PRRX1

Summary

PRRX1 (paired related homeobox 1, HGNC:9142) is a protein-coding gene on chromosome 1q24.2, encoding Paired mesoderm homeobox protein 1 (P54821). Master transcription factor of stromal fibroblasts for myofibroblastic lineage progression.

The DNA-associated protein encoded by this gene is a member of the paired family of homeobox proteins localized to the nucleus. The protein functions as a transcription co-activator, enhancing the DNA-binding activity of serum response factor, a protein required for the induction of genes by growth and differentiation factors. The protein regulates muscle creatine kinase, indicating a role in the establishment of diverse mesodermal muscle types. Alternative splicing yields two isoforms that differ in abundance and expression patterns.

Source: NCBI Gene 5396 — RefSeq curated summary.

At a glance

• Gene–disease (curated): agnathia-otocephaly complex (Strong, GenCC) — +2 more curated relationships
• GWAS associations: 77
• Clinical variants (ClinVar): 53 total — 5 pathogenic, 1 likely-pathogenic
• Phenotypes (HPO): 34
• Druggable target: yes
• MANE Select transcript: NM_022716

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:9142
Approved symbol	PRRX1
Name	paired related homeobox 1
Location	1q24.2
Locus type	gene with protein product
Status	Approved
Aliases	PHOX1
Ensembl gene	ENSG00000116132
Ensembl biotype	protein_coding
OMIM	167420
Entrez	5396

Gene structure

Transcript identifiers

Ensembl transcripts: 8 — 5 protein_coding_CDS_not_defined, 3 protein_coding

ENST00000239461, ENST00000367760, ENST00000476867, ENST00000485529, ENST00000495280, ENST00000496573, ENST00000497230, ENST00000553786

RefSeq mRNA: 2 — MANE Select: NM_022716 NM_006902, NM_022716

CCDS: CCDS1290, CCDS1291

Canonical transcript exons

ENST00000239461 — 4 exons

Exon	Start	End
ENSE00001445579	170664131	170664459
ENSE00001821799	170736048	170739421
ENSE00002347336	170719726	170719901
ENSE00003617120	170726220	170726401

Expression profiles

Bgee: expression breadth ubiquitous, 266 present calls, max score 99.48.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 44.9586 / max 737.2161, expressed in 1044 samples.

FANTOM5 promoters (35 alternative TSS)

Promoter ID	TPM avg	Samples expressed
6554	11.2687	751
6578	7.8934	803
6576	3.9832	713
6559	2.7919	584
6568	2.7589	680
6570	2.1473	526
6553	1.6375	564
6558	1.4375	475
6564	1.3585	495
6552	1.1870	475

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
calcaneal tendon	UBERON:0003701	99.48	gold quality
tendon	UBERON:0000043	99.39	gold quality
urethra	UBERON:0000057	99.33	gold quality
tendon of biceps brachii	UBERON:0008188	99.12	gold quality
saphenous vein	UBERON:0007318	99.07	gold quality
parietal pleura	UBERON:0002400	98.96	gold quality
synovial joint	UBERON:0002217	98.94	gold quality
vena cava	UBERON:0004087	98.81	gold quality
pericardium	UBERON:0002407	98.51	gold quality
skin of hip	UBERON:0001554	98.48	gold quality
seminal vesicle	UBERON:0000998	98.13	gold quality
stromal cell of endometrium	CL:0002255	97.73	gold quality
mammalian vulva	UBERON:0000997	97.69	gold quality
tibial artery	UBERON:0007610	97.56	gold quality
popliteal artery	UBERON:0002250	97.55	gold quality
penis	UBERON:0000989	97.53	gold quality
endocervix	UBERON:0000458	97.48	gold quality
cauda epididymis	UBERON:0004360	97.32	gold quality
skeletal muscle tissue of rectus abdominis	UBERON:0004511	97.26	gold quality
pleura	UBERON:0000977	97.22	gold quality
skeletal muscle tissue of biceps brachii	UBERON:0004502	97.07	gold quality
ectocervix	UBERON:0012249	96.85	gold quality
body of tongue	UBERON:0011876	96.75	gold quality
visceral pleura	UBERON:0002401	96.68	gold quality
superficial temporal artery	UBERON:0001614	96.51	gold quality
right coronary artery	UBERON:0001625	96.38	gold quality
biceps brachii	UBERON:0001507	96.32	gold quality
body of uterus	UBERON:0009853	96.16	gold quality
epithelium of nasopharynx	UBERON:0001951	96.15	gold quality
subcutaneous adipose tissue	UBERON:0002190	96.14	gold quality

Single-cell (SCXA)

Detected in 11 experiment(s), a significant marker in 11.

Experiment	Marker?	Max mean expression
E-GEOD-124472	yes	451.97
E-MTAB-9388	yes	198.08
E-MTAB-10287	yes	103.38
E-MTAB-10137	yes	102.93
E-HCAD-1	yes	75.16
E-GEOD-135922	yes	55.87
E-HCAD-10	yes	40.19
E-MTAB-8142	yes	38.27
E-ANND-3	yes	26.89
E-ENAD-27	yes	6.90
E-GEOD-130148	yes	4.10

Regulation

Is transcription factor: yes

Downstream targets (CollecTRI)

8 targets.

Target	Regulation
ACP3
CKM
SOX9
SP7	Repression
TGFB2	Activation
TGFB3	Activation
TNC	Unknown
VEGFA	Unknown

JASPAR motifs

Motif	Name	Family
MA0716.1	PRRX1	Paired-related HD factors
MA0716.2	PRRX1	Paired-related HD factors

JASPAR matrix evidence (PMIDs): PMID:18585360

Upstream regulators (CollecTRI, top): MYC, SRF, TP53

miRNA regulators (miRDB)

187 targeting PRRX1, 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-1277-5P	100.00	73.95	5056
HSA-MIR-9-5P	100.00	72.28	2361
HSA-MIR-450A-1-3P	100.00	69.33	1837
HSA-MIR-6740-5P	100.00	65.64	932
HSA-MIR-3646	100.00	73.56	5283
HSA-MIR-8485	100.00	77.57	4731
HSA-MIR-126-5P	100.00	72.71	3180
HSA-MIR-4795-3P	100.00	74.62	4024
HSA-MIR-3185	99.99	68.12	1959
HSA-MIR-4500	99.99	72.72	2367
HSA-MIR-548C-3P	99.99	74.01	7587
HSA-MIR-4534	99.99	66.58	1907
HSA-MIR-8068	99.98	73.85	2376
HSA-MIR-4482-3P	99.98	72.50	3147
HSA-LET-7A-5P	99.98	72.29	1790
HSA-LET-7B-5P	99.98	72.31	1790
HSA-LET-7C-5P	99.98	72.29	1790
HSA-LET-7E-5P	99.98	72.29	1790
HSA-LET-7F-5P	99.98	72.56	1784
HSA-LET-7G-5P	99.98	72.37	1784
HSA-LET-7I-5P	99.98	72.37	1788
HSA-MIR-98-5P	99.98	72.33	1787
HSA-MIR-512-3P	99.97	67.35	1049
HSA-LET-7D-5P	99.96	71.76	1632
HSA-MIR-4458	99.96	71.64	1650
HSA-MIR-302E	99.96	70.74	2669
HSA-MIR-3910	99.95	71.13	2227
HSA-MIR-96-5P	99.95	72.80	2140

Literature-anchored findings (GeneRIF, showing 40)

• identification of the two Prx1 target genes, which play a pivotal role in development of liver fibrosis, is a novel finding for liver pathophysiology (PMID:18296734)
• Novel evidence of the contributory role of the NUP98 sequence in conferring leukemogenic properties on a partner gene. (PMID:18604245)
• HOXA7, PIXT1 and PRRX1 homeobox genes have different patterns of expression in oral squamous cell carcinomas depending on its histological features. (PMID:21323949)
• Mutation analysis was performed after sequencing the entire coding regions of OTX2 and PRRX1 genes isolated from the proband and his parents. After thorough analysis, no DNA variations were detected. (PMID:22198066)
• The homeobox factor Prrx1 is an EMT inducer conferring migratory and invasive properties. (PMID:23201163)
• We show that the homeobox factor Prrx1 is an EMT inducer conferring migratory and invasive properties. The loss of Prrx1 is required for cancer cells to metastasize in vivo, which revert to the epithelial phenotype concomitant with the acquisition of stem cell properties. (PMID:23201163)
• PRRX1 is an indicator of metastasis and poor prognosis in colorectal cancer cases. (PMID:23807160)
• In the rare variant joint analysis, damaging variants within the PRRX1 region showed significant association with AF. (PMID:24239840)
• Overexpression of PRRX1 in stably overexpressed-miR-124 cell lines could rescue the effects of radiosensitivity enhancement brought by miR-124. (PMID:24705396)
• We conclude that miR-146b-5p has a role in cell proliferation and invasion, and that PRRX1 plays an important role in papillary thyroid carcinoma epithelial-mesenchymal transition and disease progression. (PMID:24946010)
• Decreased Expression of PRRX1 was Associated with Hepatocellular Carcinoma. (PMID:25404478)
• These findings demonstrate that PRRX1 promotes epithelial-mesenchymal transition in gastric cancer cells (PMID:25428393)
• Our results indicate that activation of Notch signaling by PRRX1 is associated with the promotion of glioblastoma cell invasion. (PMID:25522823)
• the switch from Prrx1b to Prrx1a governs EMT plasticity in both mouse models of PDAC and human PDAC (PMID:26773005)
• LGR5-expressing fraction of CD54+ cells represents gastric cancer CSCs, in which LGR5 is closely associated with stemness and EMT core genes (PMID:28033430)
• The glioma-initiating cells self-renewal function regulated by PRRX1 is mediated by dopamine D2 receptor (DRD2). PRRX1 directly binds to the DRD2 promoter and transactivates its expression in glioma-initiating cells. (PMID:28486630)
• Low PRRX1 expression is associated with hepatocellular carcinoma. (PMID:28677793)
• identified a functional genetic variant that alters PRRX1 expression, ultimately resulting in electrophysiological alterations in atrial myocytes that may promote Atrial fibrillation. (PMID:28974514)
• enforced PRRX1 expression results in reversible G1/0 arrest. (PMID:30566868)
• Our findings showed that PRRX1 may be one of the main driving forces for the cellular phenotype plasticity and tumor dormancy of HNSCC. Therefore, we can raise the possibility that EMT may help to keep cancer cell in dormant state and mesenchymal-epithelial transition may resurge dormancy in HNSCC. (PMID:30622052)
• Provide evidence of a possible PRRX1-FOXM1 axis that is critical for PDAC cells. (PMID:30705403)
• biomarker for metastasis and prognosis in clear cell renal cell carcinoma (PMID:31490389)
• findings showed that the PRRX1/PPARG2/FFAs signalling in salivary adenoid cystic carcinoma was important for accelerating tumour metastasis through the induction of EMT and the metabolic reprogramming of FFAs. (PMID:31657086)
• Findings demonstrate that decreased expression of Prrx1 stimulates SDF-1/CXCR4 signalling and contributes to organ colonisation with blood CTCs in HCC. (PMID:31752959)
• The rs7911488-T allele promotes the growth and metastasis of colorectal cancer through modulating miR-1307/PRRX1. (PMID:32811812)
• Relationship between PRRX1, circulating tumor cells, and clinicopathological parameter in patients with gastric cancer. (PMID:32862590)
• Expression and clinical significance of paired- related homeobox 1 and Smad2 in gastric cancer. (PMID:32868636)
• Exosomal CircPRRX1 Enhances Doxorubicin Resistance in Gastric Cancer by Regulating MiR-3064-5p/PTPN14 Signaling. (PMID:32882759)
• Pairedrelated homeobox 1 overexpression promotes multidrug resistance via PTEN/PI3K/AKT signaling in MCF7 breast cancer cells. (PMID:32945446)
• Circular RNA Paired-Related Homeobox 1 Promotes Gastric Carcinoma Cell Progression via Regulating MicroRNA-665/YWHAZ Axis. (PMID:33201331)
• COL6A3 expression in adipose tissue cells is associated with levels of the homeobox transcription factor PRRX1. (PMID:33214660)
• Low PRRX1 expression and high ZEB1 expression are significantly correlated with epithelial-mesenchymal transition and tumor angiogenesis in non-small cell lung cancer. (PMID:33530259)
• PRRX1 promotes lymph node metastasis of gastric cancer by regulating epithelial-mesenchymal transition. (PMID:33578599)
• PRRX1 deficiency induces mesenchymal-epithelial transition through PITX2/miR-200-dependent SLUG/CTNNB1 regulation in hepatocellular carcinoma. (PMID:33587761)
• Activation of COL11A1 by PRRX1 promotes tumor progression and radioresistance in ovarian cancer. (PMID:33970764)
• Prrx1 promotes stemness and angiogenesis via activating TGF-beta/smad pathway and upregulating proangiogenic factors in glioma. (PMID:34131109)
• PRRX1 induced by BMP signaling decreases tumorigenesis by epigenetically regulating glioma-initiating cell properties via DNA methyltransferase 3A. (PMID:34214250)
• PRRX1-NCOA1-rearranged fibroblastic tumour: a clinicopathological, immunohistochemical and molecular genetic study of six cases of a potentially under-recognised, distinctive mesenchymal tumour. (PMID:34272753)
• Dysregulated paired related homeobox 1 impacts on hepatocellular carcinoma phenotypes. (PMID:34496784)
• RNA binding protein RBMS3 is a common EMT effector that modulates triple-negative breast cancer progression via stabilizing PRRX1 mRNA. (PMID:34608266)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	prrx1a	ENSDARG00000033971
danio_rerio	prrx1b	ENSDARG00000042027
mus_musculus	Prrx1	ENSMUSG00000026586
rattus_norvegicus	Prrx1	ENSRNOG00000003720
drosophila_melanogaster	CG9876	FBGN0034821

Paralogs (50): ARX (ENSG00000004848), PAX6 (ENSG00000007372), PAX7 (ENSG00000009709), ALX4 (ENSG00000052850), GSC2 (ENSG00000063515), PITX1 (ENSG00000069011), PAX2 (ENSG00000075891), RHOXF1 (ENSG00000101883), CRX (ENSG00000105392), EVX1 (ENSG00000106038), PAX4 (ENSG00000106331), NOBOX (ENSG00000106410), PITX3 (ENSG00000107859), PHOX2B (ENSG00000109132), OTX1 (ENSG00000115507), VSX2 (ENSG00000119614), ESX1 (ENSG00000123576), PAX8 (ENSG00000125618), PAX1 (ENSG00000125813), RHOXF2 (ENSG00000131721), GSC (ENSG00000133937), RAX (ENSG00000134438), PAX3 (ENSG00000135903), ALX3 (ENSG00000156150), HESX1 (ENSG00000163666), PITX2 (ENSG00000164093), UNCX (ENSG00000164853), PHOX2A (ENSG00000165462), OTX2 (ENSG00000165588), DRGX (ENSG00000165606), PRRX2 (ENSG00000167157), SHOX2 (ENSG00000168779), OTP (ENSG00000171540), RAX2 (ENSG00000173976), EVX2 (ENSG00000174279), PROP1 (ENSG00000175325), ISX (ENSG00000175329), ALX1 (ENSG00000180318), MIXL1 (ENSG00000185155), SHOX (ENSG00000185960)

Protein

Protein identifiers

Paired mesoderm homeobox protein 1 — P54821 (reviewed: P54821)

Alternative names: Homeobox protein PHOX1, Paired-related homeobox protein 1

All UniProt accessions (2): P54821, G3V2N3

UniProt curated annotations — full annotation on UniProt →

Function. Master transcription factor of stromal fibroblasts for myofibroblastic lineage progression. Orchestrates the functional drift of fibroblasts into myofibroblastic phenotype via TGF-beta signaling by remodeling a super-enhancer landscape. Through this function, plays an essential role in wound healing process. Acts as a transcriptional regulator of muscle creatine kinase (MCK) and so has a role in the establishment of diverse mesodermal muscle types. The protein binds to an A/T-rich element in the muscle creatine enhancer. May play a role in homeostasis and regeneration of bone, white adipose tissue and derm. Transcriptional activator, when transfected in fibroblastic or myoblastic cell lines. This activity may be masked by the C-terminal OAR domain. Transcriptional repressor, when transfected in fibroblastic or myoblastic cell lines.

Subunit / interactions. Interacts with SMAD3.

Subcellular location. Nucleus.

Tissue specificity. Widely expressed in embryonic and adult tissues, with highest levels in skeletal muscle. Isoform 1 is either expressed at similar or higher levels compared to isoform 2 in all embryonic tissues but skeletal muscle and heart. In adult tissues, expressed at lower levels compared to isoform 2. Widely expressed in embryonic and adult tissues, with highest levels in skeletal muscle. Isoform 2 is either expressed at similar or lower levels compared to isoform 1 in all embryonic tissues but skeletal muscle and heart, where it is expressed at higher levels. In adult tissues, expressed at higher levels compared to isoform 1.

Disease relevance. Agnathia-otocephaly complex (AGOTC) [MIM:202650] A rare condition characterized by mandibular hypoplasia or agnathia, ventromedial auricular malposition (melotia) and/or auricular fusion (synotia), and microstomia with oroglossal hypoplasia or aglossia. Holoprosencephaly is the most commonly identified association, but skeletal, genitourinary, and cardiovascular anomalies, and situs inversus have been reported. The disorder is almost always lethal. The disease is caused by variants affecting the gene represented in this entry. Strongly expressed in cancer-associated fibroblasts (CAFs) in various cancer types. Its expression correlates with unfavorable clinical outcome. May be essential for the tumorigenicity and metastasis-inducing capacity of CAFs. Can reprogram tumor-suppressive normal fibroblasts into CAFs.

Similarity. Belongs to the paired homeobox family.

Isoforms (2)

UniProt ID	Names	Canonical?
P54821-1	1, PRRX1a, PMX1-B	yes
P54821-2	2, PRRX1b

RefSeq proteins (2): NP_008833, NP_073207* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001356	HD	Domain
IPR003654	OAR_dom	Domain
IPR009057	Homeodomain-like_sf	Homologous_superfamily
IPR017970	Homeobox_CS	Conserved_site
IPR043378	PRRX1/2	Family

Pfam: PF00046, PF03826

UniProt features (11 total): modified residue 3, region of interest 2, chain 1, DNA-binding region 1, sequence variant 1, short sequence motif 1, compositionally biased region 1, splice variant 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P54821-F1	66.38	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.

Post-translational modifications (3): 21, 160, 197

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 428 (showing top): GSE45365_CD8A_DC_VS_CD11B_DC_IFNAR_KO_UP, GSE18804_SPLEEN_MACROPHAGE_VS_BRAIN_TUMORAL_MACROPHAGE_UP, GSE37336_LY6C_POS_VS_NEG_NAIVE_CD4_TCELL_UP, GSE18804_SPLEEN_MACROPHAGE_VS_TUMORAL_MACROPHAGE_UP, GSE18804_BRAIN_VS_COLON_TUMORAL_MACROPHAGE_UP, GGGACCA_MIR133A_MIR133B, RNGTGGGC_UNKNOWN, TURASHVILI_BREAST_LOBULAR_CARCINOMA_VS_DUCTAL_NORMAL_UP, GOBP_EMBRYO_DEVELOPMENT_ENDING_IN_BIRTH_OR_EGG_HATCHING, GOBP_CARTILAGE_DEVELOPMENT, GOBP_SKELETAL_SYSTEM_DEVELOPMENT, NKX25_02, LFA1_Q6, GOBP_EMBRYONIC_SKELETAL_SYSTEM_DEVELOPMENT, XU_HGF_TARGETS_REPRESSED_BY_AKT1_DN

GO Biological Process (22): positive regulation of mesenchymal cell proliferation (GO:0002053), regulation of transcription by RNA polymerase II (GO:0006357), smoothened signaling pathway (GO:0007224), mesenchymal cell proliferation (GO:0010463), embryonic limb morphogenesis (GO:0030326), inner ear morphogenesis (GO:0042472), middle ear morphogenesis (GO:0042474), positive regulation of smoothened signaling pathway (GO:0045880), positive regulation of transcription by RNA polymerase II (GO:0045944), neuron fate determination (GO:0048664), embryonic cranial skeleton morphogenesis (GO:0048701), artery morphogenesis (GO:0048844), cartilage development (GO:0051216), roof of mouth development (GO:0060021), regulation of neuron projection regeneration (GO:0070570), stem cell proliferation (GO:0072089), neuronal stem cell population maintenance (GO:0097150), positive regulation of stem cell proliferation (GO:2000648), negative regulation of transcription by RNA polymerase II (GO:0000122), regulation of DNA-templated transcription (GO:0006355), transcription by RNA polymerase II (GO:0006366), embryonic skeletal system morphogenesis (GO:0048704)

GO Molecular Function (9): 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), DNA-binding transcription activator activity, RNA polymerase II-specific (GO:0001228), RNA polymerase II general transcription initiation factor activity (GO:0016251), RNA polymerase II-specific DNA-binding transcription factor binding (GO:0061629), HMG box domain binding (GO:0071837), DNA binding (GO:0003677), protein binding (GO:0005515)

GO Cellular Component (4): chromatin (GO:0000785), nucleus (GO:0005634), nucleoplasm (GO:0005654), cytosol (GO:0005829)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
transcription by RNA polymerase II	4
RNA polymerase II transcription regulatory region sequence-specific DNA binding	4
regulation of transcription by RNA polymerase II	3
cellular anatomical structure	3
positive regulation of cell population proliferation	2
cell population proliferation	2
ear morphogenesis	2
embryonic morphogenesis	2
DNA-binding transcription factor activity, RNA polymerase II-specific	2
mesenchymal cell proliferation	1
regulation of mesenchymal cell proliferation	1
regulation of DNA-templated transcription	1
cell surface receptor signaling pathway	1
limb morphogenesis	1
embryonic appendage morphogenesis	1
inner ear development	1
smoothened signaling pathway	1
regulation of smoothened signaling pathway	1
positive regulation of signal transduction	1
positive regulation of DNA-templated transcription	1
cell fate determination	1
neuron fate commitment	1
embryonic skeletal system morphogenesis	1
cranial skeletal system development	1
blood vessel morphogenesis	1
artery development	1
skeletal system development	1
animal organ development	1
connective tissue development	1
anatomical structure development	1
regulation of neuron projection development	1
neuron projection regeneration	1
regulation of developmental process	1
regulation of cellular response to stress	1
stem cell division	1
stem cell population maintenance	1
stem cell proliferation	1
regulation of stem cell proliferation	1
negative regulation of DNA-templated transcription	1
DNA-templated transcription	1

Protein interactions and networks

STRING

2008 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
PRRX1	METTL13	Q8N6R0	844
PRRX1	NUP98	P52948	843
PRRX1	TWIST1	Q15672	728
PRRX1	PAX9	P55771	719
PRRX1	HOXD13	P35453	674
PRRX1	DDX10	Q13206	657
PRRX1	HOXB13	Q92826	654
PRRX1	HAND2	P61296	624
PRRX1	HOXD11	P31277	623
PRRX1	SIX1	Q15475	620
PRRX1	RAP1GDS1	P52306	616
PRRX1	PSIP1	O75475	583
PRRX1	HOXC13	P31276	581
PRRX1	NSD1	Q96L73	576
PRRX1	OSR2	Q8N2R0	555

IntAct

12 interactions, top by confidence:

A	B	Type	Score
PRRX1	CINP	psi-mi:“MI:0915”(physical association)	0.560
	PRRX1	psi-mi:“MI:0915”(physical association)	0.560
SUOX	PRRX1	psi-mi:“MI:0915”(physical association)	0.560
	TK2	psi-mi:“MI:0915”(physical association)	0.400
PRRX1	ALX3	psi-mi:“MI:0914”(association)	0.350
CINP	PRRX1	psi-mi:“MI:0915”(physical association)	0.000
	PRRX1	psi-mi:“MI:0915”(physical association)	0.000
SUOX	PRRX1	psi-mi:“MI:0915”(physical association)	0.000

BioGRID (16): PRRX1 (Two-hybrid), SUOX (Two-hybrid), SAAL1 (Two-hybrid), GTF2I (Co-purification), FKBP5 (Affinity Capture-MS), ALX3 (Affinity Capture-MS), PRRX1 (Affinity Capture-MS), PRRX1 (Affinity Capture-MS), TGFB1 (Co-localization), DNMT3A (Affinity Capture-Western), PRRX1 (Affinity Capture-Western), PRRX1 (Proximity Label-MS), PRRX1 (Proximity Label-MS), PRRX1 (Proximity Label-MS), PRRX1 (Proximity Label-MS)

ESM2 similar proteins: A8XJD0, E7FDX5, F1R2J1, G5EC89, G5ECT8, L8E946, O13023, O93590, O97670, P09071, P17488, P20269, P23410, P23459, P26797, P29506, P34326, P42587, P49925, P53544, P53547, P54821, P56179, P63013, P63014, P70397, Q01704, Q03357, Q05437, Q08821, Q09604, Q0P4H6, Q0P4W6, Q22909, Q22910, Q2PYN8, Q503F2, Q504H8, Q623D4, Q6R3Q6

Diamond homologs: A1A546, A1YEV8, A1YG25, A2T711, A6NJT0, A6NNA5, A6YP92, G5EC89, G5EDS1, O08934, O14813, O18381, O35085, O35137, O35602, O35690, O42115, O42201, O42250, O42356, O42357, O42358, O42477, O42567, O70137, O73917, O75364, O77215, O95076, O97039, P06601, P0DMV5, P23759, P23760, P24610, P26367, P26630, P29506, P32242, P41935

SIGNOR signaling

7 interactions.

A	Effect	B	Mechanism
GTF2I	up-regulates	PRRX1	binding
PRRX1	up-regulates	SRF	binding
PRRX1	“down-regulates activity”	MAFF	binding
PRRX1	“down-regulates activity”	MAF	binding
PRRX1	“down-regulates activity”	MAFB	binding
PRRX1	“down-regulates activity”	MAFK	binding
PRRX1	“down-regulates activity”	MAFG	binding

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	5
Likely pathogenic	1
Uncertain significance	28
Likely benign	9
Benign	3

Top pathogenic / likely-pathogenic (6)

Variant ID	HGVS	Classification
29825	NM_022716.4(PRRX1):c.338T>C (p.Phe113Ser)	Pathogenic
29826	NM_022716.4(PRRX1):c.691G>C (p.Ala231Pro)	Pathogenic
4531312	NM_022716.4(PRRX1):c.370C>T (p.Arg124Ter)	Pathogenic
50496	NM_022716.4(PRRX1):c.269del (p.Lys90fs)	Pathogenic
50497	NM_022716.4(PRRX1):c.266_269dup (p.Arg92fs)	Pathogenic
982406	NM_022716.4(PRRX1):c.317T>C (p.Leu106Pro)	Likely pathogenic

SpliceAI

1118 predictions. Top by Δscore:

Variant	Effect	Δscore
1:170664455:GGACA:G	donor_gain	1.0000
1:170664456:GACA:G	donor_gain	1.0000
1:170664456:GACAG:G	donor_gain	1.0000
1:170664457:A:T	donor_gain	1.0000
1:170664460:G:GG	donor_gain	1.0000
1:170664464:G:GG	donor_gain	1.0000
1:170719719:A:AG	acceptor_gain	1.0000
1:170719722:CCAG:C	acceptor_loss	1.0000
1:170719724:A:AG	acceptor_gain	1.0000
1:170719724:AG:A	acceptor_loss	1.0000
1:170719725:G:GG	acceptor_gain	1.0000
1:170719897:TGCAG:T	donor_loss	1.0000
1:170719900:AGGT:A	donor_loss	1.0000
1:170719901:GGTAA:G	donor_loss	1.0000
1:170719902:G:GA	donor_loss	1.0000
1:170719903:T:G	donor_loss	1.0000
1:170726191:T:G	acceptor_gain	1.0000
1:170664022:G:GT	donor_gain	0.9900
1:170664458:CA:C	donor_gain	0.9900
1:170664459:AGT:A	donor_loss	0.9900
1:170664462:GA:G	donor_gain	0.9900
1:170664470:G:T	donor_gain	0.9900
1:170719724:AGAT:A	acceptor_gain	0.9900
1:170719725:GA:G	acceptor_gain	0.9900
1:170719725:GAT:G	acceptor_gain	0.9900
1:170719725:GATG:G	acceptor_gain	0.9900
1:170719725:GATGA:G	acceptor_gain	0.9900
1:170726190:A:AG	acceptor_gain	0.9900
1:170726199:T:A	acceptor_gain	0.9900
1:170726208:A:G	acceptor_gain	0.9900

AlphaMissense

1600 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
1:170664334:T:C	L39P	1.000
1:170719771:G:C	R96T	1.000
1:170719771:G:T	R96M	1.000
1:170719772:G:C	R96S	1.000
1:170719772:G:T	R96S	1.000
1:170719776:A:G	R98G	1.000
1:170719776:A:T	R98W	1.000
1:170719777:G:C	R98T	1.000
1:170719777:G:T	R98M	1.000
1:170719778:G:C	R98S	1.000
1:170719778:G:T	R98S	1.000
1:170719779:A:T	T99S	1.000
1:170719780:C:A	T99K	1.000
1:170719780:C:G	T99R	1.000
1:170719780:C:T	T99I	1.000
1:170719785:T:A	F101I	1.000
1:170719785:T:C	F101L	1.000
1:170719785:T:G	F101V	1.000
1:170719786:T:C	F101S	1.000
1:170719786:T:G	F101C	1.000
1:170719787:C:A	F101L	1.000
1:170719787:C:G	F101L	1.000
1:170719798:A:C	Q105P	1.000
1:170719799:G:C	Q105H	1.000
1:170719799:G:T	Q105H	1.000
1:170719801:T:A	L106Q	1.000
1:170719801:T:C	L106P	1.000
1:170719806:G:C	A108P	1.000
1:170719810:T:C	L109S	1.000
1:170719810:T:G	L109W	1.000

dbSNP variants (sampled 300 via entrez): RS1000012573 (1:170702912 A>G), RS1000042454 (1:170696994 C>A,T), RS1000056025 (1:170725516 A>G), RS1000104684 (1:170678395 G>A,C), RS1000135791 (1:170678593 A>C), RS1000207040 (1:170719246 C>G,T), RS1000256778 (1:170708587 A>G), RS1000256887 (1:170679932 T>G), RS1000287351 (1:170672405 G>C), RS1000299293 (1:170731278 C>T), RS1000317808 (1:170713162 T>G), RS1000338010 (1:170721408 C>T), RS1000350446 (1:170713320 G>A), RS1000484388 (1:170684684 C>T), RS1000533717 (1:170667235 G>A)

Disease associations

OMIM: gene MIM:167420 | disease phenotypes: MIM:202650, MIM:123100

GenCC curated gene-disease

Disease	Classification	Inheritance
agnathia-otocephaly complex	Strong	Autosomal dominant
craniosynostosis	Moderate	Autosomal dominant
multiple congenital anomalies/dysmorphic syndrome-intellectual disability	Limited	Autosomal recessive

Mondo (3): agnathia-otocephaly complex (MONDO:0008740), craniosynostosis (MONDO:0015469), multiple congenital anomalies/dysmorphic syndrome-intellectual disability (MONDO:0015159)

Orphanet (2): Agnathia-holoprosencephaly-situs inversus syndrome (Orphanet:990), Craniosynostosis (Orphanet:1531)

HPO phenotypes

34 total (30 of 34 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000007	Autosomal recessive inheritance
HP:0000160	Narrow mouth
HP:0000171	Microglossia
HP:0000175	Cleft palate
HP:0000347	Micrognathia
HP:0000358	Posteriorly rotated ears
HP:0000369	Low-set ears
HP:0000405	Conductive hearing impairment
HP:0000445	Wide nose
HP:0000478	Abnormality of the eye
HP:0000494	Downslanted palpebral fissures
HP:0001274	Agenesis of corpus callosum
HP:0001291	Abnormal cranial nerve morphology
HP:0001360	Holoprosencephaly
HP:0001561	Polyhydramnios
HP:0001684	Secundum atrial septal defect
HP:0001696	Situs inversus totalis
HP:0002089	Pulmonary hypoplasia
HP:0002098	Respiratory distress
HP:0002779	Tracheomalacia
HP:0005349	Hypoplasia of the epiglottis
HP:0007360	Aplasia/Hypoplasia of the cerebellum
HP:0008736	Hypoplasia of penis
HP:0008749	Laryngeal hypoplasia
HP:0009914	Cyclopia
HP:0009924	Aplasia/Hypoplasia involving the nose
HP:0009939	Mandibular aplasia
HP:0011386	Narrow internal auditory canal
HP:0011461	Fetal onset

GWAS associations

77 associations (top):

Study	Trait	p-value
GCST001499_4	Atrial fibrillation	8.000000e-14
GCST001520_12	Response to angiotensin II receptor blocker therapy	1.000000e-06
GCST002945_18	Emphysema imaging phenotypes	5.000000e-07
GCST002945_41	Emphysema imaging phenotypes	8.000000e-07
GCST004067_157	Hip circumference adjusted for BMI	2.000000e-06
GCST004067_215	Hip circumference adjusted for BMI	2.000000e-06
GCST004067_24	Hip circumference adjusted for BMI	2.000000e-10
GCST004295_3	Atrial fibrillation	6.000000e-16
GCST004297_11	Atrial fibrillation	6.000000e-15
GCST004301_9	Prevalent atrial fibrillation	3.000000e-12
GCST004352_3	Early onset atrial fibrillation	1.000000e-07
GCST004373_16	Atrial fibrillation	4.000000e-09
GCST004765_35	Total cholesterol change in response to fenofibrate in statin-treated type 2 diabetes	6.000000e-08
GCST005116_10	Male-pattern baldness	3.000000e-20
GCST005306_7	Atrial fibrillation	4.000000e-10
GCST005580_163	Intraocular pressure	1.000000e-08
GCST005580_267	Intraocular pressure	4.000000e-10
GCST005956_24	Waist-to-hip ratio adjusted for BMI	5.000000e-07
GCST005962_31	Waist-to-hip ratio adjusted for BMI x sex x age interaction (4df test)	3.000000e-07
GCST006061_214	Atrial fibrillation	4.000000e-11
GCST006061_88	Atrial fibrillation	2.000000e-39
GCST006061_97	Atrial fibrillation	2.000000e-42
GCST006288_609	Heel bone mineral density	8.000000e-11
GCST006288_714	Heel bone mineral density	3.000000e-07
GCST006661_31	Male-pattern baldness	1.000000e-12
GCST006976_81	Macular thickness	2.000000e-09
GCST006979_959	Heel bone mineral density	1.000000e-44
GCST008058_45	Estimated glomerular filtration rate	2.000000e-10
GCST008059_243	Estimated glomerular filtration rate	7.000000e-10
GCST008156_104	Hip circumference adjusted for BMI	2.000000e-06

EFO canonical traits (13, from GWAS)

EFO ID	Trait name
EFO:0007626	emphysema imaging measurement
EFO:0008039	BMI-adjusted hip circumference
EFO:0007806	total cholesterol change measurement
EFO:0004695	intraocular pressure measurement
EFO:0007788	BMI-adjusted waist-hip ratio
EFO:0008007	age at assessment
EFO:0008343	sex interaction measurement
EFO:0009270	heel bone mineral density
EFO:0000266	aortic stenosis
EFO:0004462	PR interval
EFO:0007789	BMI-adjusted waist circumference
EFO:0004980	appendicular lean mass
EFO:0005213	central corneal thickness

MeSH disease descriptors (1)

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

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL4879442 (SINGLE PROTEIN)

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, increases expression	4
(+)-JQ1 compound	affects cotreatment, decreases expression, increases expression	3
Benzo(a)pyrene	affects methylation, decreases expression, increases methylation	3
entinostat	increases expression, affects cotreatment	2
Panobinostat	affects cotreatment, increases expression	2
Phenylmercuric Acetate	affects cotreatment, decreases expression	2
Aflatoxin B1	decreases methylation	2
GSK-J4	increases expression	1
methylmercuric chloride	decreases expression	1
bisphenol A	affects cotreatment, decreases methylation	1
kojic acid	decreases expression	1
ethyl-p-hydroxybenzoate	increases expression	1
trichostatin A	increases expression	1
methylparaben	decreases expression	1
mono-(2-ethylhexyl)phthalate	increases abundance, increases methylation	1
cobaltous chloride	increases expression	1
sulindac sulfide	decreases expression	1
S-(1,2-dichlorovinyl)cysteine	affects response to substance, increases expression, affects cotreatment, decreases expression	1
testosterone-3-carboxymethyloxime-bovine serum albumin conjugate	affects expression	1
CGP 52608	affects binding, increases reaction	1
rofecoxib	affects expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, increases expression, decreases expression	1
abrine	increases expression	1
mirdametinib	affects cotreatment, decreases expression	1
dorsomorphin	affects cotreatment, increases expression, decreases expression	1
MRK 003	decreases expression	1
bisphenol S	increases methylation	1
incobotulinumtoxinA	increases expression	1
Temozolomide	decreases expression	1
Sunitinib	decreases expression	1

ChEMBL screening assays

11 unique, capped per target: 11 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL4812977	Binding	Inhibition of recombinant Prx1 (unknown origin) assessed as reduction in peroxidase activity at 50 uM incubated for 30 mins followed by H2O2 addition and measured after 20 mins by PEROXsay assay kit method relative to control	Epo-C12 inhibits peroxiredoxin 1 peroxidase activity. — Bioorg Med Chem

Clinical trials (associated diseases)

17 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
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