Alternative titles; symbols
HGNC Approved Gene Symbol: PITX2
SNOMEDCT: 723499000;
Cytogenetic location: 4q25 Genomic coordinates (GRCh38): 4:110,617,423-110,642,123 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 4q25 | Anterior segment dysgenesis 4 | 137600 | Autosomal dominant | 3 |
| Axenfeld-Rieger syndrome, type 1 | 180500 | Autosomal dominant | 3 | |
| Ring dermoid of cornea | 180550 | Autosomal dominant | 3 |
PITX2 belongs to the bicoid class of homeodomain transcription factors, which play essential roles in embryonic development. Various PITX2 isoforms are involved in a wide variety of developmental programs, including left-right signaling (summary by Cox et al., 2002).
Semina et al. (1996) reported a cosmid contig encompassing 2 translocations at 4q25 associated with Rieger syndrome (see 180500) and placed them approximately 50 kb from each other. They identified 5 CpG islands from these cosmids by restriction enzyme analysis and used them as probes to screen a human craniofacial cDNA library. This led to the isolation of a 2,125-bp cDNA with a predicted 271-amino acid protein, which the authors designated solurshin. Database sequence analysis indicated that the gene, which the authors called RIEG, encodes a member of the bicoid class of homeodomain proteins expressed in anterior structures in different species, as is bicoid itself. Semina et al. (1996) determined that the solurshin homeodomain showed the greatest homology with the PITX1 protein (602149), differing by only 2 residues. Both homeodomains share a lysine residue at position 9 of the third helix, a characteristic of the bicoid-related proteins as found in C. elegans, Drosophila, and murine Otx1 and Otx2. Semina et al. (1996) cloned a mouse Rieg cDNA and found that the deduced protein shares approximately 99% identity with human RIEG.
During a screen for novel homeobox genes expressed within the adult mouse pituitary gland, Gage and Camper (1997) identified the Pitx2 (Rieg) gene. The gene has a bicoid-related homeodomain and is expressed as 2 alternatively spliced mRNA products, which encode proteins of 271 and 317 amino acids, respectively. The authors named the proteins Pitx2a and Pitx2b.
Using the differential display method, Arakawa et al. (1998) isolated a gene that is downregulated in All1 double-knockout mouse embryonic stem (ES) cells. They designated the gene Arp1 (All1-responsive gene-1). A database search indicated that Arp1 was likely to be identical to Rieg. Alternative splicing gave rise to 3 transcripts: Arp1a, Arp1b, and Arp1c. Gage and Camper (1997) stated that the Arp1 gene is identical to that described as Pitx2 and is expressed in the pituitary gland.
Cox et al. (2002) noted that the PITX2A and PITX2B transcripts are generated by alternative splicing, and that PITX2C uses an alternative promoter located within intron 3. The 3 encoded proteins have dissimilar N-terminal domains, but all have an identical central bicoid-like homeodomain and C-terminal Otp (604529) and aristaless (see 602753) (OAR) domain. By PCR of a human craniofacial library, Cox et al. (2002) cloned an additional splice variant, PITX2D, that uses the same alternate promoter used by PITX2C. PITX2D results from splicing of exon 4a to a cryptic 3-prime splice site in exon 5. The deduced 205-amino acid PITX2D protein is N-terminally truncated compared with other PITX2 isoforms and contains only a partial homeodomain and the C-terminal OAR domain.
By quantitative RT-PCR of 33 human tissues, Gore-Panter et al. (2016) found highest PITX2c expression in skeletal muscle, followed by eye, left atrium, placenta, colon, and small intestine. Little to no PITX2c expression was detected in other tissues, including right atrium.
Semina et al. (1996) determined that the RIEG gene contains 4 exons and spans about 18 kb of genomic sequence. The initiation codon is located in exon 2 and the homeobox region in exons 3 and 4.
Cox et al. (2002) determined that the PITX2 gene contains 7 exons, including alternative exons 4a and 4b, and that it spans about 19.7 kb. Alternative promoters are located upstream of exons 1 and 4.
Semina et al. (1996) identified the RIEG gene within an approximately 50-kb region on chromosome 4q25 that had been associated with Rieger syndrome.
Using a fragment of the ARP1 gene as a probe in Southern analysis of DNAs from somatic cell hybrids and applying in situ hybridization, Arakawa et al. (1998) mapped the gene, later found to be identical to the RIEG gene, to 4q24-q25.
By analysis of an interspecific backcross panel, Gage and Camper (1997) mapped the mouse Pitx2 gene close to the gene for epidermal growth factor (131530), which in the human maps to 4q25 and in the mouse to chromosome 3.
By in situ hybridization experiments, Semina et al. (1996) showed in mouse embryos that Rieg mRNA localized in the periocular mesenchyme, maxillary and mandibular epithelia, and umbilicus, all consistent with the anomalies characteristic of Rieger syndrome. The gene was also expressed in the Rathke pouch, vitelline vessels, and limb mesenchyme. The high level of expression of Rieg mRNA in the Rathke pouch suggested to Semina et al. (1996) that the gene may play an important role in anterior pituitary gland development. Although the Rieger syndrome patients who were found by Semina et al. (1996) to have RIEG mutations did not show signs of abnormal pituitary function, anomalies of the pituitary gland have been associated with some cases of the syndrome (Feingold et al., 1969; Sadeghi-Nejad and Senior, 1974).
Gage and Camper (1997) found that the mouse Pitx2 gene was expressed in both developing and adult pituitary gland, eye, and brain tissues. They suggested that Pitx2 plays a role during ontogeny of the pituitary gland and other anterior structures, including the eye.
Pellegrini-Bouiller et al. (1999) noted that mouse Pitx1 and Pitx2 gene expression has been detected in the area of the pituitary primordium and is maintained throughout development in the Rathke pouch and adult pituitary. They characterized the expression of the PITX1, PITX2, and PITX3 (602669) genes in the normal human pituitary and in the different types of human pituitary adenomas. Northern blot analysis of adult and fetal normal human pituitary detected a 2.5-kb PITX2 transcript. Northern blot analysis of 60 pituitary adenomas revealed that the pattern of expression of the PITX2 gene varied among the different subsets of pituitary adenomas. No PITX2 expression was detected in corticotroph tumors. In contrast, high levels of PITX2 mRNA were measured in gonadotroph tumors, although no specific correlation to other markers of the gonadotroph lineage differentiation, such as alpha-Gsu, LHB (152780), or FSHB (136530), was found. PITX2 was expressed in pure lactotroph adenomas but not in somatotroph adenomas. The authors concluded that PITX2 is the first paired homeodomain pituitary transcription factor differentially expressed in these 2 lineages, which derive from a common precursor. The results supported a role for PITX2 in the terminal differentiation of somatotroph and lactotroph cell phenotypes.
Amendt et al. (1998) used electrophoretic mobility shift assays, protein binding, and transient transfection assays to characterize wildtype and mutant Pitx2 activities. Pitx2 preferentially binds the bicoid homeodomain binding site and transactivates reporter genes containing this site. The combination of Pitx2 and another homeodomain protein, Pit1 (173110), yielded a synergistic 55-fold activation of the prolactin promoter in gene transfection assays. Addition of Pit1 increased Pitx2 binding to the bicoid element in electrophoretic mobility shift assays. Furthermore, Amendt et al. (1998) demonstrated specific binding of Pit1 to Pitx2 in vitro. Thus, wildtype Pitx2 DNA-binding activity is modulated by protein-protein interactions. The T68P Rieger mutant (601542.0003) in the second helix of the homeodomain retained DNA-binding activity with the same apparent K(D) and only about a 2-fold reduction in the B(max). However, this mutant did not transactivate reporter genes containing the bicoid site. The mutant Pitx2 protein binds Pit1, but there was no detectable synergism on the prolactin promoter. A second mutation, L54Q (601542.0001), in a highly conserved residue in helix 1 of the homeodomain, yielded an unstable protein.
Cushman and Camper (2001) reviewed the molecular basis of pituitary dysfunction in mouse and human. They listed 12 transcription factors critical for pituitary development and function, including PITX2. They noted that pituitary development is arrested at embryonic day 12.5 in the Pitx2 knockout mouse model.
Kioussi et al. (2002) reported that the transcription factor PITX2 is rapidly induced by the WNT (164820)/DVL (601365)/beta-catenin (116806) pathway and is required for effective cell type-specific proliferation by directly activating specific growth-regulating genes. They found that regulated exchange of HDAC1 (601241)/beta-catenin converts PITX2 from repressor to activator, analogous to control of TCF (142410)/LEF1 (153245). PITX2 then serves as a competence factor required for the temporally ordered and growth factor-dependent recruitment of a series of specific coactivator complexes necessary for cyclin D2 (123833) gene induction.
By transfecting several mammalian cell lines with various PITX2 splice variants, Cox et al. (2002) showed that the PITX2 isoforms had unique promoter-specific effects on transcription. When expressed individually, PITX2A and PITX2C, but not PITX2B, activated the PLOD1 (153454) and DLX2 (126255) promoters. In contrast, PITX2B showed higher activity than the other isoforms in transactivating the prolactin (PRL; 176760) promoter. Cotransfection of PITX2B with either PITX2A or PITX2C resulted in synergistic activation of the PLOD1 and DLX2 promoters. The PITX2 isoforms also had different transcriptional activities depending on the cell line used for transfections. Unlike the other PITX2 isoforms, PITX2D did not bind DNA and showed no transcriptional activity. However, when coexpressed, PITX2D suppressed the transcriptional activities of the other PITX2 isoforms. Electrophoretic mobility shift assays and protein pull-down experiments demonstrated that all isoforms interacted with PITX2D and that PITX2B dimerized with PITX2A and PITX2C. Binding to PITX2D did not alter the stability of the other PITX2 isoforms, but it appeared to suppress their transcriptional activities by sequestration.
Venugopalan et al. (2008) showed that Pitx2 and Foxj1 (602291) were coexpressed temporally during development of mouse orofacial structures, including molar inner enamel epithelium, oral and tongue epithelium, and submandibular gland. Chromatin immunoprecipitation analysis revealed that Pitx2 bound the Foxj1 promoter in a mouse ameloblast cell line. Reporter gene assays showed that Pitx2a and Pitx2c strongly activated the Foxj1 promoter, whereas Pitx2b more weakly activated Foxj1. Pitx2a interacted with Lef1 and beta-catenin to activate the Foxj1 promoter, and once activated, Foxj1 contributed to its own activation in a positive feedback loop.
When C2C12 mouse myoblasts are exposed to bone morphogenic proteins (BMPs), they differentiate into osteoblastic cells but cannot mature into bone cells. Osterix (SP7; 606633), a transcription factor for osteoblast differentiation, is only transiently induced upon BMP stimulation in C2C12 cells, suggesting that a factor inhibits osterix and prevents complete osteoblastic differentiation. Using microarray analysis, Hayashi et al. (2008) identified Pitx2 as a transcription factor induced by stimulation of C2C12 cells with recombinant human BMP2 (112261). Overexpression of Pitx2 repressed osterix expression and subsequent osteoblastic differentiation. Conversely, downregulation of Pitx2 expression by short hairpin RNA enhanced osterix expression and osteoblastic maturation of C2C12 cells upon BMP stimulation. Hayashi et al. (2008) concluded that PITX2 plays a crucial role in protecting myoblasts from BMP-induced differentiation into osteoblasts.
By testing an established Hippo (see 605030)-deficient heart regeneration mouse model for factors that promote renewal, Tao et al. (2016) demonstrated that the expression of Pitx2 is induced in injured, Hippo-deficient ventricles. Pitx2-deficient neonatal mouse hearts failed to repair after apex resection, whereas adult mouse cardiomyocytes with Pitx2 gain of function efficiently regenerated after myocardial infarction. Genomic analyses indicated that Pitx2 activated genes encoding electron transport chain components and reactive oxygen species scavengers. A subset of Pitx2 target genes was cooperatively regulated with the Hippo pathway effector Yap (606608). Furthermore, Nrf2 (600492), a regulator of the antioxidant response, directly regulated the expression and subcellular localization of Pitx2. Pitx2 mutant myocardium had increased levels of reactive oxygen species, while antioxidant supplementation suppressed the Pitx2 loss-of-function phenotype. Tao et al. (2016) concluded that their findings revealed a genetic pathway activated by tissue damage that is essential for cardiac repair.
Using quantitative RT-PCR, Gore-Panter et al. (2016) found that differentiation of H9 human embryonic stem cells into cardiomyocytes induced expression of both PITX2c and PANCR (617286), a long noncoding RNA encoded by a gene approximately 2 kb downstream of the PITX2 gene. Both transcripts were expressed in cytoplasm of fractionated H9 cardiomyocytes. Knockdown of PANCR via short interfering RNA reduced expression of PITX2c, but knockdown of PITX2c had no effect on expression of PANCR. Expression profiling revealed overlap in the genes regulated by PANCR or PITX2c knockdown, suggesting that the major role of PANCR is to regulate PITX2c.
Nadadur et al. (2016) identified a cis regulatory element containing a functional T-box-binding site in the PITX2 promoter that was bound by TBX5 (601620). The major T allele of a common SNP, rs1906595, disrupted the central nucleotide of the T-box-binding motif, whereas the minor G allele of the SNP completed the canonical T-box-binding element. The major allele of rs1906595 completely abolished cis regulatory element activity in response to TBX5 in transfected HEK293 cells and in HL-1 mouse atrial cardiomyocytes.
Ye et al. (2016) identified a SNP, rs2595104, within intron 4 of the PITX2 gene that altered expression of PITX2c, but not PITX2a or PITX2b. The SNP is located about 10 kb upstream of the PITX2c transcription start site within a putative TFAP2A (107580)-binding motif. The minor G allele of the SNP, but not the major T allele, was associated with TFAP2A binding and increased expression of PITX2c in transfected human and mouse cell lines.
Sharp et al. (2014) found that cotransfection of Mir200a (612090) and Pitx2, but neither construct alone, resulted in conversion of mouse LS-8 oral epithelial cells and mouse MDPC-23 odontoblast mesenchymal cells into differentiated dental epithelial cells that expressed E-cadherin (CDH1; 192090) and amelogenin (see AMELX, 300391) and downregulated beta-catenin (CTNNB1; 116806) and other mesenchymal markers.
By analyzing chicken and mouse embryos, Sivakumar et al. (2018) found that morphologic asymmetry in the dorsal mesentery (DM) is first broken on the right side of the DM of embryos, not on the left, where Pitx2 is expressed and has been the focal point in governing organ laterality. The symmetry-breaking event in embryos depends on the accumulation of hyaluronan (HA), and is independent of Pitx2 in determining the gut and vascular laterality. While HA is synthesized bilaterally in the DM of embryos, Tsg6 (600410) covalently modifies HA on the right side of embryo to result in asymmetric accumulation of HA on the right, which then triggers dramatic expansion of the right side of the DM necessary for midgut rotation and gut vascular development, linking vessel patterning with the morphogenesis of the host organ. Analysis of the molecular distribution of HA, Tsg6, and the critical substrate (inter-alpha-trypsin inhibitor; see AMBP, 176870) for Tsg6 to form modified HA revealed that the molecular machinery involved in modification of HA on the right is conserved between chicken, mouse, and rat. Tsg6 -/- mice showed potentially lethal or sublethal phenotypes associated with Tsg6 loss, but some Tsg6 -/- mice were viable; females were infertile. Loss of Tsg6 in knockout mice caused failure to initiate midgut rotation. Unmodified HA on the left side plays a distinct role compared with the right and is necessary to maintain proper Pitx2 expression and function within the left DM. Knockdown of Pitx2 on the left side of the chicken embryo had no effect on the levels of HA on the left side, indicating that Tsg6-HA pathway for the left-right symmetry-breaking is independent of Pitx2 on the left.
Axenfeld-Rieger Syndrome, Type 1
Semina et al. (1996) used SSCP to analyze the RIEG gene for mutations in families with autosomal dominant Rieger syndrome (RIEG1; 180500). In 1 family, sequencing identified a missense mutation, a T-to-A transversion at nucleotide 744, that changed the CTG codon for leucine into a CAG codon for glutamine in the first helix of the homeodomain (601542.0001). Mutations were identified in 5 other families. No SSCP variants were detected in the remaining 4 classic Rieger syndrome families using primer pairs spanning the whole RIEG cDNA sequence. The translocation breakpoints associated with Rieger syndrome were found by Semina et al. (1996) to be 5 to 65 kb from the RIEG gene, suggesting that removal of a locus-specific enhancer element(s) or a chromatin-organizing region in the rearranged allele caused reduction of gene expression. They postulated that as yet unidentified exons of alternative isoforms may exist that might be interrupted by the breakpoints. Of the 6 mutations identified by Semina et al. (1996), 2 represented de novo mutations and 4 were segregating in the family as an autosomal dominant. The homeodomain region was affected in 5 of the mutations; 1 mutation was found to cause premature termination of the protein 34 amino acids C-terminal from the homeodomain.
Flomen et al. (1998) presented evidence that physical or functional haploinsufficiency of RIEG is the pathogenic mechanism for Rieger syndrome. They also suggested regions upstream of the gene that may contain sequences with a key regulatory role in the control of homeobox gene expression. Through fluorescence in situ hybridization analysis of a 460-kb sequence-ready map (PAC contig) around the RIEG locus, they demonstrated that the 4q25-linked Rieger syndrome can arise from the haploid, whole-gene deletion of RIEG, but also from a translocation break 90 kb upstream from the gene.
Kozlowski and Walter (2000) introduced mutations known to cause human disease into recombinant PITX2 cDNA by site-directed mutagenesis. PITX2 mutant proteins expressed in COS-7 cells were determined to be stable and localized to the nucleus; however, the arg53-to-pro mutant, which causes Axenfeld-Rieger syndrome type 1 (180500), also displayed cytoplasmic staining. This suggested a novel nuclear localization signal (NLS) within helix 3 of the PITX2 homeodomain, homologous to the NLS of the related transcription factor PITX1 (602149). DNA-binding shifts and transactivation studies demonstrated reduced activity of the arg46-to-trp and arg31-to-his mutant PITX2 proteins, which cause iridogoniodysgenesis syndrome type 2 (137600). The iris hypoplasia mutant retained the most activity in both studies, whereas the Axenfeld-Rieger syndrome mutant PITX2 proteins proved to be nonfunctional. The authors hypothesized that mutant PITX2 proteins that retain partial function result in milder anterior segment aberrations.
Priston et al. (2001) found 2 novel PITX2 mutations among 21 individuals affected with Axenfeld-Rieger syndrome: a val45-to-leu missense mutation (V45L; 601542.0010) within the PITX2 homeodomain, and a 7-amino acid duplication (7aaDup; 601542.0011) of residues 6 to 12 of the homeodomain. DNA-binding studies of the 2 mutant PITX2 proteins demonstrated a less than 10-fold reduction in the DNA-binding activity of the V45L mutant, but a more than 100-fold reduction in activity of the 7aaDup mutant. Luciferase reporter assays showed at least a 200% increase in PITX2 transactivation activity of the V45L mutant, while the 7aaDup mutant was unable to transactivate at detectable levels. The authors concluded that the DNA-binding domain of PITX2 may influence transactivation activity independently of DNA binding. Furthermore, they suggested that increased activity of one PITX2 allele may be as physiologically disruptive as a mutation that nullifies a PITX2 allele, with either condition resulting in Rieger syndrome.
PITX2 and DLX2 (126255) are transcription markers observed during early tooth development. Espinoza et al. (2002) demonstrated that PITX2 binds to bicoid and bicoid-like elements in the DLX2 promoter and activates this promoter 30-fold in Chinese hamster ovary cells. Mutations in PITX2 associated with Axenfeld-Rieger syndrome provided the first link of this homeodomain transcription factor to tooth development. One mutation produces Axenfeld-Rieger syndrome with iris hypoplasia but without tooth anomalies; this allele has a similar DNA binding specificity compared to wildtype PITX2 and transactivates the DLX2 promoter. In contrast, a different PITX2 mutation produces Rieger syndrome with the full spectrum of developmental anomalies, including tooth anomalies; this allele is unable to transactivate the DLX2 promoter. Since DLX2 expression is required for tooth and craniofacial development, the lack of tooth anomalies in the patient with iris hypoplasia may be due to the residual activity of this mutant in activating the DLX2 promoter. The authors proposed a molecular mechanism for tooth development involving DLX2 gene expression in Axenfeld-Rieger patients.
Lines et al. (2002) reviewed the molecular genetics of Axenfeld-Rieger malformations, including the roles of PITX2 and FOXC1 (601090) in human disease and mouse models.
Kamnasaran et al. (2003) reported a child with the translocation t(4;14)(q25;q13) who had mild craniofacial dysmorphism and agenesis of the corpus callosum without limb or ocular abnormalities. Complex molecular findings in 4q25 included a breakpoint within the 3-prime end of the PITX2 gene resulting in deletion of exons 6 and 7, and another breakpoint 47 bp distal to the 5-prime end of a putative gene of unknown function but with some similarity to kinases. One breakpoint was found in the 14q13 region within intron 3 of the 5-prime UTR of the MIPOL1 gene (606850). Kamnasaran et al. (2003) concluded that the 2 molecular breaks on 4q25 suggested a complex microrearrangement, such as an inversion, but that the alteration of the PITX2 gene was more likely to explain the phenotype.
To determine the possible role of altered PITX2 gene dosage in the etiology of malformations in the Axenfeld-Rieger spectrum, Lines et al. (2004) performed sequence analysis of the PITX2 gene in 64 patients with Axenfeld-Rieger syndrome, iridogoniodysgenesis (see IRID2, 137600), iris hypoplasia, or anterior segment dysgenesis. PITX2 dosage was concurrently examined in these patients by real-time quantitative PCR. Microsatellite markers were used to map 4q25 microdeletions at a contig scale. Six (9.4%) of the 64 patients carried an identifiable PITX2 mutation; 3 had point mutations and 3 had gross deletions. Both types of mutation appeared to produce an equivalent haploinsufficiency phenotype.
Berry et al. (2006) demonstrated that FOXC1 and the PITX2A isoform of PITX2 physically interact and that the interaction requires crucial functional domains on both proteins, e.g., the C-terminal activation domain of FOXC1 and the homeodomain of PITX2. Immunofluorescence studies revealed colocalization of FOXC1 and PITX2A within a common nuclear subcompartment, and transcription assay studies showed that PITX2A can function as a negative regulator of FOXC1 transactivity. The authors suggested that this negative regulation offers an explanation as to why increased FOXC1 gene dosage produces a phenotype resembling that of PITX2 deletions and mutations, and they concluded that functional interaction between FOXC1 and PITX2A underlies the sensitivity to FOXC1 gene dosage in Axenfeld-Rieger syndrome and related anterior segment dysgeneses.
Anterior Segment Dysgenesis 4
In the Scandinavian family in which Heon et al. (1995) demonstrated linkage of autosomal dominant iris hypoplasia (ASGD4; 137600) to chromosome 4q25, Alward et al. (1998) demonstrated that affected members carried a C-to-T substitution at the first nucleotide of codon 46 of the PITX2 gene resulting in an arginine to tryptophan amino acid change (601542.0007) in the homeodomain of the protein.
In a child with Peters anomaly, which is characterized by ocular anterior segment dysgenesis and central corneal opacification, Doward et al. (1999) reported an A-to-T transversion at the invariant -2 position of the 3-prime splice site of intron 3. The child had a number of extraocular associations, including failure of involution of the umbilical skin and signs of abnormal dental development.
Ring Dermoid of the Cornea
Ring dermoid of the cornea (RDC; 180550) is an autosomal dominant syndrome characterized by bilateral annular limbal dermoids with corneal and conjunctival extension. Xia et al. (2004) studied a Chinese family with 21 affected individuals and demonstrated linkage to 4q24-q26. They identified an R62H mutation (601542.0012) in 17 affected individuals but not in 8 genetically related but unaffected members of the kindred.
Susceptibility to Atrial Fibrillation
Ye et al. (2016) identified a functional SNP, rs2595104, within the atrial fibrillation susceptibility locus (ATFB5; 611494) identified by Gudbjartsson et al. (2007) on chromosome 4q25. The SNP lies within intron 3 and intron 4 of isoforms PITX2a and PITX2b, respectively, and approximately 10 kb upstream of the transcription start site of PITX2c, the dominant isoform in developing and adult left atrium. The reference (risk) allele T at rs2595104 displayed 44% lower enhancer activity by luciferase assay than the alternate (non-risk) allele G. Ye et al. (2016) found that rs2595104 lies within a binding site for the transcription factor TFAP2A (107580), and that TFAP2A bound robustly to the nonrisk allele, but not to the risk allele, in cardiomyocytes. CITED2 (602937), a TFAP2A binding partner that has been implicated in synergystic regulation of PITX2c, was also shown to differentially bind to rs2595104. Deletion of the region surrounding rs2595104 resulted in a one-fourth to one-third reduction of PITX2c expression in cardiomyocytes compared to wildtype, and PITX2c expression was 27% higher in cardiomyocyes carrying the nonrisk allele compared to the risk allele. Results of siRNA knockdown studies of TFAP2A and CITED2 in cardiomyocytes carrying risk or nonrisk alleles of rs2595104 suggested that differential PITX2c expression based on rs2595104 genotype is mediated through interaction with TFAP2A and CITED2. Ye et al. (2016) concluded that the SNP rs2595104 alters PITX2c expression via interaction with TFAP2A, and that this pathway could ultimately contribute to atrial fibrillation susceptibility at the 4q25 locus.
Yoshioka et al. (1998) reported that the mouse homolog of human PITX2, a bicoid-type homeobox gene expressed asymmetrically in the left lateral plate mesoderm, may be involved in determination of left-right (L-R) asymmetry in both mouse and chick. Since Pitx2 appears to be downstream of Lefty1 (603037) in the mouse pathway, they examined whether mouse Lefty proteins could affect the expression of Pitx2 in the chick. Their results indicated that a common pathway from Lefty1 to Pitx2 likely exists for determination of L-R asymmetry in vertebrates.
Logan et al. (1998) reported that the chick homolog of human PITX2 encodes a transcription factor expressed throughout the left lateral plate mesoderm and subsequently on the left side of asymmetric organs such as the heart and gut during organogenesis in the chick embryo. Pitx2 is induced by the asymmetric signals encoded by Nodal (601265) and Sonic hedgehog (600725), and its expression is blocked by prior treatment with an antibody against Sonic hedgehog. Misexpression of Pitx2 on the right side of the chick embryo is sufficient to produce reversed heart looping and heart isomerisms, reversed body rotation, and reversed gut situs.
Piedra et al. (1998) showed that modifications of the Pitx2 pattern of expression in the iv mouse mutation correlate with the situs alterations characteristic of the mutation. Misexpression experiments demonstrated that Sonic hedgehog and Nodal positively regulate Pitx2 expression. These results were compatible with a Pitx2 function in the late phase of the gene cascade controlling laterality.
Lin et al. (1999) generated mice null for the Pitx2 gene by targeted disruption. The mice were characterized by defective body-wall closure, right pulmonary isomerism, altered cardiac position, arrest in turning, and, subsequently, a block in the determination and proliferation events of anterior pituitary gland and tooth organogenesis. Pitx2 mice exhibited a severe phenotype with initial embryonic lethality about 35% on embryonic day 9.25 to 10.25 and continued attrition of mice with survival up to embryonic day 15. There was a failure to close the ventral body wall and thorax, apparent by embryonic day 9.5 and independent of gut herniation. While there were no abnormalities in cardiac development, about 50% of embryonic day 10 mutants exhibited positioning on the right rather than the midline. The authors suggested that these data indicate a role for Pitx2 in positioning the heart after the direction of cardiac looping has been determined. Lin et al. (1999) suggested a critical component of the Pitx2 -/- phenotype could be a failure to correctly activate target genes that require synergistic activation by Pitx2 and Lhx3/P-Lim. Pitx2 -/- mice also exhibited marked hypoplasia of the axial mesoderm, ventral body-wall splanchnic mesoderm, and urogenital system, as well as hypoproliferation of spleen, liver, mandible, periorbital musculature, and lens. Lin et al. (1999) concluded that the similarity of the cardiac and pulmonary phenotypes of Pitx2 -/- mice and Acvr2b (602730) -/- mice indicate that Pitx2 is the critical downstream target of Acvr2b, a putative Nodal receptor, mediating effects on both cardiac positioning and pulmonary isomerism. Since the Pitx2 phenotype extends to tissues other than those affected by Acvr2b, Pitx2 gene activation may be controlled separately in these tissues.
Lu et al. (1999) independently generated Pitx2 -/- mice. They determined that although Pitx2 -/- embryos had abnormal cardiac morphogenesis, mutant hearts looped in the normal direction. Pitx2 -/- embryos had correctly oriented, but arrested, embryonic rotation and right pulmonary isomerism. Lu et al. (1999) observed defective development of the mandibular and maxillary facial prominences, regression of the stomodeum, and arrested tooth development. They observed that Fgf8 (600483) expression was absent and Bmp4 (112262) expression was expanded in the branchial-arch ectoderm. Lu et al. (1999) concluded that these data reveal a critical role for Pitx2 in left-right asymmetry but indicate that Pitx2 may function at an intermediate step in cardiac morphogenesis and embryonic rotation.
Shiratori et al. (2001) investigated the transcriptional regulatory mechanisms that underlie L-R asymmetric expression of mouse Pitx2. Mouse Pitx2 has a left side-specific enhancer (ASE) that mediates both the initiation and maintenance of L-R asymmetric expression. This element contains 3 binding sites for the transcription factor Fast (603621). The Fast-binding sites function as Nodal-responsive elements and are sufficient for the initiation but not the maintenance of asymmetric expression. The maintenance requires an Nkx2.5 (600584)-binding site also present within the ASE. These results suggested that the left-sided expression of Pitx2 is directly initiated by Nodal signaling and is subsequently maintained by Nkx2. Such 2-step control may represent a general mechanism for gene regulation during development.
To determine the specific roles of Pitx2 in the neural crest precursor pool, Evans and Gage (2005) generated neural crest-specific Pitx2-knockout mice. Because Pitx2-knockout mice were viable, analysis of gene function in later eye development was possible. Pitx2 was intrinsically required in neural crest for specification of corneal endothelium, corneal stroma, and the sclera, and Pitx2 function in neural crest was also required for normal development of ocular blood vessels. Pitx2-knockout mice exhibited a unique optic nerve phenotype in which the eyes were progressively displaced toward the midline until they were directly attached to the ventral hypothalamus. As Pitx2 is not expressed in the optic stalk, an essential function of Pitx2 protein in neural crest may be to regulate an extrinsic factor(s) required for development of the optic nerve. Evans and Gage (2005) proposed a revised model of optic nerve development and novel mechanisms that may underlie the etiology of glaucoma in Axenfeld-Rieger patients.
Yashiro et al. (2007) showed that ablation of unilateral Pitx2 expression in mice impairs asymmetric remodeling of the branchial arch artery system, resulting in randomized laterality of the aortic arch. Pitx2-positive cells were found not to contribute to asymmetrically remodeled arteries. Instead, Pitx2 functions in the secondary heart field, and induces a dynamic morphologic change in the outflow tract of the heart, which results in the provision of an asymmetric blood supply to the sixth branchial arch artery. This uneven distribution of blood flow results in differential signaling by both the platelet-derived growth factor receptor (PDGFR; see 173410) and vascular endothelial growth factor receptor-2 (VEGFR2; 191306). The consequent stabilization of the left sixth branchial arch artery and regression of its right counterpart underlie left-sided formation of the aortic arch. Yashiro et al. (2007) concluded that hemodynamics, generated by a Pitx2-induced morphologic change in the outflow tract, is responsible for the asymmetric remodeling of the great arteries.
Pulmonary venous vessels are sheathed by a myocardial cell layer called the pulmonary myocardium. Mommersteeg et al. (2007) found that Pitx2c-null mice failed to develop a pulmonary myocardial sleeve due to the absence of pulmonary myocardial cell precursors. Genetic labeling demonstrated that the pulmonary myocardium arose from Nkx2.5-expressing precursors, while the systemic venous return arose from Nkx2.5-negative precursors. In the pulmonary myocardium of mice hypomorphic for Nkx2.5, expression of Pitx2 was unaltered, but expression of the Nkx2.5 target gap junction protein Cx40 (GJA5; 121013) was downregulated, and expression of the systemic venous return pacemaker channel Hcn4 (605206) was upregulated, resulting in a phenotype that partly resembled that of the systemic venous return. Mommersteeg et al. (2007) concluded that NKX2.5 and PITX2C play critical roles in the formation and identity of the pulmonary myocardium.
Deficiency of the transcription factor Cited2 (602937) in mice results in cardiac malformation, adrenal agenesis, neural tube and placental defects, and partially penetrant cardiopulmonary laterality defects due to disruption of the Nodal-Pitx2c pathway. Bentham et al. (2010) showed that a maternal high-fat diet more than doubled the penetrance of laterality defects and, surprisingly, induced palatal clefting in Cited2-deficient embryos. Both maternal diet and Cited2 deletion reduced embryo weight and kidney and thymus volume. Expression profiling identified 40 embryonic transcripts including Pitx2 that were significantly affected by embryonic genotype-maternal diet interaction. A high-fat diet reduced Pitx2c levels more than 2-fold in Cited2-deficient embryos. Taken together, these results defined a novel interaction between maternal high-fat diet and embryonic Cited2 deficiency that affects Pitx2c expression and results in abnormal laterality.
Lozano-Velasco et al. (2016) found that atria-specific deletion of Pitx2 in mice altered expression of genes involved in calcium handling, cell-cell junctions, G protein-coupled receptors, and Wnt signaling. Expression of these genes was perturbed in a left and right atria-dependent manner.
Using conditional mouse haploinsufficiency models, Nadadur et al. (2016) found that Tbx5 and Ptx2 antagonistically regulated gene expression in atria. Reduced Tbx5 expression profoundly disrupted cardiac channel gene expression and caused action potential abnormalities leading to primary, spontaneous atrial fibrillation. Concomitant haploinsufficiency for Pitx2 rescued the phenotype.
Based on the ocular, cardiac, and craniofacial expression pattern of Pitx2 and the pleiotropic effects of loss of PITX2 function in both mouse and human, Martin et al. (2002) hypothesized the PITX2 mutations may contribute to the multiple phenotypic anomalies present in individuals with CHARGE (214800). By direct sequencing of DNA from 29 affected individuals, they did not identify any mutations in PITX2, although they did identify 2 PITX2 sequence polymorphisms. Furthermore, large deletions in PITX2 were excluded in most patients by heterozygosity in at least 1 of several polymorphic markers near the PITX2 locus. Thus, PITX2 mutations are unlikely to be a major contributing cause of the multiple anomalies present in individuals with CHARGE.
In a family with Rieger syndrome (RIEG1; 180500), Semina et al. (1996) identified a missense mutation (744T-A) that changed the CTG codon for leu54 into a CAG codon for gln in the first helix of the homeodomain of the RIEG gene.
In a family with Rieger syndrome (RIEG1; 180500), Semina et al. (1996) demonstrated that affected members carried a G-to-C transversion in the RIEG gene at a conserved position +5 of the 5-prime splice site of the third intron.
In a family with Rieger syndrome (RIEG1; 180500), Semina et al. (1996) demonstrated that affected members had a 785A-C point mutation in the RIEG gene, changing ACA (thr) to CCA (pro) (T68P) in the second helix of the homeodomain. Amendt et al. (1998) showed that PITX2 with the T68P mutation retained DNA-binding activity with the same apparent K(D) and only about a 2-fold reduction in the B(max) compared with wildtype PITX2. However, the T68P mutant did not transactivate reporter genes containing the bicoid site. The T68P mutant bound PIT1 (173110), but there was no detectable synergism on the prolactin (PRL; 176760) promoter.
Venugopalan et al. (2008) showed that PITX2 with the T68P mutation could bind DNA and FOXJ1 (612291), but unlike wildtype PITX2, it was unable to transactivate the FOXJ1 promoter when coexpressed with FOXJ1, LEF1 (153245), and/or beta-catenin (CTNNB1; 116806).
In a family with Rieger syndrome (RIEG1; 180500), Semina et al. (1996) found that affected members had an A-to-G transition in the RIEG gene at position -11 in the third intron, which created an additional acceptor site, 5-prime from the normal one.
In a de novo case of Rieger syndrome (RIEG1; 180500), Semina et al. (1996) found an 855G-C missense mutation in the RIEG gene, changing CGG (arg) to CCG (pro) in the third helix of the homeobox.
In a de novo case of Rieger syndrome (RIEG1; 180500), Semina et al. (1996) identified a 981G-A transition that resulted in a trp133-to-ter nonsense mutation in the RIEG gene. (The mutation was described incorrectly as THR133TER in the text.)
In the family in which Heon et al. (1995) demonstrated linkage of autosomal dominant iris hypoplasia (ASGD4; 137600) to chromosome 4q25, Alward et al. (1998) demonstrated that affected members carried a C-to-T substitution of the first nucleotide of codon 46 resulting in an arginine to tryptophan amino acid change in the homeodomain of solurshin, the PITX2 gene product.
In a family with iridogoniodysgenesis (ASGD4; 137600), reported by Walter et al. (1996), Kulak et al. (1998) demonstrated a mutation in the PITX2 gene: a G-to-A transition was predicted to lead to an arg70-to-his amino acid substitution.
In a child with Peters anomaly (ASGD4; 137600), Doward et al. (1999) reported an A-to-T transversion at the invariant -2 position of the 3-prime splice site of intron 3. Peters anomaly is distinct from Rieger anomaly (see 180500). The child had a number of extraocular associations, including failure of involution of the umbilical skin and signs of abnormal dental development.
In a de novo case of Axenfeld-Rieger syndrome (RIEG1; 180500), Priston et al. (2001) identified a G-to-C transversion at position 830 that resulted in a val45-to-leu mutation in the PITX2 gene. Although the mutation demonstrated only slightly decreased DNA binding activity in vitro, reporter assays revealed a more than 200% increase in transactivation activity. The authors suggested that increased activity of one PITX2 allele may be as physiologically disruptive as a mutation that nullifies a PITX2 allele, with either condition resulting in Rieger syndrome.
In a de novo case of Axenfeld-Rieger syndrome (RIEG1; 180500), Priston et al. (2001) identified a 21-bp duplication at position 713 to 733 that resulted in duplication of amino acids 44 to 50 in the PITX2 gene. Expression of the mutated allele revealed a more than 100-fold reduction in DNA binding activity in vitro, as well as no detectable transactivation activity.
In a large Chinese family with ring dermoid of the cornea (RDC; 180550) in 4 successive generations, Xia et al. (2004) identified a 185G-A transition in the PITX2 gene, resulting in an arg62-to-his substitution (R62H) in the conserved DNA-binding homeodomain.
In an infant with characteristic features of Rieger syndrome (RIEG1; 180500), including small and dysplastic primary teeth, protuberant umbilicus, and ocular abnormalities that included bilateral anterior segment dysgenesis, Saadi et al. (2001) identified a de novo heterozygous A-to-G transition in the PITX2 gene, resulting in a lys88-to-glu (K88E) substitution in full-length PITX2A. Recombinant PITX2 with the K88E mutation showed little to no binding to a bicoid element. The K88E mutant functioned in a dominant-negative manner to suppress wildtype PITX2 activity in the presence of PIT1 (173110), likely due to formation of nonfunctional complexes between K88E and wildtype PITX2.
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