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*176310
Table of Contents
Other entities represented in this entry:
HGNC Approved Gene Symbol: PBX1
Cytogenetic location: 1q23.3 Genomic coordinates (GRCh38) : 1:164,559,184-164,886,047 (from NCBI)
PBX1 is a homeodomain transcription factor of the TALE (3 amino acid loop extension) class that regulates numerous embryonic processes, including morphologic patterning, organogenesis, and hematopoiesis. It is a component of protein complexes that regulate developmental gene expression, in part, through modulation of HOX protein (see 142950) DNA-binding and context-dependent transcriptional functions. In complex with other TALE class proteins, PBX1 may mark genes for activation through penetration of repressive chromatin and recruitment of coactivators. PBX1 has been implicated in promoting progenitor cell proliferation in multiple tissues (summary by Ficara et al., 2008).
Human pre-B-cell acute lymphoblastic leukemias are frequently associated with a t(1;19)(q23;p13.3) chromosomal rearrangement. Kamps et al. (1990) and Nourse et al. (1990) demonstrated that several cell lines carrying this translocation synthesize chimeric mRNAs with 5-prime sequences encoded by the E2A transcription factor gene (TCF3; 147141) on chromosome 19 and 3-prime sequences encoded by a homeobox-related sequence, called Prl or PBX1, on chromosome 1. In the chimeric transcription factor, the DNA binding domain of E2A is replaced by a putative DNA binding domain of PBX1. In 3 cell lines reported by Nourse et al. (1990), identical E2A-Prl mRNA junctions were observed, suggesting that the fusion transcripts are a consistent feature of this translocation.
Monica et al. (1991) confirmed the mapping of PBX1 to 1q23 by in situ hybridization.
Pseudogenes
Sugaya et al. (1994) conducted a chromosome walk in the class III region of the major histocompatibility complex (MHC) near the junction with class II. There they found a gene with the characteristics of PBX2 (176311), which, however, had been mapped to chromosome 3 (Monica et al., 1991). Fluorescence in situ hybridization confirmed the location of the 'new' gene at 6p21.3. The PBX gene on chromosome 3 was later found to be a pseudogene and the PBX gene on chromosome 6 was designated PBX2.
Kamps et al. (1991) discussed the chimeric genes created by the human t(1;19) translocation in pre-B-cell acute lymphoblastic leukemias. The authors cloned 2 different E2A-PBX1 fusion transcripts (which differed only in the PBX1 sequences they contained) and showed that NIH-3T3 cells transfected with cDNAs encoding the fusion proteins were able to cause malignant tumors in nude mice. They discussed subtle differences in the transforming ability of the 2 fusion proteins with respect to the regions of the PBX1 gene they contained.
Two distinct urokinase (PLAU; 191840) enhancer factor-3 (UEF3) complexes, which share a common 64-kD subunit but differ in having either a 50-kD or 40-kD subunit, recognize a TGACAG core DNA sequence. Berthelsen et al. (1998) identified PREP1 (PKNOX1; 602100) as the common 64-kD UEF3 subunit, PBX2 (176311) as the 50-kD subunit, and PBX1 isoform b (PBX1b) as the 40-kD subunit. Immunoprecipitation analysis confirmed that PREP1 also formed a complex with PBX1 isoform a (PBX1a), and interaction of PREP1 with its UEF3 partners was independent of DNA. Recombinant PREP1 bound to the TGACAG core sequence with low affinity. However, it bound with much higher affinity when it was cotranslated in vitro with either PBX1a, PBX1b, or PBX2, but not when it was mixed with its purified binding partners.
Mercader et al. (1999) described the role of homeobox genes Meis1 (601739), Meis2 (601740), and Pbx1 in the development of mouse, chicken, and Drosophila limbs. Mercader et al. (1999) found that Meis1 and Meis2 expression is restricted to the proximal domain, coincident with the previously reported domain in which Pbx1 is localized to the nucleus. Meis1 regulates Pbx1 activity by promoting nuclear import of the Pbx1 protein. Mercader et al. (1999) also demonstrated that ectopic expression of Meis1 in chicken disrupts distal limb development and induces distal-to-proximal transformations. Mercader et al. (1999) concluded that the restriction of Meis1 to proximal regions of the vertebrate limb is essential to specify cell fates and differentiation patterns along the proximodistal axis of the limb.
Using yeast 2-hybrid analysis and in vitro and in vivo binding assays, Abramovich et al. (2000) showed that human HPIP (PBXIP1; 618819) interacted with PBX1. The interaction required the homeodomain of PBX1 and its immediate N-terminal flanking sequence. HPIP interaction blocked formation of heterodimeric DNA-binding complexes between PBX1 and HOXB proteins, including HOXB7 (142962). HPIP also inhibited the transcriptional activation capacity of the E2A-PBX1 complex.
Wiemels et al. (2002) sequenced the genomic fusion between the PBX1 and E2A genes in 22 pre-B acute lymphoblastic leukemias and 2 cell lines. The prenatal origin of the leukemia was assessed in 15 pediatric patients by screening for the clonotypic PBX1-E2A translocation in neonatal blood spots, or Guthrie cards, obtained from the children at birth. Two patients were weakly positive for the fusion at birth, in contrast to previously studied childhood leukemia fusions, t(12;21), t(8;21), and t(4;11), which are predominantly prenatal. The presence of extensive N-nucleotides at the point of fusion in the PBX1-E2A translocation as well as specific characteristics of the IGH (147100)/TCR (see 186880) rearrangements provided additional evidence for a postnatal, pre-B cell origin. Sixteen of 24 breakpoints on the 3.2-kb E2A intron 14 were located within 5 bp, providing evidence for a site-specific recombination mechanism. Breakpoints on the 232-kb PBX1 intron 1 were more dispersed, but were highly clustered proximal to exon 2. Thus, the translocation breakpoints displayed evidence of unique temporal, ontologic, and mechanistic formation in contrast to the previously analyzed pediatric leukemia translocation breakpoints, emphasizing the need to differentiate cytogenetic and molecular subgroups for studies of leukemia causality.
Cheung et al. (2009) showed that PBX1 mRNA was constitutively expressed in both human bone-derived cells (HBDC) and murine preosteoblasts. Immunostaining revealed that PBX1 was localized in the nucleus compartment. RNAi knockdown of PBX1 murine preosteoblasts resulted in decreased expression of Runx2 (600211) and osterix (SP7; 606633), the critical transcription factors for osteogenesis, but accelerated cell proliferation and bone nodule formation.
Le Tanno et al. (2017) found expression of PBX1 in human fetal tissues, with strongest expression in the kidney and brain. Lower levels of PBX1 expression persisted in adult tissues. In the human fetal kidney, PBX1 was detected as nuclear staining in the medulla, interstitium, and mesenchyme. PBX1 was not detected in renal tubes or the ureteric bud. In child and adult tissues, PBX1 was mainly detected in endothelial cells of the glomeruli and interstitium. The findings suggested that PBX1 is expressed mainly by stromal cells to regulate nephrogenesis.
Congenital Anomalies of the Kidney and Urinary Tract Syndrome with or without Hearing Loss, Abnormal Ears, or Developmental Delay
In 3 of 204 unrelated patients with congenital anomalies of the kidney and urinary tract (CAKUT) who underwent next generation sequencing of candidate genes, Heidet et al. (2017) identified 3 different de novo heterozygous point mutations in the PBX1 gene, all of which resulted in a truncated protein (176310.0001-176310.0003). The mutations were confirmed by Sanger sequencing. Functional studies of the variants and studies of patient cells were not performed, but the mutations were predicted to result in a loss of function and haploinsufficiency. The patients had a syndromic form of the disorder: congenital anomalies of the kidney and urinary tract with or without hearing loss, abnormal ears, and developmental delay (CAKUTEHD; 617641).
In 8 unrelated patients with CAKUTEHD, Slavotinek et al. (2017) identified 7 different de novo heterozygous mutations in the PBX1 gene (see, e.g., 176310.0004-176310.0007). There were 5 missense mutations, 1 frameshift mutation, and 1 nonsense mutation. In vitro functional expression studies of 5 of the mutations showed variable disturbances in protein function. In the presence of endogenous wildtype PBX1, all 5 mutant proteins exhibited a significant decrease in transactivation capability, despite different locations of the mutations within the protein domains. These results suggested that the mutant proteins might either be directly responsible for the decrease of transactivation activity observed or might affect the capability of the endogenous protein to transactivate target genes, resembling PBX1 haploinsufficiency. Similar studies of the mutant proteins in cells with marked reduction of wildtype PBX1 showed that only 2 of the variants exhibited significantly diminished transactivation activity, suggesting that these mutations directly affect the intrinsic capability of PBX1 to transactivate downstream transcriptional targets. In addition, 2 of the variants showed decreased nuclear localization. Overall, the findings indicated that disruption of PBX1 target genes can cause variable aberrations in normal embryonic development. Slavotinek et al. (2017) noted that the pleiotropic defects observed in patients reflect the broad expression of Pbx1 during murine embryogenesis and are consistent with the multiple organ systems affected in Pbx1-knockout mice.
Associations Pending Confirmation
For discussion of a possible association between variation in the PBX1 gene and bone mineral density, see BMND2 (605833).
Selleri et al. (2001) showed that Pbx1 is required in skeletal patterning and programming. Pbx1 -/- mice died by embryonic day 15 or 16 with severe hypoplasia or aplasia of multiple organs and widespread patterning defects of the axial and appendicular skeleton. Pbx1 -/- embryos had thinning compressions and fusions of the vertebral bodies and neural arches, as well as defects in the proximal forelimbs and hindlimbs.
In vitro studies have shown that PBX1 regulates the activity of IPF1, a Para-Hox homeodomain transcription factor required for the development and function of the pancreas in mice and humans. To investigate in vivo roles of PBX1 in pancreatic development and function, Kim et al. (2002) examined pancreatic Pbx1 expression, and morphogenesis, cell differentiation, and function in mice deficient for Pbx1. Pbx1 -/- embryos had pancreatic hypoplasia and marked defects in exocrine and endocrine cell differentiation prior to death at embryonic day 15 or 16. In these embryos, expression of Isl1 (600366) and Atoh5 (604882), essential regulators of pancreatic morphogenesis and differentiation, was severely reduced. Pbx1 +/- adults had pancreatic islet malformations, impaired glucose tolerance, and hypoinsulinemia. Thus, Kim et al. (2002) concluded that PBX1 is essential for normal pancreatic development and function. Analysis of trans-heterozygous Pbx1 +/- and Ipf1 +/- mice revealed in vivo genetic interactions between Pbx1 and Ipf1 that are essential for postnatal pancreatic function. Trans-heterozygous mice developed age-dependent overt diabetes mellitus, unlike Pbx1 +/- or Ipf1 +/- mice. Mutations affecting the Ipf1 protein promote diabetes mellitus in mice and humans. Kim et al. (2002) concluded that perturbation of PBX1 activity may also promote susceptibility to diabetes mellitus.
Schnabel et al. (2003) found that Pbx1-null mouse embryos died at about E15.5. The kidneys were reduced in size and axially mispositioned, had fewer nephrons than controls, and sometimes showed unilateral agenesis. The mutant kidneys had expanded regions of mesenchymal condensates in the nephrogenic zone. Decreased branching and elongation of the ureter were also observed. These findings established a role for Pbx1 in mesenchymal-epithelial signaling, and indicated that Pbx1 is an essential regulator of mesenchymal function during renal morphogenesis.
By conditionally inactivating Pbx1 expression in the adult mouse hematopoietic system, Ficara et al. (2008) found that Pbx1 positively regulated hematopoietic stem cell (HSC) quiescence. Pbx1-deficient mice progressively lost long-term HSCs, leading to defects in maintenance of self-renewal. Pbx1-deficient long-term HSCs exhibited perturbed expression of multiple stem cell maintenance factors, and they displayed altered transcriptional responses to TGF-beta (TGFB1; 190180) stimulation in vitro.
Koss et al. (2012) found that conditional knockout of Pbx1 in splenic mesoderm of mouse embryos resulted in hyposplenia and fragmented splenules due to a defect in mesenchymal cell proliferation. Conditional knockout of Pbx1, which controls Nkx2-5 (600584) expression, resulted in decreased expression of Nkx2-5 and hyposplenia, indicating that Nkx2-5 is critical for splenic growth. Pbx1 was found to repress the cell cycle inhibitor CDKN2B (600431) in the spleen anlage; loss of Pbx1 in cultured spleen mesenchymal cells caused upregulation of Cdkn2b and reduced proliferation of these cells. Splenic expansion could be partially rescued by genetic ablation of Cdkn2b. Thus, repression of Cdkn2b by Pbx1 is required for proper organ morphogenesis and growth in vivo. Nkx2-5 was also shown to bind to and repress Cdkn2b. The findings delineated a regulatory module governing mammalian spleen organogenesis that involves Pbx1, Nkx2-5, and Cdkn2b.
In a 21-year-old woman (K175) with congenital anomalies of the kidney and urinary tract syndrome with or without hearing loss, abnormal ears, or developmental delay (CAKUTHED; 617641), Heidet et al. (2017) identified a de novo heterozygous 1-bp deletion (c.428delA, NM_002585) in the PBX1 gene, resulting in a frameshift and premature termination (Asn143ThrfsTer37). The mutation, which was found by screening of candidate genes and confirmed by Sanger sequencing, was not found in the ExAC database. The patient had hearing loss, but developmental delay was not mentioned.
In an 11-year-old girl (K179) with congenital anomalies of the kidney and urinary tract syndrome with or without hearing loss, abnormal ears, or developmental delay (CAKUTHED; 617641), Heidet et al. (2017) identified a de novo heterozygous c.550C-T transition (c.550C-T, NM_002585) in the PBX1 gene, resulting in an arg184-to-ter (R184X) substitution. The mutation, which was found by screening of candidate genes and confirmed by Sanger sequencing, was not found in the ExAC database. The patient had developmental delay, growth retardation, and long and narrow face.
In a male fetus (K186) with congenital anomalies of the kidney and urinary tract syndrome with or without hearing loss, abnormal ears, or developmental delay (CAKUTHED; 617641), Heidet et al. (2017) identified a de novo heterozygous A-to-G transition in intron 3 of the PBX1 gene (c.511-2A-G, NM_002585), predicted to result in a splice site alteration, frameshift, and premature termination. The mutation, which was found by screening of candidate genes and confirmed by Sanger sequencing, was not found in the ExAC database. The fetus had renal hypoplasia and oligohydramnios.
In 2-year-old boy (patient 3) with congenital anomalies of the kidney and urinary tract syndrome with or without hearing loss, abnormal ears, or developmental delay (CAKUTHED; 617641), Slavotinek et al. (2017) identified a de novo heterozygous c.680G-C transversion (c.680G-C, NM_002585.3) in exon 4 of the PBX1 gene, resulting in an arg227-to-pro (R227P) substitution at a highly conserved residue proximal to the predicted DNA-binding domain. The mutation was not found in the ExAC, 1000 Genomes Project, or dbSNP databases. In vitro functional expression studies in HEK293 cells that had endogenous PBX1 showed that the mutation resulted in decreased transactivation activity of PBX1 compared to wildtype. The findings suggested that the mutant protein interacts with the wildtype protein. Patient 3 did not have dysplastic ears or hearing loss but had developmental delay.
In a 2-year-old girl (patient 4) with congenital anomalies of the kidney and urinary tract syndrome with or without hearing loss, abnormal ears, or developmental delay (CAKUTHED; 617641), Slavotinek et al. (2017) identified a de novo heterozygous c.701G-C transversion (c.701G-C, NM_002585.3) in exon 4-5 of the PBX1 gene, resulting in an arg234-to-pro (R234P) substitution at a highly conserved residue in the homeodomain. The affected codon crosses a splice site. The mutation was not found in the ExAC, 1000 Genomes Project, or dbSNP databases. In vitro functional expression studies in HEK293 cells that had endogenous PBX1 showed that the mutation resulted in decreased transactivation activity of PBX1 compared to wildtype. The mutation also decreased transactivation capability when expressed in a cellular system with markedly decreased levels of PBX1, suggesting that the mutation intrinsically alters this function. This patient did not have dysplastic ears or hearing loss but had developmental delay.
In 2 unrelated children (patients 5 and 8) with congenital anomalies of the kidney and urinary tract syndrome with or without hearing loss, abnormal ears, or developmental delay (CAKUTHED; 617641), Slavotinek et al. (2017) identified a de novo heterozygous c.704G-A transition (c.704G-A, NM_002585.3) in exon 5 of the PBX1 gene, resulting in an arg235-to-gln (R235Q) substitution at a highly conserved residue. The mutation, which was found by whole-exome sequencing, was not found in the dbSNP, 1000 Genomes Project, or ExAC databases. In vitro functional expression studies in HEK293 cells that had endogenous PBX1 showed that the mutation resulted in decreased transactivation activity of PBX1 compared to wildtype. The findings suggested that the mutant protein interacts with the wildtype protein. Patient 5 had dysplastic ears and developmental delay but no hearing loss; patient 8 had normal ears and hearing and did not have developmental delay.
In a 2-year-old girl (patient 6) with congenital anomalies of the kidney and urinary tract syndrome with or without hearing loss, abnormal ears, or developmental delay (CAKUTHED; 617641), Slavotinek et al. (2017) identified a de novo heterozygous 1-bp duplication (c.783dupC, NM_002585.3) in exon 5 of the PBX1 gene, predicted to result in a frameshift and premature termination (Ser262GlnfsTer2). The mutation was not found in the dbSNP, 1000 Genomes Project, or ExAC databases. In vitro functional expression studies in HEK293 cells that had endogenous PBX1 showed that the mutation resulted in decreased transactivation activity of PBX1 compared to wildtype. The mutation also decreased transactivation capability when expressed in a cellular system with markedly decreased levels of PBX1, suggesting that the mutation intrinsically alters this function. The mutant protein also showed decreased localization to the nucleus. The patient had dysplastic ears, unilateral hearing loss, and developmental delay.
Abramovich, C., Shen, W.-F., Pineault, N., Imren, S., Montpetit, B., Largman, C., Humphries, R. K. Functional cloning and characterization of a novel nonhomeodomain protein that inhibits the binding of PBX1-HOX complexes to DNA. J. Biol. Chem. 275: 26172-26177, 2000. [PubMed: 10825160, related citations] [Full Text]
Berthelsen, J., Zappavigna, V., Mavilio, F., Blasi, F. Prep1, a novel functional partner of Pbx proteins. EMBO J. 17: 1423-1433, 1998. [PubMed: 9482739, related citations] [Full Text]
Cheung, C.-L., Chan, B. Y. Y., Chan, V., Ikegawa, S., Kou, I., Ngai, H., Smith, D., Luk, K. D. K., Huang, Q.-Y., Mori, S., Sham, P.-C., Kung, A. W. C. Pre-B-cell leukemia homeobox 1 (PBX1) shows functional and possible genetic association with bone mineral density variation. Hum. Molec. Genet. 18: 679-687, 2009. [PubMed: 19064610, related citations] [Full Text]
Ficara, F., Murphy, M. J., Lin, M., Cleary, M. L. Pbx1 regulates self-renewal of long-term hematopoietic stem cells by maintaining their quiescence. Cell Stem Cell 2: 484-496, 2008. [PubMed: 18462698, images, related citations] [Full Text]
Heidet, L., Moriniere, V., Henry, C., De Tomasi, L., Reilly, M. L., Humbert, C., Alibeu, O., Fourrage, C., Bole-Feysot, C., Nitschke, P., Tores, F., Bras, M., and 13 others. Targeted exome sequencing identifies PBX1 as involved in monogenic congenital anomalies of the kidney and urinary tract. J. Am. Soc. Nephrol. 28: 2901-2914, 2017. [PubMed: 28566479, related citations] [Full Text]
Kamps, M. P., Look, A. T., Baltimore, D. The human t(1:19) translocation in pre-B ALL produces multiple nuclear E2A-Pbx1 fusion proteins with differing transforming potentials. Genes Dev. 5: 358-368, 1991. [PubMed: 1672117, related citations] [Full Text]
Kamps, M. P., Murre, C., Sun, X., Baltimore, D. A new homeobox gene contributes the DNA binding domain of the t(1;19) translocation protein in pre-B ALL. Cell 60: 547-555, 1990. [PubMed: 1967983, related citations] [Full Text]
Kim, S. K., Selleri, L., Lee, J. S., Zhang, A. Y., Gu, X., Jacobs, Y., Cleary, M. L. Pbx1 inactivation disrupts pancreas development and in Ipf1-deficient mice promotes diabetes mellitus. Nature Genet. 30: 430-435, 2002. [PubMed: 11912494, related citations] [Full Text]
Koss, M., Bolze, A., Brendolan, A., Saggese, M., Capellini, T. D., Bojilova, E., Boisson, B., Prall, O. W. J., Elliott, D. A., Solloway, M., Lenti, E., Hidaka, C., Chang, C.-P., Mahlaoui, N., Harvey, R. P., Casanova, J.-L., Selleri, L. Congenital asplenia in mice and humans with mutations in a Pbx/Nkx2-5/p15 module. Dev. Cell 22: 913-926, 2012. [PubMed: 22560297, images, related citations] [Full Text]
Le Tanno, P., Breton, J., Bidart, M., Satre, V., Harbuz, R., Ray, P. F., Bosson, C., Dieterich, K., Jaillard, S., Odent, S., Poke, G., Beddow, R., and 18 others. PBX1 haploinsufficiency leads to syndromic congenital anomalies of the kidney and urinary tract (CAKUT) in humans. J. Med. Genet. 54: 502-510, 2017. [PubMed: 28270404, related citations] [Full Text]
Mercader, N., Leonardo, E., Azpiazu, N., Serrano, A., Morata, G., Martinez-A, C., Torres, M. Conserved regulation of proximodistal limb axis development by Meis1/Hth. Nature 402: 425-429, 1999. [PubMed: 10586884, related citations] [Full Text]
Monica, K., Galili, N., Nourse, J., Saltman, D., Cleary, M. L. PBX2 and PBX3, new homeobox genes with extensive homology to the human proto-oncogene PBX1. Molec. Cell. Biol. 11: 6149-6157, 1991. [PubMed: 1682799, related citations] [Full Text]
Nourse, J., Mellentin, J. D., Galili, N., Wilkinson, J., Stanbridge, E., Smith, S. D., Cleary, M. L. Chromosomal translocation t(1;19) results in synthesis of a homeobox fusion mRNA that codes for a potential chimeric transcription factor. Cell 60: 535-545, 1990. [PubMed: 1967982, related citations] [Full Text]
Schnabel, C. A., Godin, R. E., Cleary, M. L. Pbx1 regulates nephrogenesis and ureteric branching in the developing kidney. Dev. Biol. 254: 262-276, 2003. [PubMed: 12591246, related citations] [Full Text]
Selleri, L., Depew, M. J., Jacobs, Y., Chanda, S. K., Tsang, K. Y., Cheah, K. S. E., Rubenstein, J. L. R., O'Gorman, S., Cleary, M. L. Requirement for Pbx1 in skeletal patterning and programming of chondrocyte proliferation and differentiation. Development 128: 3543-3557, 2001. [PubMed: 11566859, related citations] [Full Text]
Slavotinek, A., Risolino, M., Losa, M., Cho, M. T., Monaghan, K. G., Schneidman-Duhovny, D., Parisotto, S., Herkert, J. C., Stegmann, A. P. A., Miller, K., Shur, N., Chui, J., and 15 others. De novo, deleterious sequence variants that alter the transcriptional activity of the homeoprotein PBX1 are associated with intellectual disability and pleiotropic developmental defects. Hum. Molec. Genet. 26: 4849-4860, 2017. [PubMed: 29036646, related citations] [Full Text]
Sugaya, K., Fukagawa, T., Matsumoto, K., Mita, K., Takahashi, E., Ando, A., Inoko, H., Ikemura, T. Three genes in the human MHC class III region near the junction with the class II: gene for receptor of advanced glycosylation end products, PBX2 homeobox gene and a Notch homolog, human counterpart of mouse mammary tumor gene int-3. Genomics 23: 408-419, 1994. [PubMed: 7835890, related citations] [Full Text]
Wiemels, J. L., Leonard, B. C., Wang, Y., Segal, M. R., Hunger, S. P., Smith, M. T., Crouse, V., Ma, X., Buffler, P. A., Pine, S. R. Site-specific translocation and evidence of postnatal origin of the t(1;19) E2A-PBX1 fusion in childhood acute lymphoblastic leukemia. Proc. Nat. Acad. Sci. 99: 15101-15106, 2002. [PubMed: 12415113, images, related citations] [Full Text]
Other entities represented in this entry:
HGNC Approved Gene Symbol: PBX1
Cytogenetic location: 1q23.3 Genomic coordinates (GRCh38) : 1:164,559,184-164,886,047 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 1q23.3 | Congenital anomalies of kidney and urinary tract syndrome with or without hearing loss, abnormal ears, or developmental delay | 617641 | Autosomal dominant | 3 |
PBX1 is a homeodomain transcription factor of the TALE (3 amino acid loop extension) class that regulates numerous embryonic processes, including morphologic patterning, organogenesis, and hematopoiesis. It is a component of protein complexes that regulate developmental gene expression, in part, through modulation of HOX protein (see 142950) DNA-binding and context-dependent transcriptional functions. In complex with other TALE class proteins, PBX1 may mark genes for activation through penetration of repressive chromatin and recruitment of coactivators. PBX1 has been implicated in promoting progenitor cell proliferation in multiple tissues (summary by Ficara et al., 2008).
Human pre-B-cell acute lymphoblastic leukemias are frequently associated with a t(1;19)(q23;p13.3) chromosomal rearrangement. Kamps et al. (1990) and Nourse et al. (1990) demonstrated that several cell lines carrying this translocation synthesize chimeric mRNAs with 5-prime sequences encoded by the E2A transcription factor gene (TCF3; 147141) on chromosome 19 and 3-prime sequences encoded by a homeobox-related sequence, called Prl or PBX1, on chromosome 1. In the chimeric transcription factor, the DNA binding domain of E2A is replaced by a putative DNA binding domain of PBX1. In 3 cell lines reported by Nourse et al. (1990), identical E2A-Prl mRNA junctions were observed, suggesting that the fusion transcripts are a consistent feature of this translocation.
Monica et al. (1991) confirmed the mapping of PBX1 to 1q23 by in situ hybridization.
Pseudogenes
Sugaya et al. (1994) conducted a chromosome walk in the class III region of the major histocompatibility complex (MHC) near the junction with class II. There they found a gene with the characteristics of PBX2 (176311), which, however, had been mapped to chromosome 3 (Monica et al., 1991). Fluorescence in situ hybridization confirmed the location of the 'new' gene at 6p21.3. The PBX gene on chromosome 3 was later found to be a pseudogene and the PBX gene on chromosome 6 was designated PBX2.
Kamps et al. (1991) discussed the chimeric genes created by the human t(1;19) translocation in pre-B-cell acute lymphoblastic leukemias. The authors cloned 2 different E2A-PBX1 fusion transcripts (which differed only in the PBX1 sequences they contained) and showed that NIH-3T3 cells transfected with cDNAs encoding the fusion proteins were able to cause malignant tumors in nude mice. They discussed subtle differences in the transforming ability of the 2 fusion proteins with respect to the regions of the PBX1 gene they contained.
Two distinct urokinase (PLAU; 191840) enhancer factor-3 (UEF3) complexes, which share a common 64-kD subunit but differ in having either a 50-kD or 40-kD subunit, recognize a TGACAG core DNA sequence. Berthelsen et al. (1998) identified PREP1 (PKNOX1; 602100) as the common 64-kD UEF3 subunit, PBX2 (176311) as the 50-kD subunit, and PBX1 isoform b (PBX1b) as the 40-kD subunit. Immunoprecipitation analysis confirmed that PREP1 also formed a complex with PBX1 isoform a (PBX1a), and interaction of PREP1 with its UEF3 partners was independent of DNA. Recombinant PREP1 bound to the TGACAG core sequence with low affinity. However, it bound with much higher affinity when it was cotranslated in vitro with either PBX1a, PBX1b, or PBX2, but not when it was mixed with its purified binding partners.
Mercader et al. (1999) described the role of homeobox genes Meis1 (601739), Meis2 (601740), and Pbx1 in the development of mouse, chicken, and Drosophila limbs. Mercader et al. (1999) found that Meis1 and Meis2 expression is restricted to the proximal domain, coincident with the previously reported domain in which Pbx1 is localized to the nucleus. Meis1 regulates Pbx1 activity by promoting nuclear import of the Pbx1 protein. Mercader et al. (1999) also demonstrated that ectopic expression of Meis1 in chicken disrupts distal limb development and induces distal-to-proximal transformations. Mercader et al. (1999) concluded that the restriction of Meis1 to proximal regions of the vertebrate limb is essential to specify cell fates and differentiation patterns along the proximodistal axis of the limb.
Using yeast 2-hybrid analysis and in vitro and in vivo binding assays, Abramovich et al. (2000) showed that human HPIP (PBXIP1; 618819) interacted with PBX1. The interaction required the homeodomain of PBX1 and its immediate N-terminal flanking sequence. HPIP interaction blocked formation of heterodimeric DNA-binding complexes between PBX1 and HOXB proteins, including HOXB7 (142962). HPIP also inhibited the transcriptional activation capacity of the E2A-PBX1 complex.
Wiemels et al. (2002) sequenced the genomic fusion between the PBX1 and E2A genes in 22 pre-B acute lymphoblastic leukemias and 2 cell lines. The prenatal origin of the leukemia was assessed in 15 pediatric patients by screening for the clonotypic PBX1-E2A translocation in neonatal blood spots, or Guthrie cards, obtained from the children at birth. Two patients were weakly positive for the fusion at birth, in contrast to previously studied childhood leukemia fusions, t(12;21), t(8;21), and t(4;11), which are predominantly prenatal. The presence of extensive N-nucleotides at the point of fusion in the PBX1-E2A translocation as well as specific characteristics of the IGH (147100)/TCR (see 186880) rearrangements provided additional evidence for a postnatal, pre-B cell origin. Sixteen of 24 breakpoints on the 3.2-kb E2A intron 14 were located within 5 bp, providing evidence for a site-specific recombination mechanism. Breakpoints on the 232-kb PBX1 intron 1 were more dispersed, but were highly clustered proximal to exon 2. Thus, the translocation breakpoints displayed evidence of unique temporal, ontologic, and mechanistic formation in contrast to the previously analyzed pediatric leukemia translocation breakpoints, emphasizing the need to differentiate cytogenetic and molecular subgroups for studies of leukemia causality.
Cheung et al. (2009) showed that PBX1 mRNA was constitutively expressed in both human bone-derived cells (HBDC) and murine preosteoblasts. Immunostaining revealed that PBX1 was localized in the nucleus compartment. RNAi knockdown of PBX1 murine preosteoblasts resulted in decreased expression of Runx2 (600211) and osterix (SP7; 606633), the critical transcription factors for osteogenesis, but accelerated cell proliferation and bone nodule formation.
Le Tanno et al. (2017) found expression of PBX1 in human fetal tissues, with strongest expression in the kidney and brain. Lower levels of PBX1 expression persisted in adult tissues. In the human fetal kidney, PBX1 was detected as nuclear staining in the medulla, interstitium, and mesenchyme. PBX1 was not detected in renal tubes or the ureteric bud. In child and adult tissues, PBX1 was mainly detected in endothelial cells of the glomeruli and interstitium. The findings suggested that PBX1 is expressed mainly by stromal cells to regulate nephrogenesis.
Congenital Anomalies of the Kidney and Urinary Tract Syndrome with or without Hearing Loss, Abnormal Ears, or Developmental Delay
In 3 of 204 unrelated patients with congenital anomalies of the kidney and urinary tract (CAKUT) who underwent next generation sequencing of candidate genes, Heidet et al. (2017) identified 3 different de novo heterozygous point mutations in the PBX1 gene, all of which resulted in a truncated protein (176310.0001-176310.0003). The mutations were confirmed by Sanger sequencing. Functional studies of the variants and studies of patient cells were not performed, but the mutations were predicted to result in a loss of function and haploinsufficiency. The patients had a syndromic form of the disorder: congenital anomalies of the kidney and urinary tract with or without hearing loss, abnormal ears, and developmental delay (CAKUTEHD; 617641).
In 8 unrelated patients with CAKUTEHD, Slavotinek et al. (2017) identified 7 different de novo heterozygous mutations in the PBX1 gene (see, e.g., 176310.0004-176310.0007). There were 5 missense mutations, 1 frameshift mutation, and 1 nonsense mutation. In vitro functional expression studies of 5 of the mutations showed variable disturbances in protein function. In the presence of endogenous wildtype PBX1, all 5 mutant proteins exhibited a significant decrease in transactivation capability, despite different locations of the mutations within the protein domains. These results suggested that the mutant proteins might either be directly responsible for the decrease of transactivation activity observed or might affect the capability of the endogenous protein to transactivate target genes, resembling PBX1 haploinsufficiency. Similar studies of the mutant proteins in cells with marked reduction of wildtype PBX1 showed that only 2 of the variants exhibited significantly diminished transactivation activity, suggesting that these mutations directly affect the intrinsic capability of PBX1 to transactivate downstream transcriptional targets. In addition, 2 of the variants showed decreased nuclear localization. Overall, the findings indicated that disruption of PBX1 target genes can cause variable aberrations in normal embryonic development. Slavotinek et al. (2017) noted that the pleiotropic defects observed in patients reflect the broad expression of Pbx1 during murine embryogenesis and are consistent with the multiple organ systems affected in Pbx1-knockout mice.
Associations Pending Confirmation
For discussion of a possible association between variation in the PBX1 gene and bone mineral density, see BMND2 (605833).
Selleri et al. (2001) showed that Pbx1 is required in skeletal patterning and programming. Pbx1 -/- mice died by embryonic day 15 or 16 with severe hypoplasia or aplasia of multiple organs and widespread patterning defects of the axial and appendicular skeleton. Pbx1 -/- embryos had thinning compressions and fusions of the vertebral bodies and neural arches, as well as defects in the proximal forelimbs and hindlimbs.
In vitro studies have shown that PBX1 regulates the activity of IPF1, a Para-Hox homeodomain transcription factor required for the development and function of the pancreas in mice and humans. To investigate in vivo roles of PBX1 in pancreatic development and function, Kim et al. (2002) examined pancreatic Pbx1 expression, and morphogenesis, cell differentiation, and function in mice deficient for Pbx1. Pbx1 -/- embryos had pancreatic hypoplasia and marked defects in exocrine and endocrine cell differentiation prior to death at embryonic day 15 or 16. In these embryos, expression of Isl1 (600366) and Atoh5 (604882), essential regulators of pancreatic morphogenesis and differentiation, was severely reduced. Pbx1 +/- adults had pancreatic islet malformations, impaired glucose tolerance, and hypoinsulinemia. Thus, Kim et al. (2002) concluded that PBX1 is essential for normal pancreatic development and function. Analysis of trans-heterozygous Pbx1 +/- and Ipf1 +/- mice revealed in vivo genetic interactions between Pbx1 and Ipf1 that are essential for postnatal pancreatic function. Trans-heterozygous mice developed age-dependent overt diabetes mellitus, unlike Pbx1 +/- or Ipf1 +/- mice. Mutations affecting the Ipf1 protein promote diabetes mellitus in mice and humans. Kim et al. (2002) concluded that perturbation of PBX1 activity may also promote susceptibility to diabetes mellitus.
Schnabel et al. (2003) found that Pbx1-null mouse embryos died at about E15.5. The kidneys were reduced in size and axially mispositioned, had fewer nephrons than controls, and sometimes showed unilateral agenesis. The mutant kidneys had expanded regions of mesenchymal condensates in the nephrogenic zone. Decreased branching and elongation of the ureter were also observed. These findings established a role for Pbx1 in mesenchymal-epithelial signaling, and indicated that Pbx1 is an essential regulator of mesenchymal function during renal morphogenesis.
By conditionally inactivating Pbx1 expression in the adult mouse hematopoietic system, Ficara et al. (2008) found that Pbx1 positively regulated hematopoietic stem cell (HSC) quiescence. Pbx1-deficient mice progressively lost long-term HSCs, leading to defects in maintenance of self-renewal. Pbx1-deficient long-term HSCs exhibited perturbed expression of multiple stem cell maintenance factors, and they displayed altered transcriptional responses to TGF-beta (TGFB1; 190180) stimulation in vitro.
Koss et al. (2012) found that conditional knockout of Pbx1 in splenic mesoderm of mouse embryos resulted in hyposplenia and fragmented splenules due to a defect in mesenchymal cell proliferation. Conditional knockout of Pbx1, which controls Nkx2-5 (600584) expression, resulted in decreased expression of Nkx2-5 and hyposplenia, indicating that Nkx2-5 is critical for splenic growth. Pbx1 was found to repress the cell cycle inhibitor CDKN2B (600431) in the spleen anlage; loss of Pbx1 in cultured spleen mesenchymal cells caused upregulation of Cdkn2b and reduced proliferation of these cells. Splenic expansion could be partially rescued by genetic ablation of Cdkn2b. Thus, repression of Cdkn2b by Pbx1 is required for proper organ morphogenesis and growth in vivo. Nkx2-5 was also shown to bind to and repress Cdkn2b. The findings delineated a regulatory module governing mammalian spleen organogenesis that involves Pbx1, Nkx2-5, and Cdkn2b.
In a 21-year-old woman (K175) with congenital anomalies of the kidney and urinary tract syndrome with or without hearing loss, abnormal ears, or developmental delay (CAKUTHED; 617641), Heidet et al. (2017) identified a de novo heterozygous 1-bp deletion (c.428delA, NM_002585) in the PBX1 gene, resulting in a frameshift and premature termination (Asn143ThrfsTer37). The mutation, which was found by screening of candidate genes and confirmed by Sanger sequencing, was not found in the ExAC database. The patient had hearing loss, but developmental delay was not mentioned.
In an 11-year-old girl (K179) with congenital anomalies of the kidney and urinary tract syndrome with or without hearing loss, abnormal ears, or developmental delay (CAKUTHED; 617641), Heidet et al. (2017) identified a de novo heterozygous c.550C-T transition (c.550C-T, NM_002585) in the PBX1 gene, resulting in an arg184-to-ter (R184X) substitution. The mutation, which was found by screening of candidate genes and confirmed by Sanger sequencing, was not found in the ExAC database. The patient had developmental delay, growth retardation, and long and narrow face.
In a male fetus (K186) with congenital anomalies of the kidney and urinary tract syndrome with or without hearing loss, abnormal ears, or developmental delay (CAKUTHED; 617641), Heidet et al. (2017) identified a de novo heterozygous A-to-G transition in intron 3 of the PBX1 gene (c.511-2A-G, NM_002585), predicted to result in a splice site alteration, frameshift, and premature termination. The mutation, which was found by screening of candidate genes and confirmed by Sanger sequencing, was not found in the ExAC database. The fetus had renal hypoplasia and oligohydramnios.
In 2-year-old boy (patient 3) with congenital anomalies of the kidney and urinary tract syndrome with or without hearing loss, abnormal ears, or developmental delay (CAKUTHED; 617641), Slavotinek et al. (2017) identified a de novo heterozygous c.680G-C transversion (c.680G-C, NM_002585.3) in exon 4 of the PBX1 gene, resulting in an arg227-to-pro (R227P) substitution at a highly conserved residue proximal to the predicted DNA-binding domain. The mutation was not found in the ExAC, 1000 Genomes Project, or dbSNP databases. In vitro functional expression studies in HEK293 cells that had endogenous PBX1 showed that the mutation resulted in decreased transactivation activity of PBX1 compared to wildtype. The findings suggested that the mutant protein interacts with the wildtype protein. Patient 3 did not have dysplastic ears or hearing loss but had developmental delay.
In a 2-year-old girl (patient 4) with congenital anomalies of the kidney and urinary tract syndrome with or without hearing loss, abnormal ears, or developmental delay (CAKUTHED; 617641), Slavotinek et al. (2017) identified a de novo heterozygous c.701G-C transversion (c.701G-C, NM_002585.3) in exon 4-5 of the PBX1 gene, resulting in an arg234-to-pro (R234P) substitution at a highly conserved residue in the homeodomain. The affected codon crosses a splice site. The mutation was not found in the ExAC, 1000 Genomes Project, or dbSNP databases. In vitro functional expression studies in HEK293 cells that had endogenous PBX1 showed that the mutation resulted in decreased transactivation activity of PBX1 compared to wildtype. The mutation also decreased transactivation capability when expressed in a cellular system with markedly decreased levels of PBX1, suggesting that the mutation intrinsically alters this function. This patient did not have dysplastic ears or hearing loss but had developmental delay.
In 2 unrelated children (patients 5 and 8) with congenital anomalies of the kidney and urinary tract syndrome with or without hearing loss, abnormal ears, or developmental delay (CAKUTHED; 617641), Slavotinek et al. (2017) identified a de novo heterozygous c.704G-A transition (c.704G-A, NM_002585.3) in exon 5 of the PBX1 gene, resulting in an arg235-to-gln (R235Q) substitution at a highly conserved residue. The mutation, which was found by whole-exome sequencing, was not found in the dbSNP, 1000 Genomes Project, or ExAC databases. In vitro functional expression studies in HEK293 cells that had endogenous PBX1 showed that the mutation resulted in decreased transactivation activity of PBX1 compared to wildtype. The findings suggested that the mutant protein interacts with the wildtype protein. Patient 5 had dysplastic ears and developmental delay but no hearing loss; patient 8 had normal ears and hearing and did not have developmental delay.
In a 2-year-old girl (patient 6) with congenital anomalies of the kidney and urinary tract syndrome with or without hearing loss, abnormal ears, or developmental delay (CAKUTHED; 617641), Slavotinek et al. (2017) identified a de novo heterozygous 1-bp duplication (c.783dupC, NM_002585.3) in exon 5 of the PBX1 gene, predicted to result in a frameshift and premature termination (Ser262GlnfsTer2). The mutation was not found in the dbSNP, 1000 Genomes Project, or ExAC databases. In vitro functional expression studies in HEK293 cells that had endogenous PBX1 showed that the mutation resulted in decreased transactivation activity of PBX1 compared to wildtype. The mutation also decreased transactivation capability when expressed in a cellular system with markedly decreased levels of PBX1, suggesting that the mutation intrinsically alters this function. The mutant protein also showed decreased localization to the nucleus. The patient had dysplastic ears, unilateral hearing loss, and developmental delay.
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