Alternative titles; symbols
HGNC Approved Gene Symbol: PTPRO
Cytogenetic location: 12p12.3 Genomic coordinates (GRCh38): 12:15,322,508-15,598,331 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 12p12.3 | Nephrotic syndrome, type 6 | 614196 | Autosomal recessive | 3 |
The PTPRO protein, termed glomerular epithelial protein-1 (GLEPP1) by Wiggins et al. (1995), is a receptor-like membrane protein tyrosine phosphatase expressed at the apical membrane of the podocyte foot processes in the kidney (Ozaltin et al., 2011).
Wiggins et al. (1995) cloned the GLEPP1 gene from a human renal cortical cDNA library and showed that the nucleotide and predicted amino acid sequences are, respectively, 90 and 97% identical to those of the homologous rabbit gene. The human GLEPP1 gene predicts a protein of 1,188 amino acids. The 1,159-amino acid predicted mature protein contains a large extracellular domain, a single transmembrane domain, and a single intracellular PTPase domain. Monoclonal and polyclonal antibodies raised against a human GLEPP1 fusion protein recognized a protein with distribution restricted to the glomerulus of the human kidney and with an apparent molecular weight of approximately 200 kD.
Seimiya et al. (1995) reported a cDNA for a novel protein tyrosine phosphatase, called PTP-U2 by them. The predicted protein of 1,216 amino acids and 140 kD contains a single transmembrane domain and a single intracellular catalytic domain. The extracellular domain contains 14 putative N-glycosylation sites and 8 repeats of fibronectin type III-like motif. They detected expression of PTPU2 as a 5.4-kb transcript in kidney and brain and as a 3.5-kb transcript in lung and placenta. The smaller transcript was also detected in human leukemia cell lines. Gene expression was enhanced by various differentiation-inducing agents.
The PTPRO gene is alternatively spliced (summary by Ozaltin et al., 2011).
The PTPRO gene contains 26 exons (summary by Ozaltin et al., 2011).
Motiwala et al. (2003) demonstrated suppression by methylation of the PTPRO gene in primary and established rat hepatomas.
By fluorescence in situ hybridization (FISH), Wiggins et al. (1995) assigned the GLEPP1 gene (also symbolized PTPRO) to 12p13-p12. Seimiya et al. (1995) assigned the PTPU2 gene to 12p13.3-p13.2 by FISH.
By homozygosity mapping followed by candidate gene sequencing of a consanguineous Turkish family with childhood-onset nephrotic syndrome type 6 (NPHS6; 614196), Ozaltin et al. (2011) identified a homozygous splice site mutation in the PTPRO gene (600579.0001) in affected sibs. By analysis of this gene in 17 additional families, they found a different homozygous mutation in 3 affected sibs in another consanguineous Turkish family (600579.0002). The oldest sib in this family, who had the most severe phenotype necessitating renal transplant, also carried a heterozygous mutation in the podocin gene (R229Q; 604766.0011), which was thought to exacerbate the clinical picture.
Wharram et al. (2000) found that deletion of Ptpro in mice resulted in a modification of podocyte structure such that the normal octopoid podocyte was simplified to a more amoeboid structure and that the foot processes were shorter and broader than normal. These changes were associated with altered distribution of the podocyte intermediate cytoskeletal protein vimentin (193060). Mutant mice had a reduced glomerular filtration rate and reduced glomerular nephrin (602716) content. However, there was no evidence of proteinuria. After removal of one or more kidneys, Ptpro-null mice had higher blood pressure than did their wildtype littermates. These data supported the conclusion that Ptpro plays a role in regulating the glomerular pressure/filtration rate relationship through an effect on podocyte structure and function.
Although the article by Motiwala et al. (2004) was considered to be the first to demonstrate methylation-mediated suppression of PTPRO in human tumors and its tumor suppressor potential, the article was retracted because of evidence of duplicated data in figures 2 and 5A.
By homozygosity mapping followed by candidate gene sequencing of a consanguineous Turkish family with nephrotic syndrome type 6 (NPHS6; 614196), Ozaltin et al. (2011) identified a homozygous 2627G-T transversion in intron 16 of the PTPRO gene, resulting in the skipping of exon 16 and the deletion of 23 highly conserved amino acids (Glu854_Trp876del). Each unaffected parent was heterozygous for the mutation, which was not seen in 180 Turkish controls. Renal biopsy from an affected individual showed proper expression and membrane localization of a shortened PTPRO protein. There was also focal segmental glomerulosclerosis and mild focal tubulointerstitial fibrosis and atrophy. Electron microscopy showed diffuse foot process effacement and widespread attenuation of the glomerular basement membranes without thickening. The podocytes appeared swollen and vacuolated.
In 3 sibs, born of consanguineous Turkish parents, with nephrotic syndrome type 6 (NPHS6; 614196), Ozaltin et al. (2011) identified a homozygous 2745G-A transition in intron 19 of the PTPRO gene, resulting in the skipping or exon 19 and introduction of a premature stop codon at the beginning of exon 20 (Asn888Lysfs*3), which was demonstrated to cause nonsense-mediated decay. Each unaffected parent was heterozygous for the mutation, which was not seen in 180 Turkish controls. Renal biopsy from an affected individual showed lack of PTPRO immunoreactivity and a pathologic diagnosis of minimal change disease. There was global sclerosing of 3 of 38 glomeruli with narrow zones of interstitial fibrosis and tubular atrophy around the globally sclerosed glomeruli. Electron microscopy showed diffuse foot process fusion and extensive microvillus transformation of the podocytes. The oldest sib, who had the most severe phenotype necessitating renal transplant, also carried a heterozygous mutation in the podocin gene (R229Q; 604766.0011), which was thought to exacerbate the clinical picture.
Motiwala, T., Ghoshal, K., Das, A., Majumder, S., Weichenhan, D., Wu, Y.-Z., Holman, K., James, S. J., Jacob, S. T., Plass, C. Suppression of the protein tyrosine phosphatase receptor type O gene (PTPRO) by methylation in hepatocellular carcinomas. Oncogene 22: 6319-6331, 2003. [PubMed: 14508512] [Full Text: https://doi.org/10.1038/sj.onc.1206750]
Motiwala, T., Kutay, H., Ghoshal, K., Bai, S., Seimiya, H., Tsuruo, T., Suster, S., Morrison, C., Jacob, S. T. Protein tyrosine phosphatase receptor-type O (PTPRO) exhibits characteristics of a candidate tumor suppressor in human lung cancer. Proc. Nat. Acad. Sci. 101: 13844-13849, 2004. Note: Retraction: Proc. Nat. Acad. Sci. 119: e2200127119, 2022. [PubMed: 15356345] [Full Text: https://doi.org/10.1073/pnas.0405451101]
Ozaltin, F., Ibsirlioglu, T., Taskiran, E. Z., Baydar, D. E., Kaymaz, F., Buyukcelik, M., Kilic, B. D., Balat, A., Iatropoulos, P., Asan, E., Akarsu, N. A., Schaefer, F., Yilmaz, E., Bakkaloglu, A., the PodoNet Consortium. Disruption of PTPRO causes childhood-onset nephrotic syndrome. Am. J. Hum. Genet. 89: 139-147, 2011. [PubMed: 21722858] [Full Text: https://doi.org/10.1016/j.ajhg.2011.05.026]
Seimiya, H., Sawabe, T., Inazawa, J., Tsuruo, T. Cloning, expression and chromosomal localization of a novel gene for protein tyrosine phosphatase (PTP-U2) induced by various differentiation-inducing agents. Oncogene 10: 1731-1738, 1995. [PubMed: 7753550]
Wharram, B. L., Goyal, M., Gillespie, P. J., Wiggins, J. E., Kershaw, D. B., Holzman, L. B., Dysko, R. C., Saunders, T. L., Samuelson, L. C., Wiggins, R. C. Altered podocyte structure in GLEPP1 (Ptpro)-deficient mice associated with hypertension and low glomerular filtration rate. J. Clin. Invest. 106: 1281-1290, 2000. [PubMed: 11086029] [Full Text: https://doi.org/10.1172/JCI7236]
Wiggins, R. C., Wiggins, J. E., Goyal, M., Wharram, B. L., Thomas, P. E. Molecular cloning of cDNAs encoding human GLEPP1, a membrane protein tyrosine phosphatase: characterization of the GLEPP1 protein distribution in human kidney and assignment of the GLEPP1 gene to human chromosome 12p12-p13. Genomics 27: 174-181, 1995. [PubMed: 7665166] [Full Text: https://doi.org/10.1006/geno.1995.1021]