PITX2

Paired-like homeodomain 2
PDB rendering based on 1yz8.
Available structures PDB Ortholog search: PDBe, RCSB List of PDB id codes 2L7F, 2L7M, 2LKX
Identifiers
Symbols	PITX2; ARP1; Brx1; IDG2; IGDS; IGDS2; IHG2; IRID2; Otlx2; PTX2; RGS; RIEG; RIEG1; RS
External IDs	OMIM: 601542 MGI: 109340 HomoloGene: 55454 GeneCards: PITX2 Gene
Gene Ontology Molecular function • transcription regulatory region sequence-specific DNA binding • sequence-specific DNA binding RNA polymerase II transcription factor activity • RNA polymerase II core promoter proximal region sequence-specific DNA binding transcription factor activity involved in negative regulation of transcription • RNA polymerase II transcription factor binding • RNA polymerase II activating transcription factor binding • RNA polymerase II transcription coactivator activity • RNA polymerase II transcription factor binding transcription factor activity involved in negative regulation of transcription • sequence-specific DNA binding transcription factor activity • protein binding • transcription factor binding • chromatin DNA binding • protein homodimerization activity • ribonucleoprotein complex binding • phosphoprotein binding Cellular component • nucleus • transcription factor complex • cytoplasm Biological process • negative regulation of transcription from RNA polymerase II promoter • patterning of blood vessels • vasculogenesis • in utero embryonic development • neuron migration • extraocular skeletal muscle development • atrioventricular valve development • cardiac neural crest cell migration involved in outflow tract morphogenesis • pulmonary myocardium development • regulation of transcription, DNA-dependent • determination of left/right symmetry • myoblast fusion • Wnt receptor signaling pathway • subthalamic nucleus development • hypothalamus cell migration • regulation of cell migration • embryonic camera-type eye development • embryonic hindlimb morphogenesis • hair cell differentiation • vascular smooth muscle cell differentiation • deltoid tuberosity development • odontogenesis • camera-type eye development • positive regulation of DNA binding • positive regulation of transcription from RNA polymerase II promoter • spleen development • embryonic digestive tract morphogenesis • atrial cardiac muscle tissue morphogenesis • ventricular cardiac muscle cell development • somatotropin secreting cell differentiation • prolactin secreting cell differentiation • ventricular septum morphogenesis • left lung morphogenesis • pulmonary vein morphogenesis • superior vena cava morphogenesis • endodermal digestive tract morphogenesis • iris morphogenesis • cell proliferation involved in outflow tract morphogenesis • left/right axis specification • positive regulation of myoblast proliferation Sources: Amigo / QuickGO
RNA expression pattern
More reference expression data
Orthologs
Species	Human	Mouse
Entrez	5308	18741
Ensembl	ENSG00000164093	ENSMUSG00000028023
UniProt	Q99697	P97474
RefSeq (mRNA)	NM_000325	NM_001042502
RefSeq (protein)	NP_000316	NP_001035967
Location (UCSC)	Chr 4: 111.54 – 111.56 Mb	Chr 3: 129.2 – 129.22 Mb
PubMed search	[1]	[2]

Paired-like homeodomain transcription factor 2 also known as pituitary homeobox 2 is a protein that in humans is encoded by the PITX2 gene.

Function

This gene encodes a member of the RIEG/PITX homeobox family, which is in the bicoid class of homeodomain proteins. This protein acts as a transcription factor and regulates procollagen lysyl hydroxylase gene expression. This protein is involved in the development of the eye, tooth and abdominal organs. This protein acts as a transcriptional regulator involved in basal and hormone-regulated activity of prolactin. A similar protein in other vertebrates is involved in the determination of left-right asymmetry during development. Three transcript variants encoding distinct isoforms have been identified for this gene.

Pitx2 is responsible for the establishment of the left-right axis, the asymmetrical development of the heart, lungs, and spleen, twisting of the gut and stomach, as well as the development of the eyes. Once activated Pitx2 will be locally expressed in the left lateral mesoderm, tubular heart, and early gut which leads to the asymmetrical development of organs and looping of the gut. When Pitx2 is deleted, the irregular morphogenesis of organs results on the left hand side. Pitx2 is left-laterally expressed controlling the morphology of the left visceral organs. Expression of Pitx2 is controlled by an intronic enhancer ASE and Nodal. It appears that while Nodal controls cranial expression of Pitx2, ASE controls left – right expression of Pitx2, which leads to the asymmetrical development of the left sided visceral organs, such as the spleen and liver. Collectively, Pitx2 first acts to prevent the apoptosis of the extraocular muscles followed by acting as the myogenic programmer of the extraocular muscle cells. There have also been studies showing different isoforms of the transcription factor: Pitx2a, Pitx2b, and Pitx2c, each with distinct and non-overlapping functions.

Clinical significance

Mutations in this gene are associated with Axenfeld-Rieger syndrome (ARS), iridogoniodysgenesis syndrome (IGDS), and sporadic cases of Peters anomaly. This protein plays a role in the terminal differentiation of somatotroph and lactotroph cell phenotypes.

Further reading

• Franco D, Campione M (2003). "The role of Pitx2 during cardiac development. Linking left-right signaling and congenital heart diseases". Trends Cardiovasc. Med. 13 (4): 157–63. doi:10.1016/S1050-1738(03)00039-2. PMID 12732450. 
• Hjalt TA, Semina EV (2007). "Current molecular understanding of Axenfeld-Rieger syndrome". Expert reviews in molecular medicine 7 (25): 1–17. doi:10.1017/S1462399405010082. PMID 16274491. 
• Murray JC, Bennett SR, Kwitek AE, et al. (1993). "Linkage of Rieger syndrome to the region of the epidermal growth factor gene on chromosome 4". Nat. Genet. 2 (1): 46–9. doi:10.1038/ng0992-46. PMID 1303248. 
• Walter MA, Mirzayans F, Mears AJ, et al. (1996). "Autosomal-dominant iridogoniodysgenesis and Axenfeld-Rieger syndrome are genetically distinct". Ophthalmology 103 (11): 1907–15. PMID 8942889. 
• Semina EV, Reiter R, Leysens NJ, et al. (1997). "Cloning and characterization of a novel bicoid-related homeobox transcription factor gene, RIEG, involved in Rieger syndrome". Nat. Genet. 14 (4): 392–9. doi:10.1038/ng1296-392. PMID 8944018. 
• Alward WL, Semina EV, Kalenak JW, et al. (1998). "Autosomal dominant iris hypoplasia is caused by a mutation in the Rieger syndrome (RIEG/PITX2) gene". Am. J. Ophthalmol. 125 (1): 98–100. doi:10.1016/S0002-9394(99)80242-6. PMID 9437321. 
• Kulak SC, Kozlowski K, Semina EV, et al. (1999). "Mutation in the RIEG1 gene in patients with iridogoniodysgenesis syndrome". Hum. Mol. Genet. 7 (7): 1113–7. doi:10.1093/hmg/7.7.1113. PMID 9618168. 
• Amendt BA, Sutherland LB, Semina EV, Russo AF (1998). "The molecular basis of Rieger syndrome. Analysis of Pitx2 homeodomain protein activities". J. Biol. Chem. 273 (32): 20066–72. doi:10.1074/jbc.273.32.20066. PMID 9685346. 
• Yoshioka H, Meno C, Koshiba K, et al. (1998). "Pitx2, a bicoid-type homeobox gene, is involved in a lefty-signaling pathway in determination of left-right asymmetry". Cell 94 (3): 299–305. doi:10.1016/S0092-8674(00)81473-7. PMID 9708732. 
• Doward W, Perveen R, Lloyd IC, et al. (1999). "A mutation in the RIEG1 gene associated with Peters' anomaly". J. Med. Genet. 36 (2): 152–5. doi:10.1136/jmg.36.2.152. PMC 1734311. PMID 10051017. 
• Pellegrini-Bouiller I, Manrique C, Gunz G, et al. (1999). "Expression of the members of the Ptx family of transcription factors in human pituitary adenomas". J. Clin. Endocrinol. Metab. 84 (6): 2212–20. doi:10.1210/jc.84.6.2212. PMID 10372733. 
• Hjalt TA, Amendt BA, Murray JC (2001). "Pitx2 Regulates Procollagen Lysyl Hydroxylase (Plod) Gene Expression: Implications for the Pathology of Rieger Syndrome". J. Cell Biol. 152 (3): 545–52. doi:10.1083/jcb.152.3.545. PMC 2196000. PMID 11157981. 
• Priston M, Kozlowski K, Gill D, et al. (2001). "Functional analyses of two newly identified PITX2 mutants reveal a novel molecular mechanism for Axenfeld-Rieger syndrome". Hum. Mol. Genet. 10 (16): 1631–8. doi:10.1093/hmg/10.16.1631. PMID 11487566. 
• Green PD, Hjalt TA, Kirk DE, et al. (2002). "Antagonistic regulation of Dlx2 expression by PITX2 and Msx2: implications for tooth development". Gene Expr. 9 (6): 265–81. PMID 11763998. 
• Vincent AL, Billingsley G, Buys Y, et al. (2002). "Digenic Inheritance of Early-Onset Glaucoma: CYP1B1, a Potential Modifier Gene". Am. J. Hum. Genet. 70 (2): 448–60. doi:10.1086/338709. PMC 384919. PMID 11774072. 
• Borges AS, Susanna R, Carani JC, et al. (2002). "Genetic analysis of PITX2 and FOXC1 in Rieger Syndrome patients from Brazil". J. Glaucoma 11 (1): 51–6. doi:10.1097/00061198-200202000-00010. PMID 11821690. 
• Cox CJ, Espinoza HM, McWilliams B, et al. (2002). "Differential regulation of gene expression by PITX2 isoforms". J. Biol. Chem. 277 (28): 25001–10. doi:10.1074/jbc.M201737200. PMID 11948188. 
• Quentien MH, Pitoia F, Gunz G, et al. (2002). "Regulation of prolactin, GH, and Pit-1 gene expression in anterior pituitary by Pitx2: An approach using Pitx2 mutants". Endocrinology 143 (8): 2839–51. doi:10.1210/en.143.8.2839. PMID 12130547. 

External links

• PITX2 protein, human at the US National Library of Medicine Medical Subject Headings (MeSH)

This article incorporates text from the United States National Library of Medicine, which is in the public domain.