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FLASH GENE
Symbol PITX2 contributors: shn/npt/pgu/shn - updated : 23-04-2012
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
    DNA
    TYPE functioning gene
    STRUCTURE 19.93 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
    Physical map
    LOC389215 4 LOC389215 LOC339979 4q25 similar to ligand-gated ion channel subunit LOC391681 4 similar to rexo70 FLJ37673 4q25 hypothetical protein FLJ37673 RPL34 4q24 ribosomal protein L34 DC2 4q25 DC2 protein AGXT2L1 4q25 alanine-glyoxylate aminotransferase 2-like 1 LOC391682 4 similar to RCC1-like COL25A1 4q25 collagen, type XXV, alpha 1 LOC389216 4 similar to heterogeneous nuclear ribonucleoprotein G - human SEC24B 4q24 SEC24 related gene family, member B (S. cerevisiae) LOC389217 4 similar to template acyivating factor-I alpha FLJ20647 4q25 hypothetical protein FLJ20647 CASP6 4q25 caspase 6, apoptosis-related cysteine protease PLA2G12 4q25 phospholipase A2, group XII IF 4q25 I factor (complement) NOLA1 4q28-q31.1 nucleolar protein family A, member 1 (H/ACA small nucleolar RNPs) RRH 4q retinal pigment epithelium-derived rhodopsin homolog FLJ44691 4q25 FLJ44691 protein LOC391683 4 similar to keratin 19; keratin, type I cytoskeletal 19; keratin, type I, 40-kd; cytokeratin 19; 40-kDa keratin intermediate filament precursor gene EGF 4q25 epidermal growth factor (beta-urogastrone) ELOVL6 4q25 ELOVL family member 6, elongation of long chain fatty acids (FEN1/Elo2, SUR4/Elo3-like, yeast) LOC132706 4q25 similar to heat shock factor binding protein 1 LOC132707 4q25 similar to Ac-like transposable element; putative Ac-like transposon; zinc finger, BED domain containing 1 LOC391684 4 similar to ribosomal protein L7-like 1 LOC391685 4 similar to KIAA2033 protein ENPEP 4q25 glutamyl aminopeptidase (aminopeptidase A) PITX2 4q25-q27 paired-like homeodomain transcription factor 2 LOC391686 4 similar to lysophospholipase I; lysophospholipase 1; lysophospholipid-specific lysophospholipase; acyl-protein thioesterase-1 LOC132719 4q25-q26 similar to beta-tubulin 4Q LOC391687 4 similar to ribosomal protein S12 FLJ39370 4q26 hypothetical protein FLJ39370 PRO0971 4q26 hypothetical protein PRO0971 T2BP 4q26 TRAF2 binding protein LAK 4q26 lymphocyte alpha-kinase LOC285412 4q26 similar to Epidermal Langerhans cell protein LCP1 NEUROG2 4q25 neurogenin 2 LOC91431 4q26 prematurely terminated mRNA decay factor-like FLJ11331 4q26 hypothetical protein FLJ11331 HDCMA18P 4q26 HDCMA18P protein LOC256085 4q26 similar to Tryptophan-rich protein (Congenital heart disease 5 protein) LOC389218 4 similar to Ribosomal protein L7A CG3314-PD LOC391688 4 similar to Transcription initiation factor TFIID 105 kDa subunit (TAFII-105) (TAFII105) LOC391689 4 similar to Heterogeneous nuclear ribonucleoprotein A1 (Helix-destabilizing protein) (Single-strand binding protein) (hnRNP core protein A1) (HDP)
    RNA
    TRANSCRIPTS type messenger
    text four alternatively spliced isoforms (PMID: 11948188)
    identificationnb exonstypebpproduct
    ProteinkDaAAspecific expressionYearPubmed
    4 splicing 2122 30.34 271 - 2002 11948188
    also known as ARP1A or variant a
    5 splicing 2250 35.37 317 - 2002 11948188
  • 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 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
    		•
    EXPRESSION
    Type
       expressed in (based on citations)
    organ(s)
    SystemOrgan level 1Organ level 2Organ level 3Organ level 4LevelPubmedSpeciesStageRna symbol
    Digestivemouthtooth    Homo sapiens
    Endocrineneuroendocrinepituitary  highly
    Nervousbrain    
    Urinarykidney   moderately
    Visualeye   moderately
    tissue
    SystemTissueTissue level 1Tissue level 2LevelPubmedSpeciesStageRna symbol
    Muscular   moderately
    cells
    SystemCellPubmedSpeciesStageRna symbol
    Digestiveodontoblast
    cell lineage
    cell lines
    fluid/secretion
    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
    PROTEIN
    PHYSICAL PROPERTIES
    STRUCTURE
    motifs/domains
  • POU specific and POU homeo (helix-turn-helix) domains
  • C terminal OAR domain found in homeo domain proteins highly expressed in craniofacial tissues
  • four transcriptional domains with left and right compoments
    • mono polymer homomer , dimer
    HOMOLOGY
    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
    Homologene
    FAMILY
  • RIEG/PITX homeobox family
    • CATEGORY DNA associated , transcription factor
    SUBCELLULAR LOCALIZATION     intracellular
    intracellular,nucleus
    text
  • 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
  • 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
  • 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 (
    • CELLULAR PROCESS nucleotide, transcription, regulation
    PHYSIOLOGICAL PROCESS development
    PATHWAY
    metabolism
    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
    • a component
    INTERACTION
    DNA
  • bicoid and bicoid-like elements in the Dlx2 promoter (
    • RNA
    small molecule
    protein
  • 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)
    • cell & other
    REGULATION
    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 (
    • ASSOCIATED DISORDERS
    corresponding disease(s) RIEG1 , IHG2 , RGDC
    Other morbid association(s)
    TypeGene ModificationChromosome rearrangementProtein expressionProtein Function
    constitutional        
    duplication of PITX2 is causal of iris hypoplasia
    Susceptibility to atrial arrhythmias (see ATFB5)
    Variant & Polymorphism other has multiple targets that are relevant to the predisposition to atrial arrhythmia
    Candidate gene
    Marker
    Therapy target
    ANIMAL & CELL MODELS
  • 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