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HGNC Approved Gene Symbol: PLAG1
Cytogenetic location: 8q12.1 Genomic coordinates (GRCh38) : 8:56,160,909-56,211,273 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 8q12.1 | Adenomas, salivary gland pleomorphic, somatic | 181030 | 3 | |
| Silver-Russell syndrome 4 | 618907 | Autosomal dominant | 3 |
PLAG1 is a transcription factor that is broadly expressed during fetal development. It regulates several growth factors, including IGF2 (147470) (summary by Karim et al., 2011).
By searching sequence databases with sequence tagged sites (STSs) located within a 300-kb region on chromosome 8 associated with recurrent translocation breakpoints in pleomorphic adenomas (see 181030 and CYTOGENETICS), Kas et al. (1997) identified an EST with sequence identity to 1 of the STSs. Northern blot analysis using this EST detected a 7.5-kb transcript representing pleomorphic adenoma gene-1 (PLAG1). Kas et al. (1997) detected the 7.5-kb PLAG1 transcript in normal human fetal lung, fetal liver, and fetal kidney, but not in the corresponding adult tissues, adult salivary gland, or fetal brain. The authors cloned human fetal kidney PLAG1 cDNAs. The deduced PLAG1 protein has 2 potential nuclear localization signals in the N-terminal region, 7 zinc finger domains, and a serine-rich C terminus.
Using X-gal staining, Juma et al. (2017) showed that Plag1 was expressed in multiple cell types in mouse seminiferous tubules.
Kas et al. (1997) determined that the PLAG1 gene contains 5 exons.
Kas et al. (1997) mapped the PLAG1 gene to chromosome 8q12.
Pleomorphic adenomas are benign epithelial tumors originating from the major and minor salivary glands (see 181030). They are characterized by recurrent chromosome translocations, the most common of which involve chromosome 8, with consistent breakpoints at band q12. Kas et al. (1997) described the construction of 2 nonoverlapping YAC contigs covering about 75% of human chromosome band 8q12, which spans approximately 9 Mb of genomic DNA and includes multiple genes and expressed sequence tags (ESTs). Using FISH, the authors determined that the majority of pleomorphic adenoma 8q12 breakpoints clustered within a 2-Mb contig that was mapped to the centromeric region of 8q12 and that was covered by 34 overlapping YAC clones, and tagged by 31 markers with an average spacing of 65 kb. Nine of 11 primary adenomas with 8q12 abnormalities had breakpoints mapping within a 300-kb interval. By searching sequence databases with sequence tagged sites (STSs) located within a 300-kb region, Kas et al. (1997) identified an EST with sequence identity to 1 of the STSs. This EST corresponds to the PLAG1 gene. Southern blot analysis of DNA from pleomorphic adenomas with t(3;8) detected rearrangements in the 5-prime noncoding region of the PLAG1 gene. Using 5-prime RACE or RT-PCR, the authors generated hybrid transcripts consisting of PLAG1 and beta-1-catenin (CTNNB1; 116806) from every primary tumor analyzed. Northern blot analysis of 3 pleomorphic adenomas with t(3;8) and 1 adenoma with a variant t(8;15) revealed that PLAG1 expression was activated by the translocations in all 4 tumors.
Astrom et al. (1999) found overexpression of PLAG1 in 23 of 47 primary benign and malignant pleomorphic adenomas of the salivary glands. In 5 adenomas with a normal karyotype, fusion transcripts were found in 3; PLAG1 and CTNNB1 were fused in 1 case, and in 2 others PLAG1 was fused with the gene encoding transcription elongation factor SII (TCEA1;601425). The fusions occurred in the 5-prime noncoding region of PLAG1, leading to exchange of regulatory control elements and, as a consequence, activation of PLAG1 gene expression. Because all of the cases had grossly normal karyotypes, the rearrangements must result from cryptic rearrangements.
Asp et al. (2006) carried out RT-PCR analysis of 27 cytogenetically characterized pleomorphic salivary gland adenomas containing chromosome 8q12 translocations that lacked PLAG1/CTNNB1 gene fusions. They detected chimeric transcripts of exon 1 of the CHCHD7 gene (611238) fused to either exons 3 and 4 of PLAG1 or to PLAG1 exons 2 to 4 in 3 tumors: a tumor containing a t(8:15)(q12;q14) translocation, a second containing at t(6;8)(p22-21.3;q13) translocation, and a third tumor with a normal karyotype. Using immunohistochemistry of tumor tissues containing CHCHD7/PLAG1 fusions, Asp et al. (2006) detected PLAG1 protein and suggested that the CHCHD7/PLAG1 gene fusion upregulates PLAG1 protein expression.
In a mother and 2 daughters and an unrelated patient with Silver-Russell syndrome (SRS4; 618907), Abi Habib et al. (2018) identified heterozygosity for different 1-bp deletions in the PLAG1 gene (603026.0001 and 603026.0002). Experiments in Hep3b cells demonstrated that PLAG1 positively regulates expression of the IGF2 (147470) promoter P3, both independently and via an HMGA2 (600698)-PLAG1-IGF2 pathway. The authors noted that disruption of any gene in the pathway results in a decrease in IGF2 expression and produces an SRS phenotype similar to that of patients carrying 11p15.5 epigenetic defects (see SRS1; 180860).
Karim et al. (2011) mapped a quantitative trait locus (QTL) with a major effect on bovine stature to an approximately 780-bp interval on chromosome 14. They identified 8 candidate quantitative trait nucleotides (QTNs) within the QTL and showed that these QTNs influenced fetal expression of 7 of the 9 genes within the QTL. Two of the QTNs are located within the approximately 500-bp intergenic region between the Plag1 and Chchd7 genes, which are oriented in a head-to-head fashion. The intergenic region is phylogenetically conserved and functions as a bidirectional promoter. Reporter gene assays and EMSA showed that these 2 QTNs influenced bidirectional promoter strength and affected binding of nuclear factors. The presence of a naturally occurring null allele excluded Chchd7 as the causative gene. Karim et al. (2011) noted that Plag1 regulates several growth factors, including Igf2 (147470), a key regulator of body size.
Juma et al. (2017) noted that Plag1 deficiency results in reduced fertility in male and female mice. Using Plag1 -/- and +/- mice, they showed that loss of Plag1 expression led to reduced expression of genes involved in spermatogenesis and testosterone synthesis, as well as upregulation of genes involved in immune responses and epididymis-specific functions. Histologic and TUNEL analyses revealed that loss of Plag1 resulted in defects in testicular appearance and apoptotic cells. Plag1 deficiency also led to reduced testis and seminal vesicle weight, daily sperm production, and sperm motility. Juma et al. (2017) concluded that PLAG1 plays important roles in testicular function and sperm motility.
In a mother and 2 daughters with Silver-Russell syndrome (SRS4; 618907), Abi Habib et al. (2018) identified heterozygosity for a 1-bp deletion (c.439del, NM_002655.2) in exon 5 of the PLAG1 gene, causing a frameshift predicted to result in a premature termination codon (Ser147ValfsTer82). The mutation was not present in the unaffected father, in polymorphism databases, or the ExAC database.
In a female patient with Silver-Russell syndrome (SRS4; 618907), Abi Habib et al. (2018) identified heterozygosity for a de novo 1-bp deletion (c.1363del, NM_002655.2) in the PLAG1 gene, causing a frameshift predicted to result in a premature termination codon (Gln455SerfsTer16). The mutation was not found in unaffected relatives, including her twin brother, an older brother, or her parents.
Abi Habib, W., Brioude, F., Edouard, T., Bennett, J. T., Lienhardt-Roussie, A., Tixier, F., Salem, J., Yuen, T., Azzi, S., Le Bouc, Y., Harbison, M. D., Netchine, I. Genetic disruption of the oncogenic HMGA2-PLAG1-IGF2 pathway causes fetal growth restriction. Genet. Med. 20: 250-258, 2018. [PubMed: 28796236] [Full Text: https://doi.org/10.1038/gim.2017.105]
Asp, J., Persson, F., Kost-Alimova, M., Stenman, G. CHCHD7-PLAG1 and TCEA1-PLAG1 gene fusions resulting from cryptic, intrachromosomal 8q rearrangements in pleomorphic salivary gland adenomas. Genes Chromosomes Cancer 45: 820-828, 2006. [PubMed: 16736500] [Full Text: https://doi.org/10.1002/gcc.20346]
Astrom, A.-K., Voz, M. L., Kas, K., Roijer, E., Wedell, B., Mandahl, N., Van de Ven, W., Mark, J., Stenman, G. Conserved mechanism of PLAG1 activation in salivary gland tumors with and without chromosome 8q12 abnormalities: identification of SII as a new fusion partner gene. Cancer Res. 59: 918-923, 1999. [PubMed: 10029085]
Juma, A. R., Grommen, S. V. H., O'Bryan, M. K., O'Connor, A. E., Merriner, D. J., Hall, N. E., Doyle, S. R., Damdimopoulou, P. E., Barriga, D., Hart, A. H., Van de Ven, W. J. M., De Groef, B. PLAG1 deficiency impairs spermatogenesis and sperm motility in mice. Sci. Rep. 7: 5317, 2017. Note: Electronic Article. [PubMed: 28706261] [Full Text: https://doi.org/10.1038/s41598-017-05676-4]
Karim, L., Takeda, H., Lin, L., Druet, T., Arias, J. A. C., Baurain, D., Cambisano, N., Davis, S. R., Farnir, F., Grisart, B., Harris, B. L., Keehan, M. D., Littlejohn, M. D., Spelman, R. J., Georges, M., Coppieters, W. Variants modulating the expression of a chromosome domain encompassing PLAG1 influence bovine stature. Nature Genet. 43: 405-413, 2011. [PubMed: 21516082] [Full Text: https://doi.org/10.1038/ng.814]
Kas, K., Roijer, E., Voz, M., Meyen, E., Stenman, G., Van de Ven, W. J. M. A 2-Mb YAC contig and physical map covering the chromosome 8q12 breakpoint cluster region in pleomorphic adenomas of the salivary glands. Genomics 43: 349-358, 1997. [PubMed: 9268638] [Full Text: https://doi.org/10.1006/geno.1997.4819]
Kas, K., Voz, M. L., Roijer, E., Astrom, A.-K., Meyen, E., Stenman, G., Van de Ven, W. J. M. Promoter swapping between the genes for a novel zinc finger protein and beta-catenin in pleiomorphic adenomas with t(3;8)(p21;q12) translocations. Nature Genet. 15: 170-174, 1997. Note: Erratum: Nature Genet. 15: 411 only, 1997. [PubMed: 9020842] [Full Text: https://doi.org/10.1038/ng0297-170]