Alternative titles; symbols
HGNC Approved Gene Symbol: PITX1
Cytogenetic location: 5q31.1 Genomic coordinates (GRCh38): 5:135,027,734-135,034,789 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 5q31.1 | Clubfoot, congenital, with or without deficiency of long bones and/or mirror-image polydactyly | 119800 | Autosomal dominant | 3 |
Lamonerie et al. (1996) cloned and characterized a mouse transcription factor gene, Ptx1, on the basis of its ability to activate pituitary transcription of the proopiomelanocortin gene (176830). Ptx1 belongs to an expanding family of bicoid-related vertebrate homeobox genes (see PITX2; 601542). These genes, like their Drosophila homologs, seem to play a role in the development of anterior structures and, in particular, the brain and facies.
Crawford et al. (1997) cloned and sequenced human PTX1. The deduced 316-amino acid human protein contains an N-terminal homeodomain, followed by 2 PTX family motifs and a conserved 14-amino acid motif. The mouse and human PTX1 proteins share 100% identity in the homeodomain and are 88% and 97% conserved in the N- and C-terminal regions, respectively.
The PTX1, PTX2, and PTX3 (602669) genes define a novel family of transcription factors, the PTX subfamily, within the paired-like class of homeodomain factors. In mice, Ptx1 and Ptx2 gene expression has been detected in the area of the pituitary primordium and is maintained throughout development in the Rathke pouch and adult pituitary. Using Northern blot analysis, Pellegrini-Bouiller et al. (1999) detected a 2.5-kb PTX1 transcript in adult and fetal normal human pituitary.
Crawford et al. (1997) determined that the PITX1 gene contains 3 exons. The open reading frame of the first exon contains a trinucleotide repeat, (GCC)5. Intron/exon boundaries are conserved between mouse and human PITX1.
Crawford et al. (1997) localized the mouse Ptx1 gene by interspecific backcross to the central region of chromosome 13, which bears syntenic homology with human 5q. Fluorescence in situ hybridization placed the human gene on 5q31. Because of the craniofacial expression pattern of Ptx1 during early development, Crawford et al. (1997) suggested that it may be involved in Treacher Collins syndrome (TCS; 154500). However, TCS maps somewhat distal to the human Ptx1 homolog, in 5q32-q33.1. Additionally, a separate gene (TCOF1) has been found to carry TCS causative mutations; its mouse homolog is on chromosome 18, not chromosome 13.
Using somatic cell hybrid analysis, radiation hybrid analysis, and YAC contig mapping, Shang et al. (1997) localized the human BFT gene to 5q22-q31. By somatic cell hybrid and interspecific backcross analyses, they mapped the mouse Bft gene to the central portion of chromosome 13, near the 'dumpy' and 'mdac' loci, which are mutant genes that cause abnormal limb development. The authors stated that the temporal and spatial expression patterns of mouse Bft during development suggest that it has a role in specifying the identity or structure of the hindlimb.
To determine the number and type of genetic changes underlying pelvic reduction in natural populations, Shapiro et al. (2004) carried out genetic crosses between threespine stickleback fish (Gasterosteus aculeatus) with complete or missing pelvic structures. Genomewide linkage mapping showed that pelvic reduction is controlled by 1 major and 4 minor chromosome regions. Pitx1 maps to the major chromosome region controlling most of the variation in pelvic size. Pelvic-reduced fish showed the same left-right asymmetry seen in Pitx1 knockout mice, but did not show changes in Pitx1 protein sequence. Instead, pelvic-reduced sticklebacks showed site-specific regulatory changes in Pitx1 expression, with reduced or absent expression in pelvic and caudal fin precursors. Shapiro et al. (2004) concluded that regulatory mutations in major developmental control genes may provide a mechanism for generating rapid skeletal changes in natural populations, while preserving the essential roles of these genes in other processes.
Using Northern blot analysis, Pellegrini-Bouiller et al. (1999) detected similar levels of PTX1 expression in all 60 human pituitary adenomas examined.
Skelly et al. (2000) studied expression of PITX1 and PROP1 (601538) in a series of 34 pituitary adenomas fully characterized for in vitro hormone secretion and histologic staining. Of the 34 pituitary adenomas studied, PITX1 expression was reduced by more than 50% compared with that of the housekeeping gene glyceraldehyde-3-phosphate dehydrogenase (138400) in the 6 corticotroph adenomas, which also had significantly reduced alpha subunit production. PROP1 expression was detected in all 34 pituitary adenomas, including 6 corticotroph adenomas and 5 gonadotroph adenomas.
Pitx1 and Tbx4 (601719) encode transcription factors that are expressed throughout the developing hindlimb, but not in forelimb buds. Logan and Tabin (1999) injected a retroviral vector carrying Pitx1 into the wing field of chicken embryos. Misexpression of Pitx1 in the chick wing bud induced distal expression of Tbx4, as well as HoxC10 (605560) and HoxC11 (605559), which are normally restricted to hindlimb expression domains. Wing buds in which Pitx1 was misexpressed developed into limbs with some morphologic characteristics of hindlimbs: the flexure was altered to that normally observed in legs, the digits were more toe-like in the relative size and shape, and the muscle pattern was transformed to that of a leg. Expression of Tbx5 (601620), normally expressed only in the forelimb, was not altered by Pitx1 misexpression.
Facioscapulohumeral muscular dystrophy (FSHD; 158900) is an autosomal dominant disorder linked to contractions of the D4Z4 repeat array in the subtelomeric region of chromosome 4q. By comparing genomewide expression profiles of muscle biopsies from patients with FSHD to those of 11 other neuromuscular disorders, Dixit et al. (2007) identified 5 genes, including PITX1, that were specifically upregulated in FSHD patients. Expression of DUX4 (606009), which maps within the D4Z4 unit, was upregulated in FSHD myoblasts at both the mRNA and protein levels. DUX4 activated expression of a reporter gene fused to the PITX1 promoter and of endogenous Pitx1 in DUX4-transfected C2C12 mouse myoblasts. In electrophoretic mobility shift assays, DUX4 specifically interacted with a 30-bp sequence containing a conserved TAAT core motif in the PITX1 promoter. Mutations of the TAAT core affected Pitx1 activation in C2C12 cells and DUX4 binding in vitro.
Qi et al. (2011) found that mouse and human PITX1 downregulated telomerase activity in melanoma cell lines by directly binding to specific PITX1-binding sites in the promoter region of the TERT (187270) gene and suppressing TERT expression. The promoter region of both mouse and human TERT contains 3 putative PITX1-binding sites. All 3 sites are functional in human, but only 1 is functional in mouse. Immunohistochemical analysis revealed lower PITX1 staining in 70% of 16 human gastric adenocarcinomas compared with adjacent normal gastric mucosa.
By analyzing Pitx1 expression in developing hindlimbs of mouse embryos, Kragesteen et al. (2018) demonstrated the presence of pan-limb regulatory elements within the Pitx1 regulatory landscape. Analysis of mice carrying Pitx1 deletion mutants revealed that a pan-limb enhancer (Pen) with strong activity both in forelimbs and hindlimbs was required for normal hindlimb-specific Pitx1 expression. Examination of the local chromatin architecture of the Pitx1 locus in mouse embryos showed that 2 divergent states of chromatin architecture in forelimbs and hindlimbs maintained Pitx1 either in an active or inactive state. Characterization of 3-dimensional (3D) chromatin folding at the Pitx1 locus in developing tissues revealed that tissue-specific 3D chromatin architecture controlled Pen and Pitx1 interaction. In forelimb, Pitx1 was physically disconnected from Pen and, as a result, was not expressed in forelimb. In hindlimb, Pitx1 was in close vicinity to Pen for interaction and was therefore expressed in hindlimb. This hindlimb-specific active 3D chromatin folding and transcription of Pitx1 was controlled by multiple factors, including homeobox C cluster genes. Consistently, tissue-specific perturbations of the Pitx1 locus conformation in mouse limbs caused ectopic Pitx1-Pen interactions, transcriptional endoactivation of Pitx1, and limb malformation. Mice carrying a mutation resembling the human Liebenberg syndrome (186550) deletion (see MOLECULAR GENETICS) exhibited misfolding of the Pitx1 regulatory landscape, causing ectopic forelimb interactions between Pen and Pitx1 and a Liebenberg syndrome-like phenotype.
Congenital Clubfoot with or without Deficiency of Long Bones and/or Mirror-Image Polydactyly
In affected members of a 5-generation family segregating clubfoot and various other lower extremity anomalies (119800), Gurnett et al. (2008) identified a missense mutation in the PITX1 gene (602149.0001). In addition to 8 affected mutation-positive individuals, there were 5 unaffected carrier females in the family.
Klopocki et al. (2012) sequenced the PITX1 gene in 8 individuals with isolated high-degree polydactyly and/or tibial hemimelia but normally developed upper extremities, and identified heterozygosity for a 35-bp deletion in exon 3 of the PITX1 gene (602149.0002) in 1 patient.
Liebenberg Syndrome
In 3 families segregating autosomal dominant Liebenberg syndrome (LBNBG; 186550), an upper-limb malformation that shows features of homeotic limb transformation in which the arms acquire morphologic characteristics of the legs, Spielmann et al. (2012) identified 3 different genomic rearrangements (2 large deletions and a chromosome 5;18 translocation, respectively) that relocated 3 putative enhancer elements into the vicinity of the PITX1 gene. The authors demonstrated that all 3 elements had forelimb-specific activity in mouse embryos, and transgenic hs1473-Pitx1 mice showed features characteristic of Pitx1 misexpression at embryonic day 15.5, with forelimb-to-hindlimb transformation (see ANIMAL MODEL). Spielmann et al. (2012) hypothesized that the arm-to-leg transformation observed in affected members of the 3 families segregating Liebenberg syndrome was due to misexpression of PITX1 in the upper extremities.
In an Italian woman and her 2 sons with mild Liebenberg syndrome, Kragesteen et al. (2019) identified an 8.5-kb deletion spanning the noncoding first exon of the H2AFY gene that segregated with disease in the family. Using CRISPR-Cas9 engineering in mice, the authors demonstrated that the promoter of the H2afy gene insulates the Pitx1 enhancer Pen from Pitx1 in forelimbs, whereas loss of the H2afy promoter results in misexpression of Pitx1 by pan-limb activity of the Pen enhancer. The level of Pitx1 mRNA determines the severity of the phenotype in mice, and the authors suggested that this may occur in the human Liebenberg phenotype, whereby the closer Pen is placed in a linear relation to PITX1, the more complete the transformation of arms into legs.
Chan et al. (2010) showed that pelvic loss in different natural populations of threespine stickleback fish has occurred through regulatory mutations deleting a tissue-specific enhancer of the Pitx1 gene. The high prevalence of deletion mutations in Pitx1 may be influenced by inherent structural features of the locus. Although Pitx1-null mutations are lethal in laboratory animals, Pitx1 regulatory mutations show molecular signatures of positive selection in pelvic-reduced populations. Chan et al. (2010) concluded that their studies illustrate how major expression and morphologic changes can arise from single mutational leaps in natural populations, producing new adaptive alleles via recurrent regulatory alterations in a key developmental control gene.
Szeto et al. (1999) found that Pitx1-deleted mice exhibited striking abnormalities in morphogenesis and growth of the hindlimb, resulting in a limb that exhibited structural changes in tibia and fibula as well as patterning alterations in patella and proximal tarsus, causing the hindlimb to more closely resemble the corresponding forelimb structures. Deletion of the Pitx1 gene resulted in decreased distal expression of the hindlimb-specific marker Tbx4. Pitx1-deleted mice also exhibited reciprocal abnormalities of 2 ventral and 1 dorsal anterior pituitary cell types, presumably on the basis of its synergistic functions with other transcription factors, and defects in the derivatives in the first branchial arch, including cleft palate, suggesting a proliferative defect in these organs analogous to that observed in the hindlimb.
By gene targeting and transgenic methods, Minguillon et al. (2005) examined the ability of Tbx4 and Pitx1 to rescue the no-forelimb phenotype of mutant mice with Tbx5 knockout restricted to limbs. Tbx4 could replace Tbx5 and rescue limb outgrowth, but Pitx1 could not. In contrast to previous chick misexpression studies, Tbx4-rescued limbs had a forelimb-like phenotype, suggesting that Tbx4 alone does not dictate hindlimb morphology and that forelimb characteristics can develop in the absence of Tbx5. To determine the role of Pitx1 in defining hindlimb characteristics, Minguillon et al. (2005) introduced forelimb-targeted Pitx1 into mice expressing endogenous Tbx5 and into mutant mice rescued by Tbx4. In both cases, forelimb-targeted Pitx1 expression caused a partial forelimb-to-hindlimb transformation, indicating that Pitx1 has a role in directing hindlimb morphology.
Alvarado et al. (2011) generated Pitx1 +/- mice and observed clubfoot-like abnormalities in 20 of 225 Pitx1 +/- mice, for a penetrance of 8.9%. Clubfoot was unilateral in 16 of the 20 affected mice, with the right and left limbs equally affected. Peroneal artery hypoplasia occurred in the clubfoot limb and corresponded spatially with small lateral muscle compartments. Tibial and fibular bone volumes were also reduced. Skeletal muscle gene expression was significantly reduced in Pitx1 -/- hindlimb buds at embryonic day 12.5 compared to wildtype, suggesting that muscle hypoplasia was due to abnormal early muscle development and not disuse atrophy. Alvarado et al. (2011) concluded that PITX1 haploinsufficiency may cause a developmental field defect preferentially affecting the lateral lower leg.
Spielmann et al. (2012) generated single-copy hs1473-Pitx1 transgenic mice and observed that at embryonic day 15.5, the mutant mice showed characteristic features of Pitx1 misexpression resulting in a forelimb-to-hindlimb transformation. The mice showed loss of the olecranon, thus recapitulating the human phenotype of Liebenberg syndrome (186550). Only 1 zeugopod bone was present. The distal head of the humerus was more similar to the distal femur, and the shape of the proximal head of the single zeugopodal element resembled the shape of the proximal tibia. Two digits were missing, and the remaining digit I had 2 phalanges and was fused to the metacarpal of digit II. Fusions of the carpals formed a structure similar in shape to the calcaneus of the hindlimb. The fusion of the carpals and radial deviation of the hands caused a foot-like appearance of the forelimb.
In affected members of a 5-generation family segregating asymmetric right-sided predominant clubfoot (119800), Gurnett et al. (2008) identified a 388G-A transition in the PITX1 gene, resulting in a glu130-to-lys (E130K) substitution in the highly conserved homeodomain of the protein. The mutation was also present in 2 tested obligate carriers and was absent in 500 control subjects. The proband had bilateral clubfoot, bilateral foot preaxial polydactyly, and right-sided tibial hemimelia. Five other family members had clubfoot. Other than the proband, none had polydactyly or tibial hemimelia. Some family members had other lower limb malformations including patellar hypoplasia, oblique talus manifesting as pes planus, and developmental hip dysplasia.
In an infant with bilateral preaxial polydactyly, talipes equinovarus, and right tibial hemimelia (119800), Klopocki et al. (2012) identified heterozygosity for a 35-bp deletion (765_799del) in exon 3 of the PITX1 gene, predicted to cause a frameshift and addition of 303 amino acids (Ala256ArgfsTer303), resulting in loss of the C-terminal part of the protein, including the 14-amino acid OAR domain. The mutation was not found in the unaffected mother or in 400 control chromosomes; DNA from the father was not available.
Alvarado, D. M., McCall, K., Aferol, H., Silva, M. J., Garbow, J. R., Spees, W. M., Patel, T., Siegel, M., Dobbs, M. B., Gurnett, C. A. Pitx1 haploinsufficiency causes clubfoot in humans and a clubfoot-like phenotype in mice. Hum. Molec. Genet. 20: 3943-3952, 2011. [PubMed: 21775501] [Full Text: https://doi.org/10.1093/hmg/ddr313]
Chan, Y. F., Marks, M. E., Jones, F. C., Villarreal, G., Jr., Shapiro, M. D., Brady, S. D., Southwick, A. M., Absher, D. M., Grimwood, J., Schmutz, J., Myers, R. M., Petrov, D., Jonsson, B., Schluter, D., Bell, M. A., Kingsley, D. M. Adaptive evolution by pelvic reduction in sticklebacks by recurrent deletion of a Pitx1 enhancer. Science 327: 302-305, 2010. [PubMed: 20007865] [Full Text: https://doi.org/10.1126/science.1182213]
Crawford, M. J., Lanctot, C., Tremblay, J. J., Jenkins, N., Gilbert, D., Copeland, N., Beatty, B., Drouin, J. Human and murine PTX1/Ptx1 gene maps to the region for Treacher Collins syndrome. Mammalian Genome 8: 841-845, 1997. [PubMed: 9337397] [Full Text: https://doi.org/10.1007/s003359900589]
Dixit, M., Ansseau, E., Tassin, A., Winokur, S., Shi, R., Qian, H., Sauvage, S., Matteotti, C., van Acker, A. M., Leo, O., Figlewicz, D., Barro, M., Laoudj-Chenivesse, D., Belayew, A., Coppee, F., Chen, Y.-W. DUX4, a candidate gene of facioscapulohumeral muscular dystrophy, encodes a transcriptional activator of PITX1. Proc. Nat. Acad. Sci. 104: 18157-18162, 2007. [PubMed: 17984056] [Full Text: https://doi.org/10.1073/pnas.0708659104]
Gurnett, C. A., Alaee, F., Kruse, L. M., Desruisseau, D. M., Hecht, J. T., Wise, C. A., Bowcock, A. M., Dobbs, M. B. Asymmetric lower-limb malformations in individuals with homeobox PITX1 gene mutation. Am. J. Hum. Genet. 83: 616-622, 2008. [PubMed: 18950742] [Full Text: https://doi.org/10.1016/j.ajhg.2008.10.004]
Klopocki, E., Kahler, C., Foulds, N., Shah, H., Joseph, B., Vogel, H., Luttgen, S., Bald, R., Besoke, R., Held, K., Mundlos, S., Kurth, I. Deletions in PITX1 cause a spectrum of lower-limb malformations including mirror-image polydactyly. Europ. J. Hum. Genet. 20: 705-708, 2012. [PubMed: 22258522] [Full Text: https://doi.org/10.1038/ejhg.2011.264]
Kragesteen, B. K., Brancati, F., Digilio, M. C., Mundlos, S., Spielmann, M. H2AFY promoter deletion causes PITX1 endoactivation and Liebenberg syndrome. J. Med. Genet. 56: 246-251, 2019. [PubMed: 30711920] [Full Text: https://doi.org/10.1136/jmedgenet-2018-105793]
Kragesteen, B. K., Spielmann, M., Paliou, C., Heinrich, V., Schopflin, R., Esposito, A., Annuziatella, C., Bianco, S., Chiariello, A. M., Jerkovic, I., Harabula, I., Guckelberger, P., and 12 others. Dynamic 3D chromatin architecture contributes to enhancer specificity and limb morphogenesis. Nature Genet. 50: 1463-1473, 2018. [PubMed: 30262816] [Full Text: https://doi.org/10.1038/s41588-018-0221-x]
Lamonerie, T., Tremblay, J. J., Lanctot, C., Thierrien, M., Gauthier, Y., Drouin, J. Ptx1, a bicoid-related homeo box transcription factor involved in transcription of the pro-opiomelanocortin gene. Genes Dev. 10: 1284-1295, 1996. [PubMed: 8675014] [Full Text: https://doi.org/10.1101/gad.10.10.1284]
Logan, M., Tabin, C. J. Role of Pitx1 upstream of Tbx4 in specification of hindlimb identity. Science 283: 1736-1739, 1999. [PubMed: 10073939] [Full Text: https://doi.org/10.1126/science.283.5408.1736]
Minguillon, C., Del Buono, J., Logan, M. P. Tbx5 and Tbx4 are not sufficient to determine limb-specific morphologies but have common roles in initiating limb outgrowth. Dev. Cell 8: 75-84, 2005. [PubMed: 15621531] [Full Text: https://doi.org/10.1016/j.devcel.2004.11.013]
Pellegrini-Bouiller, I., Manrique, C., Gunz, G., Grino, M., Zamora, A. J., Figarella-Branger, D., Grisoli, F., Jaquet, P., Enjalbert, A. Expression of the members of the Ptx family of transcription factors in human pituitary adenomas. J. Clin. Endocr. Metab. 84: 2212-2220, 1999. [PubMed: 10372733] [Full Text: https://doi.org/10.1210/jcem.84.6.5760]
Qi, D.-L., Ohhira, T., Fujisaki, C., Inoue, T., Ohta, T., Osaki, M., Ohshiro, E., Seko, T., Aoki, S., Oshimura, M., Kugoh, H. Identification of PITX1 as a TERT suppressor gene located on human chromosome 5. Molec. Cell. Biol. 31: 1624-1636, 2011. [PubMed: 21300782] [Full Text: https://doi.org/10.1128/MCB.00470-10]
Shang, J., Li, X., Ring, H. Z., Clayton, D. A., Francke, U. Backfoot, a novel homeobox gene, maps to human chromosome 5 (BFT) and mouse chromosome 13 (Bft). Genomics 40: 108-113, 1997. [PubMed: 9070926] [Full Text: https://doi.org/10.1006/geno.1996.4558]
Shapiro, M. D., Marks, M. E., Peichel, C. L., Blackman, B. K., Nereng, K. S., Jonsson, B., Schluter, D., Kingsley, D. M. Genetic and developmental basis of evolutionary pelvic reduction in threespine sticklebacks. Nature 428: 717-723, 2004. Note: Erratum: Nature 439: 1014 only, 2006. [PubMed: 15085123] [Full Text: https://doi.org/10.1038/nature02415]
Skelly, R. H., Korbonits, M., Grossman, A., Besser, G. M., Monson, J. P., Geddes, J. F., Burrin, J. M. Expression of the pituitary transcription factor Ptx-1, but not that of the trans-activating factor Prop-1, is reduced in human corticotroph adenomas and is associated with decreased alpha-subunit secretion. J. Clin. Endocr. Metab. 85: 2537-2542, 2000. [PubMed: 10902805] [Full Text: https://doi.org/10.1210/jcem.85.7.6683]
Spielmann, M., Brancati, F., Krawitz, P. M., Robinson, P. N., Ibrahim, D. M., Franke, M., Hecht, J., Lohan, S., Dathe, K., Nardone, A. M., Ferrari, P., Landi, A., Wittler, L., Timmermann, B., Chan, D., Mennen, U., Klopocki, E., Mundlos, S. Homeotic arm-to-leg transformation associated with genomic rearrangements at the PITX1 locus. Am. J. Hum. Genet. 91: 629-635, 2012. [PubMed: 23022097] [Full Text: https://doi.org/10.1016/j.ajhg.2012.08.014]
Szeto, D. P., Rodriguez-Esteban, C., Ryan, A. K., O'Connell, S. M., Liu, F., Kioussi, C., Gleiberman, A. S., Izpisua-Belmonte, J. C., Rosenfeld, M. G. Role of the Bicoid-related homeodomain factor Pitx1 in specifying hindlimb morphogenesis and pituitary development. Genes Dev. 13: 484-494, 1999. [PubMed: 10049363] [Full Text: https://doi.org/10.1101/gad.13.4.484]