	Q15672	898
MSX2	SPEN	Q96T58	887
MSX2	BGLAP	P02818	871
MSX2	BMP4	P12644	815
MSX2	FGFR2	P18443	736
MSX2	PAX9	P55771	736
MSX2	DLX5	P56178	735
MSX2	FGFR3	P22607	731
MSX2	BMP7	P18075	720
MSX2	SP7	Q8TDD2	713
MSX2	IBSP	P21815	697
MSX2	BMP2	P12643	697
MSX2	FGFR1	P11362	682
MSX2	HAND2	P61296	653

IntAct

134 interactions, top by confidence:

A	B	Type	Score
MSX2	LENG8	psi-mi:“MI:0915”(physical association)	0.560
POU2F2	MSX2	psi-mi:“MI:0915”(physical association)	0.560
MSX2	TOLLIP	psi-mi:“MI:0915”(physical association)	0.560
MSX2	TLE5	psi-mi:“MI:0915”(physical association)	0.560
POU1F1	MSX2	psi-mi:“MI:0915”(physical association)	0.560
MSX2	TSSK3	psi-mi:“MI:0915”(physical association)	0.560
GATA2	MSX2	psi-mi:“MI:0915”(physical association)	0.560
TLX3	MSX2	psi-mi:“MI:0915”(physical association)	0.560
MSX2	ZFHX3	psi-mi:“MI:0915”(physical association)	0.560
MSX2	CCDC102B	psi-mi:“MI:0915”(physical association)	0.560
MSX2	YTHDF1	psi-mi:“MI:0915”(physical association)	0.560
MSX2	NAF1	psi-mi:“MI:0915”(physical association)	0.560
HOXC9	MSX2	psi-mi:“MI:0915”(physical association)	0.560
FOXH1	MSX2	psi-mi:“MI:0915”(physical association)	0.560
	MSX2	psi-mi:“MI:0915”(physical association)	0.560
EPHB6	MSX2	psi-mi:“MI:0915”(physical association)	0.560
MSX2	RHOXF2	psi-mi:“MI:0915”(physical association)	0.560
MSX2	POU6F2	psi-mi:“MI:0915”(physical association)	0.560
MSX2	ROR2	psi-mi:“MI:0915”(physical association)	0.560
MSX2	RBPMS2	psi-mi:“MI:0915”(physical association)	0.560
MAPK1	MSX2	psi-mi:“MI:0915”(physical association)	0.560
MSX2	VEZF1	psi-mi:“MI:0915”(physical association)	0.560
CLIC3	MSX2	psi-mi:“MI:0915”(physical association)	0.560
MSX2	PITX1	psi-mi:“MI:0915”(physical association)	0.560
MSX2	SOX5	psi-mi:“MI:0915”(physical association)	0.560
MSX2	MAPK1IP1L	psi-mi:“MI:0915”(physical association)	0.560
MSX2	TCF7L2	psi-mi:“MI:0915”(physical association)	0.560
MSX2	PRR13	psi-mi:“MI:0915”(physical association)	0.560
MSX2	SMAP2	psi-mi:“MI:0915”(physical association)	0.560
MSX2	PATZ1	psi-mi:“MI:0915”(physical association)	0.560

BioGRID (202): HBS1L (Affinity Capture-MS), ZNF703 (Affinity Capture-MS), ANKRD40 (Affinity Capture-MS), ZNF703 (Affinity Capture-MS), HBS1L (Affinity Capture-MS), CEBPA (Reconstituted Complex), MSX2 (Two-hybrid), MSX2 (Two-hybrid), MSX2 (Two-hybrid), MSX2 (Two-hybrid), MSX2 (Two-hybrid), MSX2 (Two-hybrid), MSX2 (Two-hybrid), MSX2 (Two-hybrid), MSX2 (Two-hybrid)

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

10 interactions.

A	Effect	B	Mechanism
MSX2	up-regulates	SPEN	binding
FBXW2	“down-regulates quantity by destabilization”	MSX2	binding
“Cullin 1-RBX1-Skp1”	“down-regulates quantity by destabilization”	MSX2	polyubiquitination
PRKCB	“up-regulates quantity”	MSX2	phosphorylation
DLX2	“down-regulates activity”	MSX2	binding
DLX5	“down-regulates activity”	MSX2	binding
MSX2	“down-regulates activity”	DLX2	binding
MSX2	“down-regulates activity”	DLX5	binding
TBX22	“down-regulates quantity by repression”	MSX2	“transcriptional regulation”

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	10
Likely pathogenic	4
Uncertain significance	138
Likely benign	59
Benign	51

Top pathogenic / likely-pathogenic (14)

Variant ID	HGVS	Classification
1428798	NM_002449.5(MSX2):c.457C>T (p.Gln153Ter)	Pathogenic
16961	NM_002449.5(MSX2):c.443C>A (p.Pro148His)	Pathogenic
16962	NM_002449.5(MSX2):c.475_480del (p.Arg159_Lys160del)	Pathogenic
16963	NM_002449.5(MSX2):c.515G>A (p.Arg172His)	Pathogenic
16965	NM_002449.5(MSX2):c.265_266delinsTA (p.Ala89Ter)	Pathogenic
16966	NM_002449.5(MSX2):c.345del (p.Ala114_Trp115insTer)	Pathogenic
16967	NM_002449.5(MSX2):c.505_508dup (p.Ala170fs)	Pathogenic
16968	NM_002449.5(MSX2):c.548_555del (p.Glu183fs)	Pathogenic
219192	NM_002449.5(MSX2):c.443C>T (p.Pro148Leu)	Pathogenic
2664282	NM_002449.5(MSX2):c.441_442dup (p.Pro148fs)	Pathogenic
1299013	NM_002449.5(MSX2):c.577C>T (p.Arg193Ter)	Likely pathogenic
2442667	NM_002449.5(MSX2):c.1A>G (p.Met1Val)	Likely pathogenic
3591944	NM_002449.5(MSX2):c.380-2A>T	Likely pathogenic
4294501	NM_002449.5(MSX2):c.473dup (p.Arg159fs)	Likely pathogenic

SpliceAI

179 predictions. Top by Δscore:

Variant	Effect	Δscore
5:174725034:GCCAA:G	donor_gain	1.0000
5:174725039:G:GG	donor_gain	1.0000
5:174729149:T:TA	acceptor_gain	1.0000
5:174729154:TCTA:T	acceptor_loss	1.0000
5:174729155:CTA:C	acceptor_loss	1.0000
5:174729156:TA:T	acceptor_loss	1.0000
5:174729157:A:AG	acceptor_gain	1.0000
5:174729157:AG:A	acceptor_gain	1.0000
5:174729158:G:GT	acceptor_gain	1.0000
5:174729158:GG:G	acceptor_gain	1.0000
5:174729158:GGA:G	acceptor_gain	1.0000
5:174729158:GGAC:G	acceptor_gain	1.0000
5:174729158:GGACA:G	acceptor_gain	1.0000
5:174725040:T:A	donor_loss	0.9900
5:174725043:G:GG	donor_gain	0.9900
5:174725037:AA:A	donor_gain	0.9800
5:174726652:GGCTC:G	donor_gain	0.9800
5:174725011:G:GT	donor_gain	0.9700
5:174725035:CCAA:C	donor_gain	0.9700
5:174726639:G:GA	donor_gain	0.9500
5:174725036:CAA:C	donor_gain	0.9300
5:174725065:G:GT	donor_gain	0.9300
5:174725042:A:AG	donor_gain	0.9200
5:174725041:GA:G	donor_gain	0.8900
5:174726638:T:TA	donor_gain	0.8900
5:174728078:G:GT	donor_gain	0.8800
5:174728105:T:G	donor_gain	0.8700
5:174725069:T:TA	donor_gain	0.8400
5:174725070:A:AA	donor_gain	0.8400
5:174729156:TAGGA:T	acceptor_gain	0.8400

AlphaMissense

1701 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
5:174729189:G:T	R137M	1.000
5:174729209:A:G	K144E	1.000
5:174729211:G:C	K144N	1.000
5:174729211:G:T	K144N	1.000
5:174729215:C:A	R146S	1.000
5:174729215:C:G	R146G	1.000
5:174729215:C:T	R146C	1.000
5:174729216:G:A	R146H	1.000
5:174729222:C:A	P148H	1.000
5:174729224:T:A	F149I	1.000
5:174729224:T:C	F149L	1.000
5:174729224:T:G	F149V	1.000
5:174729225:T:C	F149S	1.000
5:174729225:T:G	F149C	1.000
5:174729226:T:A	F149L	1.000
5:174729226:T:G	F149L	1.000
5:174729228:C:T	T150I	1.000
5:174729238:G:C	Q153H	1.000
5:174729238:G:T	Q153H	1.000
5:174729239:C:T	L154F	1.000
5:174729240:T:A	L154H	1.000
5:174729240:T:C	L154P	1.000
5:174729243:T:C	L155P	1.000
5:174729245:G:C	A156P	1.000
5:174729249:T:A	L157Q	1.000
5:174729249:T:C	L157P	1.000
5:174729249:T:G	L157R	1.000
5:174729251:G:A	E158K	1.000
5:174729252:A:T	E158V	1.000
5:174729253:G:C	E158D	1.000

dbSNP variants (sampled 300 via entrez): RS1000110266 (5:174724039 G>A), RS1000791634 (5:174726464 A>G), RS1000930165 (5:174726242 G>A), RS1001143094 (5:174728887 TC>T,TCC), RS1001347304 (5:174727639 G>A), RS1001410827 (5:174729062 G>T), RS1001969657 (5:174726794 G>A), RS1002945812 (5:174724066 T>C), RS1003060382 (5:174726848 G>A), RS1003166459 (5:174726275 A>AGT), RS1003440126 (5:174726634 C>CAGG), RS1003509816 (5:174730743 A>G), RS1003588902 (5:174728044 A>C), RS1003803610 (5:174725391 C>G,T), RS10038500 (5:174729999 A>C,G)

Disease associations

OMIM: gene MIM:123101 | disease phenotypes: MIM:604757, MIM:168500, MIM:168550

GenCC curated gene-disease

Disease	Classification	Inheritance
craniosynostosis 2	Definitive	Autosomal dominant
parietal foramina	Definitive	Autosomal dominant
parietal foramina with cleidocranial dysplasia	Definitive	Autosomal dominant
parietal foramina 1	Strong	Autosomal dominant

ClinGen Gene-Disease Validity (2)

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

Disease	Classification	Inheritance
parietal foramina	Definitive	AD
craniosynostosis 2	Definitive	AD

Mondo (4): craniosynostosis 2 (MONDO:0011481), parietal foramina 1 (MONDO:0008197), parietal foramina with cleidocranial dysplasia (MONDO:0008198), parietal foramina (MONDO:0018953)

Orphanet (3): Craniosynostosis, Boston type (Orphanet:1541), Enlarged parietal foramina (Orphanet:60015), Parietal foramina with clavicular hypoplasia (Orphanet:251290)

HPO phenotypes

45 total (30 of 45 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000175	Cleft palate
HP:0000185	Cleft soft palate
HP:0000204	Cleft upper lip
HP:0000243	Trigonocephaly
HP:0000248	Brachycephaly
HP:0000256	Macrocephaly
HP:0000262	Turricephaly
HP:0000540	Hypermetropia
HP:0000545	Myopia
HP:0000592	Blue sclerae
HP:0000601	Hypotelorism
HP:0000894	Short clavicles
HP:0000932	Abnormal posterior cranial fossa morphology
HP:0001123	Visual field defect
HP:0001156	Brachydactyly
HP:0001199	Triphalangeal thumb
HP:0001249	Intellectual disability
HP:0001250	Seizure
HP:0001363	Craniosynostosis
HP:0002007	Frontal bossing
HP:0002013	Vomiting
HP:0002084	Encephalocele
HP:0002085	Occipital encephalocele
HP:0002315	Headache
HP:0002475	Myelomeningocele
HP:0002645	Wormian bones
HP:0002697	Parietal foramina
HP:0002762	Multiple exostoses
HP:0003593	Infantile onset

GWAS associations

13 associations (top):

Study	Trait	p-value
GCST002755_10	Depressive symptoms (SSRI exposure interaction)	5.000000e-06
GCST002987_18	Stroke	5.000000e-07
GCST003542_36	Night sleep phenotypes	1.000000e-06
GCST003542_82	Night sleep phenotypes	5.000000e-06
GCST003989_23	Chin dimples	7.000000e-14
GCST004250_46	Alanine aminotransferase (ALT) levels after remission induction therapy in actute lymphoblastic leukemia (ALL)	9.000000e-07
GCST006986_13	Red vs. brown/black hair color	5.000000e-19
GCST006988_139	Blond vs. brown/black hair color	4.000000e-13
GCST007135_1	Resistant hypertension	3.000000e-07
GCST007136_1	Resistant hypertension	4.000000e-08
GCST007576_155	Chronotype	2.000000e-10
GCST009391_183	Metabolite levels	9.000000e-06
GCST011696_12	Alzheimer’s disease	2.000000e-06

EFO canonical traits (8, from GWAS)

EFO ID	Trait name
EFO:0007006	depressive symptom measurement
EFO:0007010	drug use measurement
EFO:0007011	SSRI use measurement
EFO:0007965	response to combination chemotherapy
EFO:0003924	hair color
EFO:1002006	treatment-resistant hypertension
EFO:0008328	chronotype measurement
EFO:0010476	dimethylglycine measurement

MeSH disease descriptors (3)

Descriptor	Name	Tree numbers
C566826	Parietal Foramina (supp.)
C566827	Parietal Foramina 1 (supp.)
C566825	Parietal Foramina With Cleidocranial Dysplasia (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects cotreatment, increases expression, affects expression, decreases methylation	9
methylmercuric chloride	increases expression, affects cotreatment	5
trichostatin A	affects cotreatment, increases expression	3
Tretinoin	decreases expression, increases expression	3
sodium arsenite	decreases expression, increases abundance, increases expression	2
mercuric bromide	increases expression, affects cotreatment	2
belinostat	increases expression, affects cotreatment	2
Panobinostat	affects cotreatment, increases expression	2
Benzo(a)pyrene	affects methylation, increases expression, increases methylation	2
Phenylmercuric Acetate	affects cotreatment, increases expression	2
p-Chloromercuribenzoic Acid	affects cotreatment, increases expression	2
3-((6-(2-methoxyphenyl)pyrimidin-4-yl)amino)phenyl)methane sulfonamide	decreases expression	1
bisphenol A	decreases expression, increases methylation	1
deoxynivalenol	increases expression	1
beta-lapachone	decreases expression	1
arsenite	increases methylation	1
cobaltous chloride	increases expression	1
manganese chloride	increases abundance, increases expression	1
benzo(e)pyrene	decreases methylation	1
octa-2,4,6-trienoic acid	decreases expression	1
tebuconazole	decreases expression	1
CGP 52608	affects binding, increases reaction	1
entinostat	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
ICG 001	decreases expression	1
abrine	increases expression	1
dorsomorphin	affects cotreatment, increases expression	1
LG 100815	decreases expression	1
(+)-JQ1 compound	increases expression	1
GSK-2816126	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_A4G1	SEES3-1V human MSX2, clone1	Embryonic stem cell	Male
CVCL_A4G2	SEES3-1V human MSX2, clone2	Embryonic stem cell	Male
CVCL_A4G3	SEES3-1V human MSX2, clone3	Embryonic stem cell	Male

Clinical trials (associated diseases)

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