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Symbol PITX2 contributors: shn/npt/pgu/shn - updated : 18-01-2017
HGNC name paired-like homeodomain 2
HGNC id 9005
Corresponding disease
IHG2 iridogoniodysgenesis, type 2
RGDC ring dermoid of the cornea
RIEG1 Axenfeld-Rieger syndrome 1
Location 4q25      Physical location : 111.538.581 - 111.558.508
Synonym name
  • paired-like homeodomain transcription factor 2
  • solurshin
  • RIEG bicoid-related homeobox transcription factor 1
  • pituitary homeobox 2
  • ALL1-responsive protein ARP1
  • Synonym symbol(s) ARP1, Brx1, IDG2, IGDS, IGDS2, IHG2, IRID2, MGC111022, MGC20144, Otlx2, PTX2, RGS, RIEG, RIEG1, RS
    TYPE functioning gene
    STRUCTURE 24.70 kb     5 Exon(s)
    10 Kb 5' upstream gene genomic sequence study
    regulatory sequence Binding site   enhancer
    text structure
  • the last exon is not coded
  • asymetric enhancer containing three FAST (FOXH) and one NKX2 sites
  • MAPPING cloned Y linked N status confirmed
    Map cen - D4S1571 - D4S2945 - PITX2 - D4S2940 - D4S406 - qter
    TRANSCRIPTS type messenger
    text four alternatively spliced isoforms (PMID: 11948188)
    identificationnb exonstypebpproduct
    ProteinkDaAAspecific expressionYearPubmed
    4 splicing 2122 30.34 271 - 2010 20457925
    also known as ARP1A or variant a
    5 splicing 2250 35.37 317 - 2010 20457925
  • also known as ARP1B or variant b
  • colocalized with FOXC1 within a common nuclear subcompartment
  • functioning as a negative regulator of FOXC1 transactivity
  • 3 splicing 2337 35.7 324 . left lateral plate mesoderm, in the postnatal left atrium and pulmonary vein . PITX2c is the dominant isoform in the developing and adult left atrium 2010 20457925
  • also known as ARP1C or variant c
  • transcript produced by an alternative splicing from a promoter located in intron 3
  • required for the development of the heart
  • Pitx2c isoform plays a critical role as a late effector in left/right asymmetry (LRA), a fundamental component of organ morphogenesis in vertebrates
  • only PITX2C can synergistically activate the NPPA promoter in the presence of NKX2-5
  • major downstream effector of the Nodal pathway
  • 4 - 1736 - 271 - 2010 20457925
    5 - 1874 - 317 - 2010 20457925
    7 - 3482 - 317 - 2010 20457925
       expressed in (based on citations)
    SystemOrgan level 1Organ level 2Organ level 3Organ level 4LevelPubmedSpeciesStageRna symbol
    Digestivemouthgingiva  moderately Homo sapiens
     mouthtooth    Homo sapiens
    Endocrineneuroendocrinepituitary  highly Homo sapiens
    Nervousbrain     Homo sapiensAdult
     brain     Homo sapiensFetal
    Visualeye   moderately Homo sapiens
    SystemTissueTissue level 1Tissue level 2LevelPubmedSpeciesStageRna symbol
    Muscular   moderately
    SystemCellPubmedSpeciesStageRna symbol
    Digestiveepithelial cell Homo sapiens
    Digestiveodontoblast Homo sapiens
    cell lineage
    cell lines
    at STAGE
    physiological period fetal, pregnancy
    Text Rathke pouch at an early stage of pituitary and dental development, vitelline vessels, mesenchyme of limb,
    trabecular meshwork
  • POU specific and POU homeo (helix-turn-helix) domains
  • four transcriptional domains with left and right compoments
  • C terminal OAR domain found in homeo domain proteins highly expressed in craniofacial tissues, and that can each independently interact with factors to regulate its transcriptional activity
  • mono polymer homomer , dimer
    interspecies ortholog to Pitx2, Rattus norvegicus
    ortholog to Pitx2, Mus musculus
    ortholog to pitx2, Danio rerio
    ortholog to PITX2, Pan troglodytes
    intraspecies homolog to PTX1
  • RIEG/PITX homeobox family
  • CATEGORY DNA associated , transcription factor
    SUBCELLULAR LOCALIZATION     intracellular
  • expressed in neural crest and the mesoderm-derived precursors of the periocular mesenchyme
  • co-localizes with PAWR in nucleus
  • basic FUNCTION
  • a critical role for pitx2 in left-right asymmetry and may function at an intermediate step in cardiac morphogenesis and embryonic rotation
  • a role in the terminal differentiation of somatotroph and lactotroph cell phenotypes
  • a transcriptional marker of tooth development
  • acts as a transcription factor and regulates procollagen lysyl hydroxylase gene expression
  • involved in the development of the eye, tooth and abdominal organs, and acts as a transcriptional regulator involved in basal and hormone-regulated activity of prolactin
  • plays an important role in development and maintenance of anterior structures
  • plays with EBAF, LEFTYB, NODAL a critical role in the intermediate steps controlling left-right asymetry, cardiac morphogenesis and embryonic rotation, in response to NODAL
  • RNA polymerase 2 transcription factor, involved in the regulation of heart development through the regulation of NPPA and PLOD1 gene expression and NKX2-5 transcriptional activity
  • plays an important role in corneal development
  • plays an essential role in neural crest in regulating an extrinsic factor(s) required for development of the optic nerve
  • controls the number of muscle precursors through TBX1 in the first branchial arch mesodermal core
  • acts as a transcriptional activator but can be repressed through its interaction with other transcription factors
  • required in neural crest for specification of corneal endothelium, corneal stroma and the sclera and or normal development of ocular blood vessels
  • plays a key role in pulmonary myocardium formation
  • also plays a central role in determining left/right asymmetry
  • plays an important role during cardiac asymmetric development
  • homeodomain transcription factor, functioning to regulate the early stages of smooth muscle cell differentiation
  • first demonstrated upstream activator of myogenesis in the extraocular muscles
  • regulates SLC13A3 transcription and modulates with SLC13A3 responses to oxidative stress in ocular cells (
  • LHX6 and the PITX2 homeodomain transcription factor have overlapping expression patterns during tooth and craniofacial development
  • is the first transcriptional marker of tooth development and is specifically expressed in the oral and dental epithelium
  • influences the expression of transcription factors and signaling molecules involved in the differentiation of the cushion mesenchyme during heart development
  • PITX2 and PITX3 are key regulators of the intracellular redox state preventing DNA damage as cells undergo differentiation
  • is essential for axis formation, and it acts as a direct regulator of GDF1 expression by binding to enhancers within neighbouring genes
  • dose-dependent relation between PITX2 expression and the expression of Atrial fibrillation (AF) susceptibility genes, calcium handling, and microRNAs and identify a complex regulatory network orchestrated by PITX2 with large impact on atrial arrhythmogenesis susceptibility
  • might play an important role in regulating gene expression and electrical function of the adult left atrium (LA)
  • CELLULAR PROCESS nucleotide, transcription, regulation
    signaling sensory transduction/vision
  • PITX2/Cyclin D pathway might be a prototypic module used to regulate cell-type-specific proliferation during embryogenesis
  • TGFB1-FGF9-PITX2 signaling cascade regulates cranial neural crest cell proliferation during palate formation
  • CITED2 plays a role in left–right patterning through the NODAL-PITX2C pathway
  • a component
  • bicoid and bicoid-like elements in the Dlx2 promoter (
  • RNA
    small molecule
  • POU domain class 1 transcription factor 1, Pit1 (
  • glial cells missing homolog 1, GCM1 (pmid/ 15385555)
  • beta-catenin, CTNNB1 and lymphoid enhancer factor, LEF-1 (
  • ANF (atrial natriuretic factor), prolactin promoters are targets of PITX2
  • TBX1
  • forkhead box C1, FOXC1
  • C-terminal leucine zipper domain of PRKC apoptosis WT1 regulator, PAWR (
  • binds and activates transcription of the MYF5 and MYOD1 promoters, indicating these genes are direct targets (
  • WDR5 (
  • interaction with SHROOM3 (SHROOM3 and CDH2 function cooperatively downstream of PITX2 to directly regulate cell shape changes necessary for early gut tube morphogenesis)
  • directly interacts with PITX2 to inhibit PITX2 transcriptional activities and activation of multiple promoters
  • PITX2 associates with PAXIP1-containing histone H3 lysine 4 methyltransferase complex
  • PITX2 is similarly reactivated in postnatal/adult heart at distinct heart failure (HF) phenotypes, suggesting that PITX2 is involved, directly or indirectly, in the regulation of MYF5 expression in cardiomyocytes
  • PITX2-mediated repression of DEPDC1B expression contributes to the regulation of multiple molecular pathways, such as Rho GTPase signaling
  • potent BARX1 functions in intestinal rotation and stomach myogenesis occur through ISL1, PITX1, SIX2 and PITX2, intermediary transcription factors
  • SOX2 and LEF1 interact with PITX2 to regulate incisor development and stem cell renewal
  • cell & other
  • induced by the Wnt/Dvl/beta-catenin pathway and is required for effective cell-type-specific proliferation by directly activating specific growth-regulating genes (
    corresponding disease(s) RIEG1 , IHG2 , RGDC
    Other morbid association(s)
    TypeGene ModificationChromosome rearrangementProtein expressionProtein Function
    duplication of PITX2 is causal of iris hypoplasia
    constitutional germinal mutation     loss of function
    with increased susceptibility to tetralogy of Fallot (TOF)
    constitutional germinal mutation      
    induces cerebral small-vessel disease
    constitutional germinal mutation     loss of function
    association between PITX2c loss-of-function mutations and the transposition of the great arteries and ventricular septal defect
  • to atrial arrhythmias (see ATFB5)
  • to atrial fibrillation (AF)
  • to tetralogy of Fallot (TOF)
  • Variant & Polymorphism other
  • has multiple targets that are relevant to the predisposition to atrial arrhythmia
  • enhancer regulating PITX2c expression, and activity of this enhancer is modulated by SNP rs2595104, which almost completely abolished binding of TFAP2A, leading to decreased PITX2c expression and potentially a higher risk of AF
  • Candidate gene
  • PITX2 methylation is useful as a biomarker of poor outcome of prostate cancer
  • Therapy target
    . PITX2 and ion channels regulating the resting membrane potential may provide novel targets for antiarrhythmic drug development and companion therapeutics in AF
  • Pitx2 gene-deleted mice display defective body-wall closure, right pulmonary isomerism, altered cardiac position, arrest in turning and a block in the determination and proliferation events of anterior pituitary gland and tooth organogenesis (
  • Pitx2-/- mice embryos had correctly oriented, but arrested, embryonic rotation and right pulmonary isomerism, defective development of the mandibular and maxillary facial prominences, regression of the stomodeum and arrested tooth development (
  • Complete Pitx2 loss of function in mice results in agenesis or severe disruption of periocular mesenchyme structures and extrinsic defects in early optic nerve development (
  • neural crest-specific Pitx2 knockout mice are viable and exhibit an optic nerve phenotype in which the eyes are progressively displaced towards the midline until they are directly attached to the ventral hypothalamus (
  • ablation of unilateral Pitx2 expression in mice impairs asymmetric remodelling of the branchial arch artery system, resulting in randomized laterality of the aortic arch
  • Pitx2c-deficient mice do not develop a pulmonary myocardial sleeve because they fail to form the initial pulmonary myocardial cells