PITX1

Summary

PITX1 (paired like homeodomain 1, HGNC:9004) is a protein-coding gene on chromosome 5q31.1, encoding Pituitary homeobox 1 (P78337). Sequence-specific transcription factor that binds gene promoters and activates their transcription.

This gene encodes a member of the RIEG/PITX homeobox family, which is in the bicoid class of homeodomain proteins. Members of this family are involved in organ development and left-right asymmetry. This protein acts as a transcriptional regulator involved in basal and hormone-regulated activity of prolactin.

Source: NCBI Gene 5307 — RefSeq curated summary.

At a glance

• Gene–disease (curated): familial clubfoot due to PITX1 point mutation (Strong, GenCC) — +2 more curated relationships
• GWAS associations: 19
• Clinical variants (ClinVar): 114 total — 3 pathogenic, 6 likely-pathogenic
• Phenotypes (HPO): 30
• Transcription factor: yes — 44 downstream targets (CollecTRI)
• MANE Select transcript: NM_002653

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:9004
Approved symbol	PITX1
Name	paired like homeodomain 1
Location	5q31.1
Locus type	gene with protein product
Status	Approved
Aliases	PTX1, POTX
Ensembl gene	ENSG00000069011
Ensembl biotype	protein_coding
OMIM	602149
Entrez	5307

Gene structure

Transcript identifiers

Ensembl transcripts: 6 — 4 protein_coding, 1 protein_coding_CDS_not_defined, 1 retained_intron

ENST00000265340, ENST00000502676, ENST00000503586, ENST00000504936, ENST00000506438, ENST00000507253

RefSeq mRNA: 1 — MANE Select: NM_002653 NM_002653

CCDS: CCDS4182

Canonical transcript exons

ENST00000265340 — 3 exons

Exon	Start	End
ENSE00001372731	135033713	135034228
ENSE00001560087	135027734	135029321
ENSE00002495342	135031276	135031508

Expression profiles

Bgee: expression breadth ubiquitous, 180 present calls, max score 99.62.

FANTOM5 (CAGE): breadth broad, TPM avg 16.1065 / max 466.5460, expressed in 907 samples.

FANTOM5 promoters (7 alternative TSS)

Promoter ID	TPM avg	Samples expressed
63513	10.6305	813
63512	4.4285	569
63514	0.4030	240
63509	0.2882	172
63510	0.1713	100
63511	0.1449	83
63508	0.0403	10

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
lower esophagus mucosa	UBERON:0035834	99.62	gold quality
esophagus mucosa	UBERON:0002469	99.05	gold quality
pharyngeal mucosa	UBERON:0000355	97.85	gold quality
pituitary gland	UBERON:0000007	96.26	gold quality
minor salivary gland	UBERON:0001830	96.15	gold quality
mouth mucosa	UBERON:0003729	96.15	gold quality
adenohypophysis	UBERON:0002196	95.75	gold quality
esophagus squamous epithelium	UBERON:0006920	95.47	gold quality
gingiva	UBERON:0001828	95.38	gold quality
gingival epithelium	UBERON:0001949	95.24	gold quality
epithelium of esophagus	UBERON:0001976	95.17	gold quality
mucosa of stomach	UBERON:0001199	94.93	gold quality
saliva-secreting gland	UBERON:0001044	94.29	gold quality
hindlimb stylopod muscle	UBERON:0004252	93.82	gold quality
olfactory segment of nasal mucosa	UBERON:0005386	93.46	gold quality
body of tongue	UBERON:0011876	93.25	gold quality
oral cavity	UBERON:0000167	91.66	gold quality
tongue	UBERON:0001723	91.07	gold quality
esophagogastric junction muscularis propria	UBERON:0035841	89.66	gold quality
vagina	UBERON:0000996	89.15	gold quality
tonsil	UBERON:0002372	88.79	gold quality
esophagus	UBERON:0001043	88.54	gold quality
squamous epithelium	UBERON:0006914	88.29	gold quality
tongue squamous epithelium	UBERON:0006919	87.65	gold quality
superior surface of tongue	UBERON:0007371	87.65	gold quality
body of stomach	UBERON:0001161	87.48	gold quality
amniotic fluid	UBERON:0000173	86.81	gold quality
fundus of stomach	UBERON:0001160	86.38	gold quality
stomach	UBERON:0000945	86.14	gold quality
popliteal artery	UBERON:0002250	85.69	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-MTAB-9906	yes	1099.15
E-HCAD-1	yes	285.64
E-CURD-114	yes	56.80
E-GEOD-135922	yes	49.04
E-ANND-3	yes	26.70

Regulation

Is transcription factor: yes

Downstream targets (CollecTRI)

44 targets.

Target	Regulation
ADAM2
AP1	Repression
CRH
CXCL2
CYP11B1
DUX4	Unknown
FGFR1
FHL1
FSHB	Unknown
GDF15	Activation
GNRH1	Repression
GNRHR
HES1	Repression
HOXC10
HOXC11
IFN1@
IFNA1	Repression
IFNA4
IFNA5	Repression
IRF2	Repression
IRF7	Repression
JUN	Repression
KRAS
KRT27
LHB	Unknown
MCAT
NKX3-1	Repression
PIN1
PITX1
POMC	Activation

JASPAR motifs

Motif	Name	Family
MA0682.2	PITX1	Paired-related HD factors
MA0682.3	PITX1	Paired-related HD factors

JASPAR matrix evidence (PMIDs): PMID:8675014

Upstream regulators (CollecTRI, top): AP1, DUX4, ISL1, LHX3, MSX1, NEUROD1, PITX1, STAT5A, STAT5B, TP53

miRNA regulators (miRDB)

22 targeting PITX1, 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-4481	100.00	66.42	1669
HSA-MIR-30A-5P	100.00	76.31	3233
HSA-MIR-30B-5P	100.00	76.29	3248
HSA-MIR-30C-5P	100.00	76.29	3248
HSA-MIR-30D-5P	100.00	76.32	3233
HSA-MIR-30E-5P	100.00	76.32	3242
HSA-MIR-19A-3P	99.98	75.33	2762
HSA-MIR-19B-3P	99.98	75.44	2754
HSA-MIR-4745-5P	99.98	65.95	1028
HSA-MIR-6768-5P	99.92	67.36	1942
HSA-MIR-6885-3P	99.75	70.36	3187
HSA-MIR-4802-3P	99.72	70.13	1273
HSA-MIR-10399-5P	99.17	69.87	2610
HSA-MIR-6504-3P	99.17	69.31	2891
HSA-MIR-511-5P	98.97	70.94	2268
HSA-MIR-455-3P	98.94	67.68	878
HSA-MIR-6870-3P	98.08	65.10	692
HSA-MIR-6515-5P	97.08	65.48	1219
HSA-MIR-3178	89.40	60.05	100
HSA-MIR-6850-3P	88.96	69.27	33
HSA-MIR-6784-5P	84.56	60.91	126
HSA-MIR-1292-3P	72.98	63.40	23

Literature-anchored findings (GeneRIF, showing 40)

• the paired-like homeobox transcription factors Pitx1 and Pitx2 are factors functionally activating the proximal human prolactin promoter (hPRL-164luc) (PMID:12223489)
• Modulation of interferon expression by co expression of hepatitis C virus NS5A protein and human homeodomain protein PTX1 (PMID:12620797)
• this study represents the first demonstration for a role of pituitary homeobox 1 in the regulation of transcription of enzymes involved in adrenal steroidogenesis (PMID:12915995)
• PITX1 mRNA expression is decreased in Barrett’s esophagus, compared with matching normal squamous esophagus specimens, and is further decreased in Barrett’s-associated cancer (PMID:16291394)
• Pitx1 is expressed in normal human knee joint cartilage and its loss occurs in patients with knee osteoarthritis. (PMID:17549029)
• p53 is a direct transcriptional target gene of hPitx1. This observation is concordant with the recent identification of hPitx1 as a tumor suppressor gene. (PMID:17762884)
• up-regulation of both DUX4 and PITX1 in FSHD muscles may play critical roles in the molecular mechanisms of the disease (PMID:17984056)
• Haplotype analys. within PITX1 showed overtransmission of the A-C haplotype of markers rs11959298 - rs6596189. Individuals homozygous for the A-C haplotype risk allele were 2.54 fold more likely to be autistic than indiv. who were not carrying the allele (PMID:18053270)
• Down-regulation of PITX1 may be a frequent molecular event in gastric carcinogenesis; Aberrant levels of PITX1 expression may be closely correlated with the progression and differentiation of gastric cancer (PMID:18186570)
• Asymmetric lower-limb malformations in individuals with homeobox PITX1 gene mutation are reported. (PMID:18950742)
• High BFT expression is associated with non-small cell lung cancer. (PMID:19414376)
• Suggest that the PITX1 polymorphism (rs479632) is not a risk factor for knee ostoearthritis susceptibility in the Chinese Han population. (PMID:20054692)
• SEDLIN is present in the nucleus, forms homodimers and that SEDT-associated mutations cause a loss of interaction with the transcription factors MBP1, PITX1 and SF1. (PMID:20498720)
• These findings provide evidence that c-Abl participates in modulating Pitx1 expression in the apoptotic response to DNA damage. (PMID:20563669)
• PITX1 suppresses TERT transcription through direct binding to the TERT promoter, which ultimately regulates telomerase activity (PMID:21300782)
• HOXA7, PIXT1 and PRRX1 homeobox genes have different patterns of expression in oral squamous cell carcinomas depending on its histological features. (PMID:21323949)
• leukemic activation of PITX1, a novice PRD-class homeobox gene in a subset of early-staged T-ALL, which may promote leukemogenesis by inhibiting T-cell development. (PMID:21425961)
• These studies identify PITX1 as a new ERalpha transcriptional target. (PMID:21868451)
• mutations in PITX1 can cause a broad spectrum of isolated lower-limb malformations including clubfoot, deficiency of long bones, and mirror-image polydactyly. (PMID:22258522)
• High expression of desmocollin 1 (DSC1) was observed in 41.6%, DSC2 in 58.0%, DSC3 in 61.4%, E-cadherin in 71.4%, CDX2 in 58.0%, PITX1 in 55.0%, CDK4 in 0.2%, TLE1 in 1.3%, Factor H in 42.5%, and MDM2 in 0.2% of colorectal carcinomas. (PMID:22438068)
• Identified two deletions and a translocation 5’ of PITX1. (PMID:23022097)
• DUX4 gene is activated in a small number of myonuclei, the DUX4 proteins diffuse to adjacent nuclei where they activate target genes such as PITX1. (PMID:23206257)
• Lienberg syndrome results from a misexpression of PITX1 in upper extremities. (PMID:23395106)
• A deletion in H2AFY gene and 190,428bp of its downstream region contains a regulatory sequence that suppresses the expression of PITX1 in the upper limb buds and causes Liebenberg syndrome. (PMID:23587911)
• Down-regulation of PITX1 expression might contribute to the progression of cutaneous malignant melanoma via promoting cell proliferative activity (PMID:23816528)
• We discuss the genetic abnormality that causes Liebenberg syndrome, the genomic rearrangement at the PITX1 locus on chromosome 5. (PMID:23940102)
• PITX1 regulates HIF-1a activity by binding to HIF-1b and regulatingHIF recruitment to specific target promoters. (PMID:25558831)
• Low PITX1 expression is associated with lung metastasis in osteosarcoma. (PMID:25936343)
• To date, at least ten loci and four non-syndromic polydactyly-causing genes, including the GLI3 gene, the ZNF141 gene, the MIPOL1 gene and the PITX1 gene, have been identified. (Review) (PMID:26515020)
• PTP1B dephosphorylates PITX1 to weaken its protein stability and the transcriptional activity for p120RasGAP gene expression (PMID:26840794)
• PITX1 expression may be involved in tumor progression and is a potential tumor suppressor gene and prognostic marker for cutaneous malignant melanoma. (PMID:27742032)
• we demonstrated a novel oncogenic mechanism of PTP1B on affecting PITX1/p120RasGAP in colorectal carcinoma(CRC). Regorafenib inhibited CRC survival through reserving PTP1B-dependant PITX1/p120RasGAP downregulation. PTP1B may be a potential biomarker predicting regorafenib effectiveness, and a potential solution for CRC (PMID:27752061)
• role for E2F1 and TFDP1 in the transcriptional regulation of PITX1 in articular chondrocytes (PMID:27802335)
• Our results suggest that mutation of a specific loop both affects the global G4 structure and impacts the ability to interact with a G4 binding protein and small molecule ligand. (PMID:28412358)
• Methylation status of PITX1 and even more so of lincRNA C5orf66-AS1 is a promising prognostic biomarker in HNSCC, in particular for HPV-negative patients. Further prospective evaluation is warranted (PMID:29425237)
• As a transcriptional activator, PITX1 regulates apoptosis-related genes, including PDCD5, during gastric carcinogenesis. (PMID:29734189)
• Significantly higher methylation level and lower PITX1 gene expression are found in adolescent idiopathic scoliosis. (PMID:29743058)
• PITX1 might serve as a potential biomarker for early detection and prognosis prediction of patients with lung adenocarcinoma. (PMID:30322808)
• upregulated miR-1204 in non-small-cell lung cancer (NSCLC) is associated with NSCLC progression and promotes NSCLC cell proliferation by downregulating PITX1. (PMID:30549141)
• Our data indicate that housekeeping promoters may titrate promiscuous enhancer activity to ensure normal morphogenesis. The deletion of the H2AFY promoter as a cause of Liebenberg syndrome highlights this new mutational mechanism and its role in congenital disease. (PMID:30711920)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	pitx2	ENSDARG00000036194
mus_musculus	Pitx1	ENSMUSG00000021506
rattus_norvegicus	Pitx1	ENSRNOG00000011423

Paralogs (50): ARX (ENSG00000004848), PAX6 (ENSG00000007372), PAX7 (ENSG00000009709), ALX4 (ENSG00000052850), GSC2 (ENSG00000063515), PAX2 (ENSG00000075891), RHOXF1 (ENSG00000101883), CRX (ENSG00000105392), EVX1 (ENSG00000106038), PAX4 (ENSG00000106331), NOBOX (ENSG00000106410), PITX3 (ENSG00000107859), PHOX2B (ENSG00000109132), OTX1 (ENSG00000115507), PRRX1 (ENSG00000116132), 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

Pituitary homeobox 1 — P78337 (reviewed: P78337)

Alternative names: Hindlimb-expressed homeobox protein backfoot, Homeobox protein PITX1, Paired-like homeodomain transcription factor 1

All UniProt accessions (4): P78337, D6R955, D6R9U1, X5D9A5

UniProt curated annotations — full annotation on UniProt →

Function. Sequence-specific transcription factor that binds gene promoters and activates their transcription. May play a role in the development of anterior structures, and in particular, the brain and facies and in specifying the identity or structure of hindlimb.

Subunit / interactions. Interacts with POU1F1.

Subcellular location. Nucleus.

Disease relevance. Clubfoot, congenital, with or without deficiency of long bones and/or mirror-image polydactyly (CCF) [MIM:119800] A congenital limb deformity defined as fixation of the foot in cavus, adductus, varus, and equinus (i.e., inclined inwards, axially rotated outwards, and pointing downwards) with concomitant soft tissue abnormalities. Clubfoot may occur in isolation or as part of a syndrome. Some patients present tibial hemimelia, bilateral patellar hypoplasia, and preaxial mirror-image polydactyly. The disease is caused by variants affecting the gene represented in this entry. Liebenberg syndrome (LBNBG) [MIM:186550] An upper limb-malformation syndrome characterized by the combination of dysplastic elbow joints and the fusion of wrist bones with consequent radial deviation. The gene represented in this entry is involved in disease pathogenesis. A chromosomal aberration involving the PITX1 locus results in LBNBG. Translocation t(5;18)(q31.1;q12.3). Additionally, two chromosome 5 deletions located 5’of PITX1 have been found in LBNBG patients. These structural variations cause altered expression of PITX1 in the forelimb via the activation of ectopic enhancers.

Similarity. Belongs to the paired homeobox family. Bicoid subfamily.

RefSeq proteins (1): NP_002644* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001356	HD	Domain
IPR003654	OAR_dom	Domain
IPR009057	Homeodomain-like_sf	Homologous_superfamily
IPR016233	Homeobox_Pitx/unc30	Family
IPR017970	Homeobox_CS	Conserved_site

Pfam: PF00046, PF03826

UniProt features (15 total): modified residue 3, compositionally biased region 3, sequence variant 2, region of interest 2, short sequence motif 2, chain 1, DNA-binding region 1, sequence conflict 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P78337-F1	62.81	0.20

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): 46, 48, 1

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 266 (showing top): BUYTAERT_PHOTODYNAMIC_THERAPY_STRESS_DN, GOBP_MUSCLE_TISSUE_DEVELOPMENT, BENPORATH_ES_WITH_H3K27ME3, GOBP_CARTILAGE_DEVELOPMENT, GOBP_SKELETAL_SYSTEM_DEVELOPMENT, GOBP_HINDLIMB_MORPHOGENESIS, BECKER_TAMOXIFEN_RESISTANCE_UP, GOBP_PITUITARY_GLAND_DEVELOPMENT, CHX10_01, GOBP_FOREBRAIN_DEVELOPMENT, GOBP_MUSCLE_STRUCTURE_DEVELOPMENT, FOSTER_TOLERANT_MACROPHAGE_DN, KOYAMA_SEMA3B_TARGETS_UP, GOBP_SKELETAL_MUSCLE_ORGAN_DEVELOPMENT, GOBP_APPENDAGE_DEVELOPMENT

GO Biological Process (12): skeletal system development (GO:0001501), regulation of transcription by RNA polymerase II (GO:0006357), anatomical structure morphogenesis (GO:0009653), branchiomeric skeletal muscle development (GO:0014707), pituitary gland development (GO:0021983), embryonic hindlimb morphogenesis (GO:0035116), negative regulation of DNA-templated transcription (GO:0045892), myoblast fate commitment (GO:0048625), cartilage development (GO:0051216), regulation of DNA-templated transcription (GO:0006355), hindlimb morphogenesis (GO:0035137), positive regulation of transcription by RNA polymerase II (GO:0045944)

GO Molecular Function (8): RNA polymerase II cis-regulatory region sequence-specific DNA binding (GO:0000978), DNA-binding transcription factor activity, RNA polymerase II-specific (GO:0000981), DNA-binding transcription activator activity, RNA polymerase II-specific (GO:0001228), DNA-binding transcription factor activity (GO:0003700), RNA polymerase II-specific DNA-binding transcription factor binding (GO:0061629), sequence-specific double-stranded DNA binding (GO:1990837), DNA binding (GO:0003677), protein binding (GO:0005515)

GO Cellular Component (4): chromatin (GO:0000785), nucleus (GO:0005634), transcription regulator complex (GO:0005667), cytoplasm (GO:0005737)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
regulation of DNA-templated transcription	3
RNA polymerase II transcription regulatory region sequence-specific DNA binding	3
transcription by RNA polymerase II	2
DNA-templated transcription	2
regulation of transcription by RNA polymerase II	2
cellular anatomical structure	2
system development	1
developmental process	1
anatomical structure development	1
muscle organ development	1
skeletal muscle tissue development	1
diencephalon development	1
endocrine system development	1
gland development	1
embryonic limb morphogenesis	1
hindlimb morphogenesis	1
negative regulation of RNA biosynthetic process	1
cell fate commitment	1
myoblast differentiation	1
skeletal system development	1
animal organ development	1
connective tissue development	1
regulation of gene expression	1
regulation of RNA biosynthetic process	1
limb morphogenesis	1
positive regulation of DNA-templated transcription	1
cis-regulatory region sequence-specific DNA binding	1
chromatin	1
DNA-binding transcription factor activity	1
DNA-binding transcription factor activity, RNA polymerase II-specific	1
DNA-binding transcription activator activity	1
positive regulation of transcription by RNA polymerase II	1
transcription cis-regulatory region binding	1
transcription regulator activity	1
DNA-binding transcription factor binding	1
double-stranded DNA binding	1
sequence-specific DNA binding	1
nucleic acid binding	1
binding	1
chromosome	1

Protein interactions and networks

STRING

1438 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
PITX1	TBX4	P57082	921
PITX1	TBX19	O60806	870
PITX1	TBX5	Q99593	810
PITX1	EGR1	P18146	794
PITX1	POU1F1	P28069	774
PITX1	FSHB	P01225	703
PITX1	NR5A1	Q13285	685
PITX1	LHX3	Q9UBR4	652
PITX1	MIPOL1	Q8TD10	651
PITX1	LHX4	Q969G2	624
PITX1	TBX3	O15119	589
PITX1	POMC	P01189	573
PITX1	ZCCHC10	Q8TBK6	570
PITX1	TBX6	O95947	569
PITX1	NEUROD1	Q13562	569

IntAct

304 interactions, top by confidence:

A	B	Type	Score
RBPMS	PITX1	psi-mi:“MI:0915”(physical association)	0.800
PITX1	RBPMS	psi-mi:“MI:0915”(physical association)	0.800
PITX1	RBPMS	psi-mi:“MI:0915”(physical association)	0.670
PITX1	IPO13	psi-mi:“MI:0915”(physical association)	0.670
PITX1	MAGED1	psi-mi:“MI:0915”(physical association)	0.670
PITX1	SPAG8	psi-mi:“MI:0915”(physical association)	0.670
PITX1	TRIM23	psi-mi:“MI:0915”(physical association)	0.670
PITX1	ZBTB32	psi-mi:“MI:0915”(physical association)	0.670
TRIM23	PITX1	psi-mi:“MI:0915”(physical association)	0.670
PITX1	DVL3	psi-mi:“MI:0915”(physical association)	0.670
IPO13	PITX1	psi-mi:“MI:0915”(physical association)	0.670
PITX1	MDFI	psi-mi:“MI:0915”(physical association)	0.560
PITX1	GOLGA2	psi-mi:“MI:0915”(physical association)	0.560
PITX1	PSMB11	psi-mi:“MI:0915”(physical association)	0.560
PITX1	PLEKHB2	psi-mi:“MI:0915”(physical association)	0.560
	PITX1	psi-mi:“MI:0915”(physical association)	0.560
KRT34	PITX1	psi-mi:“MI:0915”(physical association)	0.560
PITX1	PRR20D	psi-mi:“MI:0915”(physical association)	0.560
PITX1	TRAF1	psi-mi:“MI:0915”(physical association)	0.560

BioGRID (142): RBPMS (Two-hybrid), PITX1 (Affinity Capture-Western), TRAPPC2 (Two-hybrid), RBPMS (Two-hybrid), RHOXF2 (Two-hybrid), PITX1 (Two-hybrid), PITX1 (Proximity Label-MS), PITX1 (Affinity Capture-MS), GOLGA2 (Two-hybrid), RBPMS (Two-hybrid), FOXO1 (Reconstituted Complex), PITX1 (Affinity Capture-MS), PITX1 (Affinity Capture-MS), PITX1 (Affinity Capture-MS), SOX2 (Affinity Capture-Western)

ESM2 similar proteins: A0A0G2JTZ2, A3RK74, A3RK75, A4L7N3, B3DM43, B3LYS5, B3P0K6, B4G4S8, B4HF64, B4KBF6, B4MB78, B4PTD3, E1BPQ1, F1R8Z9, G3V7R4, O43524, O76971, O93385, P20009, P32315, P40645, P40647, P56673, P70314, P78337, P84961, Q12778, Q298W7, Q32NP8, Q66JJ0, Q68F77, Q6EUW1, Q6EUW2, Q6LD29, Q6SR68, Q6SR69, Q6SZ65, Q7T1R4, Q7YTC2, Q810W5

Diamond homologs: A1A546, A1YEY5, A1YFI3, A1YG57, A1YGA2, A2T733, A2T777, A2T7P4, A6NFQ7, A6NJG6, A6NJT0, A6NNA5, A6YP92, F1NEA7, G5EC89, O08934, O14813, O15266, O15499, O35085, O35160, O35690, O35750, O42115, O42250, O43186, O54751, O60902, O70137, O73592, O75364, O93385, O95076, O97670, P21711, P22810, P29454, P32242, P53544, P53545

SIGNOR signaling

8 interactions.

A	Effect	B	Mechanism
PTPN1	“down-regulates quantity by destabilization”	PITX1	dephosphorylation
ABL1	“up-regulates activity”	PITX1	phosphorylation
EGR1	“up-regulates activity”	PITX1	binding
PITX1	“up-regulates quantity by expression”	LHB	“transcriptional regulation”
PITX1	“down-regulates quantity by repression”	GNRH1	“transcriptional regulation”
DUX4	“up-regulates quantity by expression”	PITX1	“transcriptional regulation”
PITX1	“up-regulates activity”	POU1F1	binding

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 84 IntAct physical interaction partners (hypergeometric vs the genome-wide background, BH-FDR, gene-set size 15–500, ranked by fold). A functional readout of the neighbourhood — distinct from this gene’s own memberships above, and biased toward well-studied / hub proteins, so read it as themes rather than proof.

Reactome pathways:

Pathway	Partners	Fold	FDR
Keratinization	11	14.6×	2e-08

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	3
Likely pathogenic	6
Uncertain significance	68
Likely benign	15
Benign	15

Top pathogenic / likely-pathogenic (9)

Variant ID	HGVS	Classification
37253	NM_002653.5(PITX1):c.765_799del (p.Ala256fs)	Pathogenic
3767675	NM_002653.5(PITX1):c.186_187dup (p.Glu63fs)	Pathogenic
7505	NM_002653.5(PITX1):c.388G>A (p.Glu130Lys)	Pathogenic
1033526	NM_002653.5(PITX1):c.414G>T (p.Lys138Asn)	Likely pathogenic
2498978	NM_002653.5(PITX1):c.738del (p.Asn246fs)	Likely pathogenic
2499600	NM_002653.5(PITX1):c.292del (p.Ser98fs)	Likely pathogenic
390430	NM_002653.5(PITX1):c.170-2A>G	Likely pathogenic
4819354	NM_002653.5(PITX1):c.392dup (p.Arg132fs)	Likely pathogenic
933134	NM_002653.5(PITX1):c.412A>C (p.Lys138Gln)	Likely pathogenic

SpliceAI

385 predictions. Top by Δscore:

Variant	Effect	Δscore
5:135029317:CAGAC:C	acceptor_gain	1.0000
5:135029318:AGAC:A	acceptor_gain	1.0000
5:135029321:CCTGG:C	acceptor_loss	1.0000
5:135029322:C:CA	acceptor_loss	1.0000
5:135029322:C:CC	acceptor_gain	1.0000
5:135033707:GCTTA:G	donor_loss	1.0000
5:135033708:CTTA:C	donor_loss	1.0000
5:135033709:TTAC:T	donor_loss	1.0000
5:135033710:TA:T	donor_loss	1.0000
5:135029319:GAC:G	acceptor_gain	0.9900
5:135029320:AC:A	acceptor_gain	0.9900
5:135029320:ACCTG:A	acceptor_gain	0.9900
5:135029321:CC:C	acceptor_gain	0.9900
5:135029321:CCTG:C	acceptor_gain	0.9900
5:135029322:C:A	acceptor_gain	0.9900
5:135029322:C:T	acceptor_gain	0.9900
5:135033711:A:AC	donor_gain	0.9900
5:135033712:C:CC	donor_gain	0.9900
5:135033712:CCTGG:C	donor_gain	0.9900
5:135029319:GACC:G	acceptor_gain	0.9800
5:135029323:T:G	acceptor_gain	0.9800
5:135031270:GCTCA:G	donor_loss	0.9800
5:135031271:CT:C	donor_loss	0.9800
5:135031272:T:TA	donor_loss	0.9800
5:135031273:C:CC	donor_loss	0.9800
5:135031320:C:CA	donor_gain	0.9800
5:135029318:AGACC:A	acceptor_gain	0.9700
5:135031274:A:AC	donor_gain	0.9700
5:135031275:C:CC	donor_gain	0.9700
5:135031263:ACC:A	donor_gain	0.9600

AlphaMissense

2048 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
5:135029284:C:G	R147P	1.000
5:135029286:C:A	K146N	1.000
5:135029286:C:G	K146N	1.000
5:135029288:T:C	K146E	1.000
5:135029290:C:G	R145P	1.000
5:135029291:G:A	R145C	1.000
5:135029291:G:T	R145S	1.000
5:135029292:C:A	W144C	1.000
5:135029292:C:G	W144C	1.000
5:135029294:A:G	W144R	1.000
5:135029294:A:T	W144R	1.000
5:135029295:C:A	K143N	1.000
5:135029295:C:G	K143N	1.000
5:135029296:T:A	K143M	1.000
5:135029297:T:C	K143E	1.000
5:135029299:G:A	A142V	1.000
5:135029299:G:T	A142D	1.000
5:135029300:C:G	A142P	1.000
5:135029302:C:G	R141P	1.000
5:135029303:G:C	R141G	1.000
5:135029305:C:A	R140L	1.000
5:135029305:C:G	R140P	1.000
5:135029306:G:A	R140W	1.000
5:135029306:G:C	R140G	1.000
5:135029307:G:C	N139K	1.000
5:135029307:G:T	N139K	1.000
5:135029308:T:A	N139I	1.000
5:135029308:T:C	N139S	1.000
5:135029308:T:G	N139T	1.000
5:135029309:T:C	N139D	1.000

dbSNP variants (sampled 300 via entrez): RS1000504155 (5:135036265 G>A), RS1000797004 (5:135027272 G>C), RS1001043071 (5:135033030 A>G), RS1001761597 (5:135027543 C>T), RS1002077312 (5:135032383 C>A), RS1002130428 (5:135027316 A>C), RS1002241607 (5:135031723 A>T), RS1002506161 (5:135035356 T>C), RS1002723358 (5:135028328 C>A), RS1002757451 (5:135028461 C>T), RS1002807127 (5:135029690 A>G), RS1002958133 (5:135034810 A>G), RS1003053250 (5:135035480 G>A), RS1003242946 (5:135033003 C>A,G,T), RS1003295053 (5:135034575 C>A)

Disease associations

OMIM: gene MIM:602149 | disease phenotypes: MIM:119800, MIM:186550, MIM:192350, MIM:607014

GenCC curated gene-disease

Disease	Classification	Inheritance
clubfoot	Strong	Autosomal dominant
familial clubfoot due to PITX1 point mutation	Strong	Autosomal dominant
brachydactyly-elbow wrist dysplasia syndrome	Supportive	Autosomal dominant

Mondo (6): clubfoot (MONDO:0007342), brachydactyly-elbow wrist dysplasia syndrome (MONDO:0008520), VACTERL/vater association (MONDO:0008642), multiple congenital anomalies/dysmorphic syndrome (MONDO:0019042), Hurler syndrome (MONDO:0011758), familial clubfoot due to PITX1 point mutation (MONDO:0017383)

Orphanet (5): Familial clubfoot with or without associated lower limb anomalies (Orphanet:199315), Brachydactyly-elbow wrist dysplasia syndrome (Orphanet:1275), VACTERL/VATER association (Orphanet:887), Multiple congenital anomalies/dysmorphic syndrome (Orphanet:68341), Hurler syndrome (Orphanet:93473)

HPO phenotypes

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

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000256	Macrocephaly
HP:0000316	Hypertelorism
HP:0000369	Low-set ears
HP:0000494	Downslanted palpebral fissures
HP:0001156	Brachydactyly
HP:0001231	Abnormal fingernail morphology
HP:0001387	Joint stiffness
HP:0001762	Talipes equinovarus
HP:0001776	Bilateral talipes equinovarus
HP:0001841	Preaxial foot polydactyly
HP:0002079	Hypoplasia of the corpus callosum
HP:0002280	Enlarged cisterna magna
HP:0003042	Elbow dislocation
HP:0003065	Patellar hypoplasia
HP:0003577	Congenital onset
HP:0003826	Stillbirth
HP:0003829	Typified by incomplete penetrance
HP:0004209	Clinodactyly of the 5th finger
HP:0004322	Short stature
HP:0005048	Synostosis of carpal bones
HP:0005280	Depressed nasal bridge
HP:0006501	Aplasia/Hypoplasia of the radius
HP:0009099	Median cleft palate
HP:0009556	Absent tibia
HP:0009756	Popliteal pterygium
HP:0009832	Abnormal distal phalanx morphology of finger
HP:0010691	Mirror image foot polydactyly
HP:0031095	Abnormal humerus morphology
HP:0040071	Abnormal morphology of ulna

GWAS associations

19 associations (top):

Study	Trait	p-value
GCST000175_35	Height	8.000000e-06
GCST000817_59	Height	2.000000e-13
GCST001547_2	Immune response to anthrax vaccine	4.000000e-06
GCST001792_5	Colorectal cancer	4.000000e-10
GCST001792_7	Colorectal cancer	1.000000e-10
GCST001956_80	Height	9.000000e-10
GCST001958_2	Bulimia nervosa	3.000000e-06
GCST002022_4	Testicular germ cell tumor	2.000000e-08
GCST002454_13	Colorectal cancer	2.000000e-14
GCST002702_84	Height	5.000000e-07
GCST004713_21	Testicular germ cell tumor	9.000000e-06
GCST007552_6	Colorectal cancer	3.000000e-15
GCST007856_79	Colorectal cancer or advanced adenoma	5.000000e-15
GCST008486_1	Atrial fibrillation	2.000000e-08
GCST008839_492	Height	8.000000e-18
GCST012227_189	Hip circumference adjusted for BMI	2.000000e-14
GCST012227_190	Hip circumference adjusted for BMI	2.000000e-14
GCST90000025_13	Appendicular lean mass	9.000000e-43
GCST90093090_4	DHEAS levels	2.000000e-06

EFO canonical traits (4, from GWAS)

EFO ID	Trait name
EFO:0004645	response to vaccine
EFO:0008039	BMI-adjusted hip circumference
EFO:0004980	appendicular lean mass
EFO:0007001	dehydroepiandrosterone sulphate measurement

MeSH disease descriptors (2)

Descriptor	Name	Tree numbers
D003025	Clubfoot	C05.330.488.655.063; C05.330.495.681.063; C05.660.585.512.380.813.063; C16.131.621.585.512.500.681.063
C566090	Synostosis, Carpal, with Dysplastic Elbow Joints and Brachydactyly (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Estradiol	affects expression, affects binding, increases expression	4
sodium arsenite	affects expression, decreases expression, increases abundance	3
arsenite	decreases expression, increases abundance, increases methylation	2
TAK-243	increases sumoylation	1
methylmercuric chloride	decreases expression	1
bisphenol A	increases expression	1
sulforaphane	decreases expression	1
antimonite	decreases expression, increases abundance	1
K 7174	decreases expression	1
ICG 001	increases expression	1
jinfukang	affects cotreatment, decreases expression	1
Temozolomide	increases expression	1
Air Pollutants	decreases expression, increases abundance	1
Antimony Potassium Tartrate	decreases expression, increases abundance	1
Aspirin	increases expression	1
Benzo(a)pyrene	increases methylation	1
Cisplatin	affects cotreatment, decreases expression	1
Cytarabine	decreases expression	1
Doxorubicin	increases expression	1
Malathion	decreases expression	1
Phthalic Acids	increases methylation	1
Selenium	increases expression, affects cotreatment	1
Smoke	decreases expression	1
Tobacco Smoke Pollution	increases expression	1
Tretinoin	decreases expression	1
Triclosan	increases expression	1
Valproic Acid	increases methylation	1
Vitamin E	affects cotreatment, increases expression	1
Aflatoxin B1	decreases methylation	1
Antirheumatic Agents	increases expression	1

Cellosaurus cell lines

4 cell lines: 3 embryonic stem cell, 1 induced pluripotent stem cell

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

Cellosaurus	Name	Category	Sex
CVCL_A5I9	SEES3-1V human PITX1, clone1	Embryonic stem cell	Male
CVCL_A5J0	SEES3-1V human PITX1, clone2	Embryonic stem cell	Male
CVCL_A5J1	SEES3-1V human PITX1, clone3	Embryonic stem cell	Male
CVCL_C0JK	SMBCi018-A	Induced pluripotent stem cell	Male

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT04564430	PHASE4	UNKNOWN	Clonidine for Tourniquet-related Pain in Children
NCT04766684	PHASE4	COMPLETED	Clubfoot Tenotomy Trial
NCT00258011	PHASE3	COMPLETED	Study of Aldurazyme® Replacement Therapy in Patients With Mucopolysaccharidosis I (MPS I) Disease
NCT00146757	PHASE2	COMPLETED	A Study Evaluating the Safety and Pharmacokinetics of Aldurazyme® (Laronidase) in MPS I Patients Less Than 5 Years Old
NCT00176891	PHASE2	COMPLETED	Stem Cell Transplant w/Laronidase for Hurler
NCT01043640	PHASE2	COMPLETED	Allogeneic Bone Marrow Transplant for Inherited Metabolic Disorders
NCT02171104	PHASE2	ACTIVE_NOT_RECRUITING	MT2013-31: Allo HCT for Metabolic Disorders and Severe Osteopetrosis
NCT00638547	PHASE1	COMPLETED	Intrathecal Enzyme Replacement for Hurler Syndrome
NCT01173016	PHASE1	COMPLETED	Administration of IV Laronidase Post Bone Marrow Transplant in Hurler
NCT01917708	PHASE1	COMPLETED	Bone Marrow Transplant With Abatacept for Non-Malignant Diseases
NCT02815215	EARLY_PHASE1	UNKNOWN	Efficacy Analysis of Minimally Invasive Carroll’s Technique in Treatment of Congenital Idiopathic Clubfoot
NCT00175708	Not specified	COMPLETED	Pedobarographic Assessments of Clubfoot Treated Patients
NCT00474032	Not specified	UNKNOWN	Using Botox to Treat Patients With Idiopathic Clubfoot
NCT00474344	Not specified	COMPLETED	Genetic Linkage Study of Idiopathic Talipes Equinovarus (ITEV) (Clubfoot)
NCT00475631	Not specified	WITHDRAWN	Economic Evaluation of Clubfoot Treatment: One Centre’s Experience
NCT00607191	Not specified	COMPLETED	Clubfoot DNA Repository
NCT01050088	Not specified	UNKNOWN	Sucrose Analgesia in Infants Undergoing Casting for Club Foot
NCT01067651	Not specified	COMPLETED	Comparison of Casting Materials for the Treatment of Clubfoot Using the Ponseti Method
NCT01088828	Not specified	COMPLETED	Exploring the Causes of Clubfoot Using Magnetic Resonance Imaging, MRI
NCT01481324	Not specified	COMPLETED	Outcomes of Compliance With Brace Wear in Clubfoot
NCT02022267	Not specified	COMPLETED	Gait Analysis in Ponseti Clubfoot
NCT02395185	Not specified	COMPLETED	A Randomized Controlled Trial of Three Non-pharmacologic Analgesic Techniques for Casting of Clubfoot Infants
NCT02815306	Not specified	COMPLETED	Polyaxial Brace Fixing for the Treatment of Congenital Clubfoot
NCT03249805	Not specified	UNKNOWN	MiracleFeet Foot Abduction Brace Sensor Trial
NCT03580746	Not specified	WITHDRAWN	Comparison of Ponseti Method Versus Older Treatments in Talipes Equinovarus Through Gait Analysis and Clinical Results
NCT03671863	Not specified	COMPLETED	Children Born With Club Feet
NCT03749265	Not specified	UNKNOWN	Rate Of Residual Clubfoot Deformity With Correlation To Absence Of Peroneus Tertius Muscle
NCT03853811	Not specified	TERMINATED	Customized Orthosis for Children With Clubfoot
NCT03953430	Not specified	COMPLETED	Gait Analysis in Children With Clubfoot Treated With Tibialis Anterior Tendon Transfer
NCT04212663	Not specified	UNKNOWN	A Study on the Treatment of Recurrent Clubfoot With the Tendon Release of Musculi Tibialis Posterior
NCT04693065	Not specified	UNKNOWN	Pronostic Factors of Long Term Outcome in Patients With Clubfoot Treated by the Ponseti Method
NCT04737083	Not specified	UNKNOWN	CGH Array in Bilateral Clubfoot
NCT04897100	Not specified	COMPLETED	Outcome After Needle vs Blade Achilles Tenotomy in Clubfoot
NCT05293743	Not specified	COMPLETED	Novel Dynamic Foot Abduction Bar for Treatment of Clubfoot
NCT05456737	Not specified	COMPLETED	Functional Assessment in Children With Clubfoot
NCT05767762	Not specified	RECRUITING	Evertor Muscle Activity as a Predictor of Achilles Tenotomy in the Management of Idiopathic Varus Equinus Clubfoot
NCT05794334	Not specified	COMPLETED	Low Dye Taping Technique Versus Robert Debre Method On Foot Posture And Range Of Motion In Children With Club Foot.
NCT05913934	Not specified	UNKNOWN	Clubfeet and Twins and Gait Analysis
NCT05957627	Not specified	UNKNOWN	Management of Congenital Talipes Equinovarus by Saleem’s Protocol
NCT06033638	Not specified	COMPLETED	Video Documented PBS-Score in Children With Clubfoot