PITX3

Summary

PITX3 (paired like homeodomain 3, HGNC:9006) is a protein-coding gene on chromosome 10q24.32, encoding Pituitary homeobox 3 (O75364). Transcriptional regulator which is important for the differentiation and maintenance of meso-diencephalic dopaminergic (mdDA) neurons during development.

This gene encodes a member of the RIEG/PITX homeobox family, which is in the bicoid class of homeodomain proteins. Members of this family act as transcription factors. This protein is involved in lens formation during eye development. Mutations of this gene have been associated with anterior segment mesenchymal dysgenesis and congenital cataracts.

Source: NCBI Gene 5309 — RefSeq curated summary.

At a glance

• Gene–disease (curated): anterior segment dysgenesis 1 (Definitive, GenCC) — +4 more curated relationships
• GWAS associations: 10
• Clinical variants (ClinVar): 3 total — 1 pathogenic
• Phenotypes (HPO): 17
• Dosage sensitivity (ClinGen): haploinsufficiency no evidence, triplosensitivity no evidence
• Transcription factor: yes — 24 downstream targets (CollecTRI)
• MANE Select transcript: NM_005029

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:9006
Approved symbol	PITX3
Name	paired like homeodomain 3
Location	10q24.32
Locus type	gene with protein product
Status	Approved
Ensembl gene	ENSG00000107859
Ensembl biotype	protein_coding
OMIM	602669
Entrez	5309

Gene structure

Transcript identifiers

Ensembl transcripts: 1 — 1 protein_coding

ENST00000370002

RefSeq mRNA: 1 — MANE Select: NM_005029 NM_005029

CCDS: CCDS7532

Canonical transcript exons

ENST00000370002 — 4 exons

Exon	Start	End
ENSE00000722566	102231588	102231790
ENSE00001026454	102241333	102241512
ENSE00001451450	102230189	102231101
ENSE00001451451	102231963	102232092

Expression profiles

Bgee: expression breadth broad, 64 present calls, max score 86.42.

FANTOM5 (CAGE): breadth tissue_specific, TPM avg 0.3208 / max 45.6743, expressed in 110 samples.

FANTOM5 promoters (2 alternative TSS)

Promoter ID	TPM avg	Samples expressed
111143	0.2304	81
111144	0.0904	37

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
hindlimb stylopod muscle	UBERON:0004252	86.42	gold quality
triceps brachii	UBERON:0001509	86.29	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	85.61	gold quality
gastrocnemius	UBERON:0001388	81.98	gold quality
gluteal muscle	UBERON:0002000	81.33	gold quality
muscle of leg	UBERON:0001383	80.15	gold quality
muscle organ	UBERON:0001630	79.17	gold quality
skeletal muscle tissue	UBERON:0001134	75.21	gold quality
skeletal muscle tissue of biceps brachii	UBERON:0004502	74.86	gold quality
skeletal muscle tissue of rectus abdominis	UBERON:0004511	74.77	gold quality
heart right ventricle	UBERON:0002080	73.54	gold quality
type B pancreatic cell	CL:0000169	73.50	gold quality
cervix squamous epithelium	UBERON:0006922	72.96	gold quality
olfactory bulb	UBERON:0002264	72.51	gold quality
vena cava	UBERON:0004087	71.94	gold quality
dorsal motor nucleus of vagus nerve	UBERON:0002870	71.82	gold quality
tongue squamous epithelium	UBERON:0006919	71.74	gold quality
inferior olivary complex	UBERON:0002127	70.92	gold quality
muscle tissue	UBERON:0002385	70.06	gold quality
parotid gland	UBERON:0001831	69.73	gold quality
orbitofrontal cortex	UBERON:0004167	69.36	gold quality
lateral globus pallidus	UBERON:0002476	69.12	gold quality
secondary oocyte	CL:0000655	68.31	gold quality
substantia nigra pars compacta	UBERON:0001965	67.39	silver quality
cervix epithelium	UBERON:0004801	67.09	gold quality
nasal cavity epithelium	UBERON:0005384	66.95	gold quality
epithelial cell of pancreas	CL:0000083	66.89	gold quality
substantia nigra pars reticulata	UBERON:0001966	66.87	gold quality
diaphragm	UBERON:0001103	66.77	gold quality
saphenous vein	UBERON:0007318	66.75	gold quality

Single-cell (SCXA)

Detected in 1 experiment(s), a significant marker in 0.

Experiment	Marker?	Max mean expression
E-ANND-3	no	0.48

Regulation

Is transcription factor: yes

Downstream targets (CollecTRI)

24 targets.

Target	Regulation
ALDH1A1	Activation
ALDH2
BDNF	Activation
C1QA
CCK
DLK1
F3	Unknown
GDNF	Activation
IL1B
KLHL1	Unknown
MIP	Activation
MPO
NES	Repression
PITX3
PTPRU	Unknown
PTX3
SLC18A2	Activation
SLC6A3	Activation
SOX2	Repression
TH	Activation
TNF
TNFAIP3
TNFAIP6
TNPO1

JASPAR motifs

Motif	Name	Family
MA0714.1	PITX3	Paired-related HD factors
MA0714.2	PITX3	Paired-related HD factors

JASPAR matrix evidence (PMIDs): PMID:18585360

Upstream regulators (CollecTRI, top): FOXP1, LMX1A, LMX1B, NR4A2, PITX3, WNT1

miRNA regulators (miRDB)

18 targeting PITX3, 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-5696	99.98	72.36	4487
HSA-MIR-6783-3P	99.89	67.92	2059
HSA-MIR-1343-3P	99.89	66.78	1815
HSA-MIR-4728-5P	99.85	69.39	4718
HSA-MIR-6785-5P	99.82	68.68	4428
HSA-MIR-6764-5P	99.75	67.89	2304
HSA-MIR-4729	99.69	72.18	4233
HSA-MIR-4516	99.61	67.78	3390
HSA-MIR-1915-3P	99.58	66.79	1988
HSA-MIR-510-3P	99.54	70.06	2965
HSA-MIR-7974	99.24	65.48	1137
HSA-MIR-4434	99.10	67.01	1984
HSA-MIR-5703	99.10	67.09	2053
HSA-MIR-4676-5P	97.54	65.29	715
HSA-MIR-575	97.54	65.18	718
HSA-MIR-5588-3P	94.96	65.59	500
HSA-MIR-6889-5P	90.26	64.13	291
HSA-MIR-542-5P	87.47	60.42	76

Functional genomics

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

Literature-anchored findings (GeneRIF, showing 40)

• A family with posterior polar cataract with a novel deletion mutation in PITX3. (PMID:15286169)
• we mapped dominant congenital posterior polar cataracts to chromosome 10q24. On sequencing the coding region of PITX3, we found a 17-base-pair duplication in exon 4. (PMID:16272057)
• Nurr1 and Pitx3 cooperatively promote terminal maturation to the midbrain dopamine neuron phenotype in murine and human ES cell cultures. (PMID:16477036)
• This is the first report of homozygous PITX3 mutations in humans. The phenotype in these individuals highlights the role of PITX3 in ocular and central nervous system (CNS) development. (PMID:16565358)
• The 657ins17bp duplication of the PITX3 gene is the cause of the cataract phenotype in the large pedigree. (PMID:16636655)
• we discuss the role of Pitx3 in molecular mechanisms involved in the regional specification, neuronal specification and differentiation of mDA neurons–REVIEW (PMID:17017509)
• The G219fs mutation was found in multiple families affected with congenital cataracts along with anterior segment malformations. The S13N mutant showed only minor alteration and may represent a rare polymorphism in the PITX3 gene. (PMID:17888164)
• We provide evidence for a novel, strong and reproducible association of the PITX3 promoter SNP rs3758549: C>T (p=0.004) with Parkinson Disease. (PMID:17905480)
• The A-allele of a HapMap tagging SNP (rs4919621) that was genotyped in a population of Parkinson’s disease (PD) patients, was significantly more common in PD patients with an early age of onset. (PMID:18420308)
• Duplication of a segment of PITX3 can result in severe symptoms leading to functional blindness while in other individuals in the same family or in other families, the same duplication leads to treatable cataract with minimal visual impairment. (PMID:18989383)
• The result of this study found a strong association between the PITX3 promoter rs3758549 polymorphism and Parkinson’s disease. (PMID:19345444)
• PITX3 may play a role in the pathogenesis of Parkinson disease. (PMID:19394114)
• The absence of PITX3 mutations in a family presenting congenital cataract and mental retardation, is reported. (PMID:20376326)
• Genetic variation in PITX3 may increase the risk of developing schizophrenia. (PMID:20570600)
• The single nucleotide polymorphism rs3758549 (C >T substitution) in the Pitx3 gene is a potential risk for sporadic Parkinson disease (PD), especially early-onset PD in Chinese Han population. (PMID:21138504)
• This study found that rs2281983 and rs4919621 appeared to confer susceptibility to Parkinson’s disease, especially in early-onset Parkinson’s disease and familial Parkinson’s disease. (PMID:21469209)
• This study suggested that the PITX3 gene rs3758549 polymorphism may increase the susceptibility of Parkinson’s disease in chinese. (PMID:21524731)
• Allele & genotype frequencies did not differ between patients & controls for rs2281983, rs4919621, & rs3758549. These SNP sites do not contribute to the risk of developing PD in late-onset sporadic PD in this Chinese population. (PMID:21565251)
• The 542delC is a novel mutation in PITX3 causing an isolated posterior polar cataract. (PMID:21633712)
• Data show that BFSP2 and PITX3, hitherto known to cause eye defects only in a dominant fashion, can also present recessively. (PMID:21836522)
• The results of this study suggested that these PITX3 SNPs do not contribute to the risk of developing PD in EOPD or LOPD in Chinese. (PMID:22037506)
• we report the absence of mutations in all studied genes in four families with phenotypes associating cataract, mental retardation and microcephaly. (PMID:22103961)
• Deletion of PITX3 is associated with aggressive neurobehavioral phenotype in Smith-Magenis Syndrome. (PMID:22223473)
• This study provided that NURR1 and PITX3 gene expression is decreased in the peripheral blood lymphocytes of Chinese patients with Parkinson’s disease patients. (PMID:22309633)
• novel synonymous SNP in PITX3 gene may contribute to PD risk in the Chinese population. (PMID:22411443)
• Presence of the rs4919621 allele A in PITX3 significantly increases the risk of Parkinson’s disease (PD) patients in a Caucasian population, while rs2281983 allele C and rs4919621 allele A were both risk factors in early onset PD. (PMID:22429667)
• Mutations in PITX3 are not a common cause or a risk factor for multisystem atrophy and progressive supranuclear palsy in the Polish population. (PMID:23694789)
• our data demonstrate that key midbrain dopamine regulators (Nurr1, Pitx3, and Lmx1a) play overlapping as well as distinct roles during neurogenesis and neurotransmitter phenotype determination of mDA neurons (PMID:24172139)
• the SNP rs3758549 might contribute to the occurrence of Parkinson disease (PD) in the Asian population, especially early onset PD in the Asian population. (PMID:24394914)
• Meta-analysis suggests that rs3758549, rs2281983, and rs4919621 single nucleotide polymorphisms are not major determinants of the risk for Parkinson’s disease (PMID:24525476)
• novel PITX3 mutation c.573del, p.(Ser192Alafs*117), was identified in heterozygous state in a Belgo-Romanian family with a similar phenotype (PMID:24555714)
• PITX3 variants rs3758549 and rs4919621 are not associated with ET in Chinese Han population. (PMID:27145793)
• Study showed that PITX3 and PITX2 were hypermethylated in prostate carcinomas (PCa) and significantly associated with established clinicopathologic parameters characteristic of PCa. (PMID:27708722)
• Study showed that PITX3 methylation was significantly methylated in head and neck squamous cell carcinoma (HNSCC) tumor compared to normal adjacent tissue and correlated with lymph node status. These results provide evidence that PITX3 DNA methylation is an independent prognostic biomarker for overall survival in patients with HNSCC and might aid in the process of risk stratification for individualized treatment. (PMID:28174607)
• These findings suggest that p.A203fs in PITX3 is the cause of cataracts in the recruited family. (PMID:28249924)
• Results show that a common polymorphism in the PITX3 gene affects the risk of developing Parkinson’s disease (PD) dementia and visuospatial dysfunction in idiopathic PD. If validated, these findings can provide new insights into the neurobiology and genetics of non-motor symptoms in PD. (PMID:28991698)
• Heterozygous mutation in the PITX3 gene is associated with ocular developmental defects. (PMID:29405783)
• The functional analysis of these 2 PITX3 mutations in the in vitro functional studies is an important complement and extension, which provides a potential interpretation for the pathogenesis and molecular mechanism of PITX3 mutations associated with CC. (PMID:30816539)
• The mutation c.797_814del, p.Ser266_Ala271del is a novel mutation in the conserved DNA-binding OAR domain of PITX3 that causes congenital cataract. (PMID:30894134)
• Complementation of dopaminergic signaling by Pitx3-GDNF synergy induces dopamine secretion by multipotent Ntera2 cells. (PMID:31310388)

Cross-species orthologs

2 orthologs

Organism	Symbol	Gene ID
mus_musculus	Pitx3	ENSMUSG00000025229
rattus_norvegicus	Pitx3	ENSRNOG00000019194

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), 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 3 — O75364 (reviewed: O75364)

Alternative names: Homeobox protein PITX3, Paired-like homeodomain transcription factor 3

All UniProt accessions (1): O75364

UniProt curated annotations — full annotation on UniProt →

Function. Transcriptional regulator which is important for the differentiation and maintenance of meso-diencephalic dopaminergic (mdDA) neurons during development. In addition to its importance during development, it also has roles in the long-term survival and maintenance of the mdDA neurons. Activates NR4A2/NURR1-mediated transcription of genes such as SLC6A3, SLC18A2, TH and DRD2 which are essential for development of mdDA neurons. Acts by decreasing the interaction of NR4A2/NURR1 with the corepressor NCOR2/SMRT which acts through histone deacetylases (HDACs) to keep promoters of NR4A2/NURR1 target genes in a repressed deacetylated state. Essential for the normal lens development and differentiation. Plays a critical role in the maintenance of mitotic activity of lens epithelial cells, fiber cell differentiation and in the control of the temporal and spatial activation of fiber cell-specific crystallins. Positively regulates FOXE3 expression and negatively regulates PROX1 in the anterior lens epithelium, preventing activation of CDKN1B/P27Kip1 and CDKN1C/P57Kip2 and thus maintains lens epithelial cells in cell cycle.

Subunit / interactions. Interacts with SFPQ.

Subcellular location. Nucleus.

Tissue specificity. Highly expressed in developing eye lens.

Disease relevance. Anterior segment dysgenesis 1 (ASGD1) [MIM:107250] A form of anterior segment dysgenesis, a group of defects affecting anterior structures of the eye including cornea, iris, lens, trabecular meshwork, and Schlemm canal. Anterior segment dysgeneses result from abnormal migration or differentiation of the neural crest derived mesenchymal cells that give rise to components of the anterior chamber during eye development. Different anterior segment anomalies may exist alone or in combination, including iris hypoplasia, enlarged or reduced corneal diameter, corneal vascularization and opacity, posterior embryotoxon, corectopia, polycoria, abnormal iridocorneal angle, ectopia lentis, and anterior synechiae between the iris and posterior corneal surface. Clinical conditions falling within the phenotypic spectrum of anterior segment dysgeneses include aniridia, Axenfeld anomaly, Reiger anomaly/syndrome, Peters anomaly, and iridogoniodysgenesis. The disease is caused by variants affecting the gene represented in this entry. Cataract 11, multiple types (CTRCT11) [MIM:610623] An opacification of the crystalline lens of the eye that frequently results in visual impairment or blindness. Opacities vary in morphology, are often confined to a portion of the lens, and may be static or progressive. CTRCT11 includes posterior polar cataract, among others. Posterior polar cataract is a subcapsular opacity, usually disk-shaped, located at the back of the lens. Some CTRCT11 patients can present a severe phenotype including microphthalmia and neurological dysfunction. The disease is caused by variants affecting the gene represented in this entry.

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

RefSeq proteins (1): NP_005020* (*=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 (9 total): short sequence motif 2, modified residue 2, chain 1, DNA-binding region 1, region of interest 1, compositionally biased region 1, sequence variant 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-O75364-F1	63.71	0.22

Functional residue map

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

Post-translational modifications (2): 52, 57

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 169 (showing top): GGGACCA_MIR133A_MIR133B, GOBP_RESPONSE_TO_NITROGEN_COMPOUND, GOBP_LENS_FIBER_CELL_DIFFERENTIATION, GOBP_EPITHELIUM_DEVELOPMENT, GOBP_NEGATIVE_REGULATION_OF_CELL_DEVELOPMENT, BENPORATH_ES_WITH_H3K27ME3, GOBP_BEHAVIOR, GOBP_RESPONSE_TO_COCAINE, GOBP_RESPONSE_TO_AMINE, GOBP_RESPONSE_TO_IMMOBILIZATION_STRESS, XU_GH1_AUTOCRINE_TARGETS_UP, GOBP_NEGATIVE_REGULATION_OF_GLIOGENESIS, AP4_Q6, GOBP_NEUROGENESIS, GOBP_REGULATION_OF_NERVOUS_SYSTEM_DEVELOPMENT

GO Biological Process (22): lens development in camera-type eye (GO:0002088), lens morphogenesis in camera-type eye (GO:0002089), regulation of DNA-templated transcription (GO:0006355), regulation of transcription by RNA polymerase II (GO:0006357), locomotory behavior (GO:0007626), anatomical structure morphogenesis (GO:0009653), animal organ morphogenesis (GO:0009887), negative regulation of gliogenesis (GO:0014014), midbrain development (GO:0030901), response to immobilization stress (GO:0035902), response to cocaine (GO:0042220), positive regulation of neuron apoptotic process (GO:0043525), positive regulation of DNA-templated transcription (GO:0045893), neuron development (GO:0048666), lens fiber cell differentiation (GO:0070306), dopaminergic neuron differentiation (GO:0071542), response to methamphetamine hydrochloride (GO:1904313), positive regulation of cell proliferation in midbrain (GO:1904935), cellular response to glial cell derived neurotrophic factor (GO:1990792), regulation of gene expression (GO:0010468), positive regulation of transcription by RNA polymerase II (GO:0045944), negative regulation of neurogenesis (GO:0050768)

GO Molecular Function (6): 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), sequence-specific double-stranded DNA binding (GO:1990837), DNA binding (GO:0003677), DNA-binding transcription factor activity (GO:0003700)

GO Cellular Component (2): chromatin (GO:0000785), nucleus (GO:0005634)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
anatomical structure development	3
regulation of DNA-templated transcription	3
RNA polymerase II transcription regulatory region sequence-specific DNA binding	3
lens development in camera-type eye	2
anatomical structure morphogenesis	2
DNA-templated transcription	2
neuron differentiation	2
camera-type eye development	1
camera-type eye morphogenesis	1
regulation of gene expression	1
regulation of RNA biosynthetic process	1
transcription by RNA polymerase II	1
behavior	1
developmental process	1
animal organ development	1
regulation of gliogenesis	1
gliogenesis	1
negative regulation of neurogenesis	1
brain development	1
response to stress	1
response to alkaloid	1
response to oxygen-containing compound	1
positive regulation of apoptotic process	1
regulation of neuron apoptotic process	1
neuron apoptotic process	1
positive regulation of RNA biosynthetic process	1
cell development	1
epithelial cell differentiation	1
response to amine	1
cell proliferation in midbrain	1
regulation of cell proliferation in midbrain	1
positive regulation of neural precursor cell proliferation	1
cellular response to growth factor stimulus	1
response to glial cell derived neurotrophic factor	1
gene expression	1
regulation of macromolecule biosynthetic process	1
cis-regulatory region sequence-specific DNA binding	1
chromatin	1
DNA-binding transcription factor activity	1
regulation of transcription by RNA polymerase II	1

Protein interactions and networks

STRING

1176 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
PITX3	NR4A2	P43354	965
PITX3	FOXE3	Q13461	934
PITX3	BFSP2	Q13515	878
PITX3	GJA8	P48165	855
PITX3	GJA3	Q9Y6H8	850
PITX3	CRYGD	P07320	846
PITX3	CRYBB2	P43320	826
PITX3	CRYGS	P22914	802
PITX3	TH	P07101	793
PITX3	CRYBB1	P53674	787
PITX3	SLC18A2	Q05940	699
PITX3	FOXA2	Q9Y261	688
PITX3	CRYAB	P02511	681
PITX3	MAF	O75444	680
PITX3	SLC6A3	Q01959	668

IntAct

1 interactions, top by confidence:

A	B	Type	Score
CCL11	PITX3	psi-mi:“MI:0915”(physical association)	0.370

BioGRID (9): PITX3 (Proximity Label-MS), PITX3 (Affinity Capture-MS), PITX3 (Affinity Capture-MS), PITX3 (Affinity Capture-RNA), SFPQ (Affinity Capture-MS), NONO (Affinity Capture-MS), SFPQ (Affinity Capture-Western), MTA1 (Co-localization), PARK7 (Co-localization)

ESM2 similar proteins: A1YEV8, A1YF08, A1YG25, A1YG85, A2RU54, A2T711, A2T756, A8MTQ0, O14813, O15522, O35160, O35602, O43763, O70218, O75364, P13297, P28360, P42580, P43687, P50223, P52945, P70118, P70354, P81062, Q06348, Q2VL79, Q2VL84, Q2VL85, Q2VL87, Q2VL88, Q61663, Q62066, Q62782, Q6XYB7, Q7YRX0, Q96IS3, Q99811, Q9DED6, Q9ER42, Q9GK08

Diamond homologs: A0A1W2PPF3, A1YEY5, A1YFI3, A1YG57, A2T733, A2T7P4, A6NLW8, A6NNA5, F1NEA7, G5EBU4, G5EDS1, O18381, O35137, O35160, O42250, O43186, O43316, O43812, O54751, O70137, O73917, O75360, O75364, O95076, P09088, P0CJ85, P0CJ86, P0CJ87, P0CJ88, P0CJ89, P0CJ90, P21711, P22810, P26367, P26630, P29454, P32242, P32243, P34764, P34765

SIGNOR signaling

2 interactions.

A	Effect	B	Mechanism
PITX3	“up-regulates activity”	MTA1	binding
FOXP1	“up-regulates quantity by expression”	PITX3	“transcriptional regulation”

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	1
Likely pathogenic	0
Uncertain significance	1
Likely benign	0
Benign	0

Top pathogenic / likely-pathogenic (1)

Variant ID	HGVS	Classification
6939	NM_005029.4(PITX3):c.650del (p.Gly217fs)	Pathogenic

SpliceAI

189 predictions. Top by Δscore:

Variant	Effect	Δscore
10:102231097:CACAC:C	acceptor_gain	1.0000
10:102231099:CAC:C	acceptor_gain	1.0000
10:102231100:ACCT:A	acceptor_loss	1.0000
10:102231101:CCTGC:C	acceptor_loss	1.0000
10:102231102:C:CA	acceptor_loss	1.0000
10:102231102:C:CC	acceptor_gain	0.9900
10:102231962:CCG:C	donor_gain	0.9900
10:102231109:C:CT	acceptor_gain	0.9800
10:102231581:AGCAT:A	donor_loss	0.9800
10:102231582:GCATA:G	donor_loss	0.9800
10:102231583:CATAC:C	donor_loss	0.9800
10:102231584:ATAC:A	donor_loss	0.9800
10:102231585:TA:T	donor_loss	0.9800
10:102231586:A:AC	donor_gain	0.9800
10:102231586:A:AT	donor_loss	0.9800
10:102231587:C:CC	donor_gain	0.9800
10:102231787:GAGTC:G	acceptor_gain	0.9800
10:102231791:C:CC	acceptor_gain	0.9800
10:102231961:A:AC	donor_gain	0.9800
10:102231962:C:CC	donor_gain	0.9800
10:102231098:ACAC:A	acceptor_gain	0.9700
10:102231099:CACC:C	acceptor_gain	0.9700
10:102231587:CCCG:C	donor_gain	0.9700
10:102231586:AC:A	donor_gain	0.9600
10:102231587:CC:C	donor_gain	0.9600
10:102231758:C:CT	acceptor_gain	0.9600
10:102231788:AGTC:A	acceptor_loss	0.9600
10:102231789:GTCT:G	acceptor_gain	0.9600
10:102231790:TCTG:T	acceptor_loss	0.9600
10:102231957:GCTT:G	donor_loss	0.9600

AlphaMissense

1914 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
10:102231066:C:A	K119N	1.000
10:102231066:C:G	K119N	1.000
10:102231070:C:G	R118P	1.000
10:102231074:A:G	W117R	1.000
10:102231074:A:T	W117R	1.000
10:102231075:T:A	K116N	1.000
10:102231075:T:G	K116N	1.000
10:102231076:T:A	K116I	1.000
10:102231077:T:C	K116E	1.000
10:102231079:G:T	A115D	1.000
10:102231080:C:G	A115P	1.000
10:102231082:C:T	R114H	1.000
10:102231083:G:A	R114C	1.000
10:102231083:G:C	R114G	1.000
10:102231083:G:T	R114S	1.000
10:102231085:C:A	R113L	1.000
10:102231085:C:G	R113P	1.000
10:102231086:G:A	R113W	1.000
10:102231086:G:C	R113G	1.000
10:102231087:G:C	N112K	1.000
10:102231087:G:T	N112K	1.000
10:102231088:T:A	N112I	1.000
10:102231088:T:C	N112S	1.000
10:102231088:T:G	N112T	1.000
10:102231089:T:C	N112D	1.000
10:102231089:T:G	N112H	1.000
10:102231090:C:A	K111N	1.000
10:102231090:C:G	K111N	1.000
10:102231092:T:C	K111E	1.000
10:102231093:G:C	F110L	1.000

dbSNP variants (sampled 300 via entrez): RS1000138388 (10:102233605 G>A,C), RS1000397125 (10:102239902 C>T), RS1000426784 (10:102233265 C>T), RS1000849495 (10:102238485 C>T), RS1000962056 (10:102238825 C>T), RS1001854410 (10:102237208 C>T), RS1002018732 (10:102230175 A>C), RS1002197584 (10:102243431 A>G), RS1002741938 (10:102241959 C>T), RS1002799418 (10:102242113 C>T), RS1002859513 (10:102235609 C>T), RS1002975447 (10:102235979 G>A), RS1004135953 (10:102230584 G>A,C), RS1004212468 (10:102240810 C>A,T), RS1004765852 (10:102242721 G>A)

Disease associations

OMIM: gene MIM:602669 | disease phenotypes: MIM:107250, MIM:610623

GenCC curated gene-disease

Disease	Classification	Inheritance
anterior segment dysgenesis 1	Definitive	Autosomal dominant
cataract 11 multiple types	Strong	Autosomal dominant
disorder of visual system	Strong	Autosomal dominant
cataract-glaucoma syndrome	Supportive	Autosomal dominant
early-onset posterior polar cataract	Supportive	Autosomal dominant

Mondo (5): anterior segment dysgenesis 1 (MONDO:0007138), cataract 11 multiple types (MONDO:0012527), cataract-glaucoma syndrome (MONDO:0015567), early-onset posterior polar cataract (MONDO:0020378), disorder of visual system (MONDO:0024458)

Orphanet (2): Early onset non-syndromic cataract (Orphanet:91492), Congenital cataract-anterior segment dysgenesis syndrome (Orphanet:162)

HPO phenotypes

17 total (17 of 17 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000007	Autosomal recessive inheritance
HP:0000482	Microcornea
HP:0000518	Cataract
HP:0000519	Developmental cataract
HP:0000568	Microphthalmia
HP:0000618	Blindness
HP:0000659	Peters anomaly
HP:0001115	Posterior polar cataract
HP:0001249	Intellectual disability
HP:0001276	Hypertonia
HP:0001315	Reduced tendon reflexes
HP:0002072	Chorea
HP:0003577	Congenital onset
HP:0007700	Ocular anterior segment dysgenesis
HP:0007759	Opacification of the corneal stroma
HP:0007906	Ocular hypertension

GWAS associations

10 associations (top):

Study	Trait	p-value
GCST005141_71	Cognitive ability (MTAG)	3.000000e-13
GCST005142_30	Cognitive ability	3.000000e-06
GCST005316_72	Intelligence (MTAG)	6.000000e-19
GCST005956_50	Waist-to-hip ratio adjusted for BMI	8.000000e-06
GCST005958_15	Waist-to-hip ratio adjusted for BMI (age >50)	4.000000e-06
GCST005962_36	Waist-to-hip ratio adjusted for BMI x sex x age interaction (4df test)	6.000000e-07
GCST006061_115	Atrial fibrillation	2.000000e-11
GCST006269_517	General cognitive ability	8.000000e-15
GCST009391_920	Metabolite levels	7.000000e-07
GCST010002_298	Refractive error	3.000000e-22

EFO canonical traits (6, from GWAS)

EFO ID	Trait name
EFO:0004337	intelligence
EFO:0004784	self reported educational attainment
EFO:0007788	BMI-adjusted waist-hip ratio
EFO:0008007	age at assessment
EFO:0008343	sex interaction measurement
EFO:0010443	triacylglycerol 58:9 measurement

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
C535344	Cataract, posterior polar, 4 (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

11 total (human), top 11 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
sulforaphane	increases methylation	1
S-(1,2-dichlorovinyl)cysteine	increases expression	1
Resveratrol	affects cotreatment, decreases expression	1
Benzo(a)pyrene	increases methylation	1
Cocaine	decreases expression	1
Diazinon	increases methylation	1
Dust	decreases expression	1
Plant Extracts	affects cotreatment, decreases expression	1
Rotenone	decreases expression	1
Triclosan	increases expression	1
Urethane	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_A5J5	SEES3-1V human PITX3, clone1	Embryonic stem cell	Male
CVCL_A5J6	SEES3-1V human PITX3, clone2	Embryonic stem cell	Male
CVCL_A5J7	SEES3-1V human PITX3, clone3	Embryonic stem cell	Male

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT05641103	Not specified	COMPLETED	PREDIGA 2: Spanish Acronym of Educational and Diagnostic Project for Gaucher and ASMD