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Gene Review

PITX2  -  paired-like homeodomain 2

Homo sapiens

Synonyms: ALL1-responsive protein ARP1, ARP1, Brx1, Homeobox protein PITX2, IDG2, ...
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Disease relevance of PITX2

  • Mutation in PITX2 is associated with ring dermoid of the cornea [1].
  • In the developmental glaucomas, mutations in the PITX2 gene on chromosome 4q25 have been associated with Rieger syndrome, iris hypoplasia, and iridogoniodysgenesis [2].
  • Thus, proteasomal regulation of RGS expression in HEK293 cells strongly controls RGS function and a novel RGS2 mutation with decreased protein expression could be relevant to the pathophysiology of hypertension in humans [3].
  • Mutations in PITX2 may contribute to cases of omphalocele and VATER-like syndromes [4].
  • In this study, we report a marked decrease in RGS2 (but not other major cardiac RGS proteins (RGS3-RGS5)) that occurs prior to hypertrophy development in different models with enhanced G(q/11) signaling (transgenic expression of activated Galpha(q)(*) and pressure overload due to aortic constriction) [5].

Psychiatry related information on PITX2

  • We also showed for the first time that PITX2 is expressed at early stages of the human embryonic and fetal periocular mesenchyme, as well as at later stages of human development in the fetal ciliary body, ciliary processes, irido corneal angle and corneal endothelium [6].
  • Rho-kinase and RGS-containing RhoGEFs as molecular targets for the treatment of erectile dysfunction [7].
  • Deficits in M1 muscarinic receptor system signaling in Alzheimer's disease (AD) prompted an analysis of components of these systems, namely, the G(q/11) protein and the regulator of G-protein signaling (RGS) 4 protein [8].
  • The success of the present application of the RS theory strengthens the argument that individual differences for hand preference depend on a continuous distribution of asymmetry, not on the 'types' commonly assumed in the literature [9].
  • Finally, we consider if RGS proteins represent viable targets for drug abuse medications [10].

High impact information on PITX2

  • DEP-domain-mediated tethering promotes downregulation by placing the RGS protein in proximity to its substrate (receptor-activated Galpha subunit) [11].
  • RIEG characterization provides opportunities for understanding ocular, dental and umbilical development and the pleiotropic interactions of pituitary and limb morphogenesis [12].
  • We report the human cDNA and genomic characterization of a new homeobox gene, RIEG, causing this disorder [12].
  • Rieger syndrome (RIEG) is an autosomal-dominant human disorder that includes anomalies of the anterior chamber of the eye, dental hypoplasia and a protuberant umbilicus [12].
  • Introduction of RGS family members into yeast blunts signal transduction through the pheromone-response pathway [13].

Chemical compound and disease context of PITX2


Biological context of PITX2

  • The PLOD-1 promoter induces the expression of a luciferase reporter gene in the presence of PITX2 in cotransfection experiments [18].
  • The PITX2 T68P ARS mutation occurs at a protein kinase C phosphorylation site in the homeodomain [19].
  • These results suggest that the position 50 residue in the PITX2 homeodomain plays an important role in both DNA binding and dimerization activities [20].
  • PITX2 isoform activities are both promoter- and cell-specific, and our data reveal new mechanisms for PITX2-regulated gene expression [21].
  • The synergism was dependent on promoter context, because it required MEF2 binding sites and was not seen with two other PITX2 target promoters [22].

Anatomical context of PITX2

  • Because Axenfeld-Rieger syndrome is autosomal dominant and affects development of the oral epithelium, we tested one of the known PITX2 mutants [22].
  • Mutations in PITX2 cause some cases of Rieger syndrome, an autosomal dominant disorder affecting eyes, teeth, and umbilicus [23].
  • PITX2 mutant proteins expressed in COS-7 cells were determined to be stable and localized to the nucleus; however, the Arg53Pro ARS mutant also displayed cytoplasmic staining [24].
  • PITX2 is required for normal development of neurons in the mouse subthalamic nucleus and midbrain [25].
  • Electrophoretic mobility shift assays demonstrate that factors in the LS-8 cell line specifically interact with PITX2 [26].

Associations of PITX2 with chemical compounds

  • Analysis of the NMR structure of the PITX2 homeodomain indicates that the lysine at position 50 makes contacts with two guanines on the antisense strand of the DNA, adjacent to the TAAT core DNA sequence, consistent with the structure of EnQ50K [27].
  • This mutation is a G-->A transition altering an arginine residue to a histidine in a highly conserved location in the second helix of the homeobox of RIEG1 [28].
  • Adrenergic modulation of NMDA receptors in prefrontal cortex is differentially regulated by RGS proteins and spinophilin [29].
  • These results identify for the first time a phosphorylation-induced change in the activity of an RGS protein and suggest a mechanism for potentiation of inositol lipid signaling by PKC [30].
  • Expression of RGS2, but not other RGS proteins, abolished androgen-independent AR activity in androgen-independent LNCaP cells and CWR22Rv1 cells [31].

Physical interactions of PITX2

  • Ultimately, PITX2 loss of function mutations have a compound effect: the reduced expression of PITX2-target genes coupled with the extensive activation of FOXC1-regulated targets [32].
  • The mutant Pitx2 protein binds Pit-1, but there was no detectable synergism on the prolactin promoter [33].
  • A protease-resistant domain of Axin that contains the APC-binding site is a member of the regulators of G-protein signaling (RGS) superfamily [34].
  • Recent evidence has raised the possibility that RGS proteins may interact directly with G-protein-coupled receptors to modulate their activity [35].

Regulatory relationships of PITX2

  • PITX2 DeltaT1261 is unable to interact with a cellular factor to synergistically activate transcription and demonstrates the first link of ARS with defective PITX2 protein interactions [36].
  • PKC phosphorylation regulates PITX2 DNA binding and transcriptional activity [36].
  • RGS proteins negatively regulate heterotrimeric G protein signaling [37].
  • Regulators of G-protein Signalling (RGS) regulate the functional lifetime of G-Protein Coupled Receptor (GPCR)-activated heterotrimeric G-protein by serving as GTPase Accelerating Proteins (GAPs) for the G(alpha) subunit [38].

Other interactions of PITX2

  • We studied the role of MYOC, CYP1B1, and PITX2 in a population (n=60) affected with juvenile or early-onset glaucoma from the greater Toronto area [39].
  • By a combination of single-strand conformation polymorphism and direct cycle sequencing, MYOC mutations were detected in 8 (13.3%) of the 60 individuals, CYP1B1 mutations were detected in 3 (5%) of the 60 individuals, and no PITX2 mutations were detected [39].
  • We have examined the interaction of PITX2 isoforms with myocyte-enhancing factor 2A (MEF2A), which is a known regulator of cardiac development [22].
  • PURPOSE: Axenfeld-Rieger malformations of the anterior segment are clinically heterogeneous, and up to 50% of cases are attributable to PITX2 or FOXC1 mutation [40].
  • Mutations in the PITX2, FOXC1, and PAX6 genes have been associated with Rieger syndrome [41].

Analytical, diagnostic and therapeutic context of PITX2


  1. Mutation in PITX2 is associated with ring dermoid of the cornea. Xia, K., Wu, L., Liu, X., Xi, X., Liang, D., Zheng, D., Cai, F., Pan, Q., Long, Z., Dai, H., Hu, Z., Tang, B., Zhang, Z., Xia, J. J. Med. Genet. (2004) [Pubmed]
  2. Glaucoma genetics: where are we? Where will we go? Craig, J.E., Mackey, D.A. Current opinion in ophthalmology. (1999) [Pubmed]
  3. N-Terminal Residues Control Proteasomal Degradation of RGS2, RGS4, and RGS5 in Human Embryonic Kidney 293 Cells. Bodenstein, J., Sunahara, R.K., Neubig, R.R. Mol. Pharmacol. (2007) [Pubmed]
  4. Mutations in PITX2 may contribute to cases of omphalocele and VATER-like syndromes. Katz, L.A., Schultz, R.E., Semina, E.V., Torfs, C.P., Krahn, K.N., Murray, J.C. Am. J. Med. Genet. A (2004) [Pubmed]
  5. Selective loss of fine tuning of Gq/11 signaling by RGS2 protein exacerbates cardiomyocyte hypertrophy. Zhang, W., Anger, T., Su, J., Hao, J., Xu, X., Zhu, M., Gach, A., Cui, L., Liao, R., Mende, U. J. Biol. Chem. (2006) [Pubmed]
  6. Identification of four new PITX2 gene mutations in patients with Axenfeld-Rieger syndrome. Vieira, V., David, G., Roche, O., de la Houssaye, G., Boutboul, S., Arbogast, L., Kobetz, A., Orssaud, C., Camand, O., Schorderet, D.F., Munier, F., Rossi, A., Delezoide, A.L., Marsac, C., Ricquier, D., Dufier, J.L., Menasche, M., Abitbol, M. Mol. Vis. (2006) [Pubmed]
  7. Rho-kinase and RGS-containing RhoGEFs as molecular targets for the treatment of erectile dysfunction. Linder, A.E., Webb, R.C., Mills, T.M., Ying, Z., Lewis, R.W., Teixeira, C.E. Curr. Pharm. Des. (2005) [Pubmed]
  8. Differences in regional and subcellular localization of G(q/11) and RGS4 protein levels in Alzheimer's disease: correlation with muscarinic M1 receptor binding parameters. Muma, N.A., Mariyappa, R., Williams, K., Lee, J.M. Synapse (2003) [Pubmed]
  9. Predicting combinations of left and right asymmetries. Annett, M. Cortex; a journal devoted to the study of the nervous system and behavior. (2000) [Pubmed]
  10. REGULATORs OF G PROTEIN SIGNALING & DRUGS OF ABUSE. Traynor, J.R., Neubig, R.R. Molecular interventions. (2005) [Pubmed]
  11. DEP-Domain-Mediated Regulation of GPCR Signaling Responses. Ballon, D.R., Flanary, P.L., Gladue, D.P., Konopka, J.B., Dohlman, H.G., Thorner, J. Cell (2006) [Pubmed]
  12. Cloning and characterization of a novel bicoid-related homeobox transcription factor gene, RIEG, involved in Rieger syndrome. Semina, E.V., Reiter, R., Leysens, N.J., Alward, W.L., Small, K.W., Datson, N.A., Siegel-Bartelt, J., Bierke-Nelson, D., Bitoun, P., Zabel, B.U., Carey, J.C., Murray, J.C. Nat. Genet. (1996) [Pubmed]
  13. Inhibition of G-protein-mediated MAP kinase activation by a new mammalian gene family. Druey, K.M., Blumer, K.J., Kang, V.H., Kehrl, J.H. Nature (1996) [Pubmed]
  14. PC cell-derived growth factor confers resistance to dexamethasone and promotes tumorigenesis in human multiple myeloma. Wang, W., Hayashi, J., Serrero, G. Clin. Cancer Res. (2006) [Pubmed]
  15. Endogenous regulator of g protein signaling proteins reduce {mu}-opioid receptor desensitization and down-regulation and adenylyl cyclase tolerance in C6 cells. Clark, M.J., Traynor, J.R. J. Pharmacol. Exp. Ther. (2005) [Pubmed]
  16. Intraoperative detection of lung cancer by octreotide labeled to Indium-111. Pastore, V., Di Lieto, E., Mansi, L., Rambaldi, P.F., Santini, M., Mancusi, R. Seminars in surgical oncology. (1998) [Pubmed]
  17. Second messengers regulate RGS2 expression which is targeted to the nucleus. Zmijewski, J.W., Song, L., Harkins, L., Cobbs, C.S., Jope, R.S. Biochim. Biophys. Acta (2001) [Pubmed]
  18. PITX2 regulates procollagen lysyl hydroxylase (PLOD) gene expression: implications for the pathology of Rieger syndrome. Hjalt, T.A., Amendt, B.A., Murray, J.C. J. Cell Biol. (2001) [Pubmed]
  19. A molecular basis for differential developmental anomalies in Axenfeld-Rieger syndrome. Espinoza, H.M., Cox, C.J., Semina, E.V., Amendt, B.A. Hum. Mol. Genet. (2002) [Pubmed]
  20. Dominant negative dimerization of a mutant homeodomain protein in Axenfeld-Rieger syndrome. Saadi, I., Kuburas, A., Engle, J.J., Russo, A.F. Mol. Cell. Biol. (2003) [Pubmed]
  21. Differential regulation of gene expression by PITX2 isoforms. Cox, C.J., Espinoza, H.M., McWilliams, B., Chappell, K., Morton, L., Hjalt, T.A., Semina, E.V., Amendt, B.A. J. Biol. Chem. (2002) [Pubmed]
  22. Cell-specific activation of the atrial natriuretic factor promoter by PITX2 and MEF2A. Toro, R., Saadi, I., Kuburas, A., Nemer, M., Russo, A.F. J. Biol. Chem. (2004) [Pubmed]
  23. The human BARX2 gene: genomic structure, chromosomal localization, and single nucleotide polymorphisms. Hjalt, T.A., Murray, J.C. Genomics (1999) [Pubmed]
  24. Variation in residual PITX2 activity underlies the phenotypic spectrum of anterior segment developmental disorders. Kozlowski, K., Walter, M.A. Hum. Mol. Genet. (2000) [Pubmed]
  25. PITX2 is required for normal development of neurons in the mouse subthalamic nucleus and midbrain. Martin, D.M., Skidmore, J.M., Philips, S.T., Vieira, C., Gage, P.J., Condie, B.G., Raphael, Y., Martinez, S., Camper, S.A. Dev. Biol. (2004) [Pubmed]
  26. Antagonistic regulation of Dlx2 expression by PITX2 and Msx2: implications for tooth development. Green, P.D., Hjalt, T.A., Kirk, D.E., Sutherland, L.B., Thomas, B.L., Sharpe, P.T., Snead, M.L., Murray, J.C., Russo, A.F., Amendt, B.A. Gene Expr. (2001) [Pubmed]
  27. Solution structure of the K50 class homeodomain PITX2 bound to DNA and implications for mutations that cause Rieger syndrome. Chaney, B.A., Clark-Baldwin, K., Dave, V., Ma, J., Rance, M. Biochemistry (2005) [Pubmed]
  28. Mutation in the RIEG1 gene in patients with iridogoniodysgenesis syndrome. Kulak, S.C., Kozlowski, K., Semina, E.V., Pearce, W.G., Walter, M.A. Hum. Mol. Genet. (1998) [Pubmed]
  29. Adrenergic modulation of NMDA receptors in prefrontal cortex is differentially regulated by RGS proteins and spinophilin. Liu, W., Yuen, E.Y., Allen, P.B., Feng, J., Greengard, P., Yan, Z. Proc. Natl. Acad. Sci. U.S.A. (2006) [Pubmed]
  30. Protein kinase C phosphorylates RGS2 and modulates its capacity for negative regulation of Galpha 11 signaling. Cunningham, M.L., Waldo, G.L., Hollinger, S., Hepler, J.R., Harden, T.K. J. Biol. Chem. (2001) [Pubmed]
  31. Regulator of G-protein signaling 2 (RGS2) inhibits androgen-independent activation of androgen receptor in prostate cancer cells. Cao, X., Qin, J., Xie, Y., Khan, O., Dowd, F., Scofield, M., Lin, M.F., Tu, Y. Oncogene (2006) [Pubmed]
  32. Functional interactions between FOXC1 and PITX2 underlie the sensitivity to FOXC1 gene dose in Axenfeld-Rieger syndrome and anterior segment dysgenesis. Berry, F.B., Lines, M.A., Oas, J.M., Footz, T., Underhill, D.A., Gage, P.J., Walter, M.A. Hum. Mol. Genet. (2006) [Pubmed]
  33. The molecular basis of Rieger syndrome. Analysis of Pitx2 homeodomain protein activities. Amendt, B.A., Sutherland, L.B., Semina, E.V., Russo, A.F. J. Biol. Chem. (1998) [Pubmed]
  34. Structural basis of the Axin-adenomatous polyposis coli interaction. Spink, K.E., Polakis, P., Weis, W.I. EMBO J. (2000) [Pubmed]
  35. Selective inhibition of alpha1A-adrenergic receptor signaling by RGS2 association with the receptor third intracellular loop. Hague, C., Bernstein, L.S., Ramineni, S., Chen, Z., Minneman, K.P., Hepler, J.R. J. Biol. Chem. (2005) [Pubmed]
  36. Protein kinase C phosphorylation modulates N- and C-terminal regulatory activities of the PITX2 homeodomain protein. Espinoza, H.M., Ganga, M., Vadlamudi, U., Martin, D.M., Brooks, B.P., Semina, E.V., Murray, J.C., Amendt, B.A. Biochemistry (2005) [Pubmed]
  37. A functional polymorphism in RGS6 modulates the risk of bladder cancer. Berman, D.M., Wang, Y., Liu, Z., Dong, Q., Burke, L.A., Liotta, L.A., Fisher, R., Wu, X. Cancer Res. (2004) [Pubmed]
  38. Galpha protein dependent and independent effects of human RGS1 expression in yeast. Li, X.Y., Yang, Z., Greenwood, M.T. Cell. Signal. (2004) [Pubmed]
  39. Digenic inheritance of early-onset glaucoma: CYP1B1, a potential modifier gene. Vincent, A.L., Billingsley, G., Buys, Y., Levin, A.V., Priston, M., Trope, G., Williams-Lyn, D., Héon, E. Am. J. Hum. Genet. (2002) [Pubmed]
  40. Reduced human and murine corneal thickness in an axenfeld-rieger syndrome subtype. Asai-Coakwell, M., Backhouse, C., Casey, R.J., Gage, P.J., Lehmann, O.J. Invest. Ophthalmol. Vis. Sci. (2006) [Pubmed]
  41. Novel identification of a four-base-pair deletion mutation in PITX2 in a Rieger syndrome family. Wang, Y., Zhao, H., Zhang, X., Feng, H. J. Dent. Res. (2003) [Pubmed]
  42. A novel mutation in the PITX2 gene in a family with Axenfeld-Rieger syndrome. Brooks, B.P., Moroi, S.E., Downs, C.A., Wiltse, S., Othman, M.I., Semina, E.V., Richards, J.E. Ophthalmic Genet. (2004) [Pubmed]
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