Alternative titles; symbols
HGNC Approved Gene Symbol: PTPRT
Cytogenetic location: 20q12-q13.11 Genomic coordinates (GRCh38): 20:42,031,890-43,189,906 (from NCBI)
For general information about receptor-type protein-tyrosine phosphatases, see PTPRA (176884).
By RT-PCR using primers for dystroglycan (128239), followed by screening cerebellar and frontal cortex cDNA libraries and RACE-PCR, McAndrew et al. (1998) isolated a full-length cDNA encoding PTPRT, which they called RPTP-rho. The deduced 1,461-amino acid PTPRT protein contains a meprin (see 600388)-A5-PTP-mu (176888) (MAM) domain, an immunoglobulin-like domain, 4 fibronectin (135600) type III repeats, a single transmembrane (TM) domain, a potential proteolytic cleavage site, and 2 highly conserved phosphatase domains, 1 of which contains an 11-amino acid hallmark catalytic sequence. McAndrew et al. (1998) also identified a splice variant lacking a 57-bp exon (19 amino acids) in cerebellar and frontal cortex. Northern blot analysis detected a 12-kb PTPRT transcript solely in brain. In situ hybridization showed expression of mouse Ptprt throughout the adult brain, with highest expression in the hippocampus and dentate gyrus, olfactory bulb, subiculum, cerebral cortex, pyriform cortex, medullary motor nuclei, and anterior cerebellum. During development, Ptprt expression was mainly restricted to postmigratory cells in the olfactory bulbs and the frontal cortex. Expression of Ptprt was then downregulated in these cells and appeared in the cerebellum at postnatal days 8 to 10.
Besco et al. (2001) reported that PTPRT encodes a predicted 1,463-amino acid protein. They cloned murine Ptprt, which encodes a 1,451-amino acid protein that shares 96% identity with human PTPRT. Using RT-PCR, Besco et al. (2001) identified 3 alternatively spliced exons in human and mouse PTPRT, including the variant exon reported by McAndrew et al. (1998). These variant exons encode a 19-amino acid region before the TM domain, a 10-amino acid region between the TM domain and the first phosphatase domain, and a 20-amino acid region within the first phosphatase domain.
McAndrew et al. (1998) performed in situ hybridization analysis of Ptprt expression in normal and 'meander tail' mutant mouse cerebellum. Ptprt expression was restricted to the granular cell layer within lobules 1 to 6 in a manner similar to FGF1 (131220), thus defining a boundary between anterior and posterior cerebellar compartments. This boundary was close to the boundary of the disorganized anterior cerebellum in meander tail and to the anterior boundary of Otx2 (600037) expression.
Besco et al. (2001) determined that the PTPRT gene contains at least 33 coding exons and spans 1 Mb.
McAndrew et al. (1998) used somatic cell hybrid analysis to map the PTPRT gene to chromosome 20. They mapped the mouse Ptprt gene to chromosome 2 in a region that shows homology of synteny to human chromosome 20q12-q13.1.
Wang et al. (2004) performed a mutational analysis of the tyrosine phosphatase gene superfamily in human cancers and identified 83 somatic mutations in 6 protein-tyrosine phosphatases (PTPRF, 179590; PTPRG, 176886; PTPRT; PTPN3, 176877; PTPN13, 600267; and PTPN14, 603155), affecting 26% of colorectal cancers and a smaller fraction of lung, breast, and gastric cancers. Fifteen mutations were nonsense, frameshift, or splice site alterations predicted to result in truncated proteins lacking phosphatase activity. Wang et al. (2004) biochemically examined 5 missense mutations in PTPRT, the most commonly altered protein-tyrosine phosphatase, and found that they reduced phosphatase activity. Expression of wildtype but not a mutant PTPRT in human cancer cells inhibited cell growth. Wang et al. (2004) concluded that their observations suggested that the mutated tyrosine phosphatases are tumor suppressor genes, regulating cellular pathways that may be amenable to therapeutic intervention.
See 608712.0001 for discussion of a possible association of intellectual disability with variation in the PTPRT gene.
This variant is classified as a variant of unknown significance because its contribution to intellectual disability has not been confirmed.
In 3 Dutch sibs, born of unrelated parents, with severe intellectual disability, Schuurs-Hoeijmakers et al. (2013) identified a heterozygous c.4094C-T transition in the PTPRT gene, resulting in a thr1365-to-met (T1365M) substitution at a highly conserved residue in the second tyrosine phosphatase catalytic domain. The variant, which was found by exome sequencing and confirmed by Sanger sequencing, was present in less than 1% of dbSNP (build 134) samples and in less than 1% of 672 in-house exomes. Array analysis showed that all 3 sibs carried a heterozygous 150-kb intronic deletion of chromosome 20q12-q13.11, which removed more than half of intron 1 of the PTPRT gene, on the other allele. The mother, who had borderline intellectual disability, was heterozygous for the deletion; genetic status of the father was not reported. Two additional affected sibs had died; DNA was not available from them. The phenotype was complex and included behavioral problems, microcephaly, congenital heart defects, short stature, and diaphragmatic herniation. Schuurs-Hoeijmakers et al. (2013) noted that the PTPRT gene is expressed in the brain or in neuronal tissue. No functional studies were performed. The family was 1 of 19 nonconsanguineous families with intellectual disability that underwent exome sequencing.
Besco, J. A., Frostholm, A., Popescu, M. C., Burghes, A. H. M., Rotter, A. Genomic organization and alternative splicing of the human and mouse RPTP-rho genes. BMC Genomics 2: 1, 2001. Note: Electronic Article. Erratum: BMC Genomics 2: 5, 2001. [PubMed: 11423001] [Full Text: https://doi.org/10.1186/1471-2164-2-1]
McAndrew, P. E., Frostholm, A., Evans, J. E., Zdilar, D., Goldowitz, D., Chiu, I.-M., Burghes, A. H. M., Rotter, A. Novel receptor protein tyrosine phosphatase (RPTP-rho) and acidic fibroblast growth factor (FGF-1) transcripts delineate a rostrocaudal boundary in the granule cell layer of the murine cerebellar cortex. J. Comp. Neurol. 391: 444-455, 1998. [PubMed: 9486824] [Full Text: https://doi.org/10.1002/(sici)1096-9861(19980222)391:4<444::aid-cne3>3.0.co;2-0]
McAndrew, P. E., Frostholm, A., White, R. A., Rotter, A., Burghes, A. H. M. Identification and characterization of RPTP-rho, a novel RPTP-mu/kappa-like receptor protein tyrosine phosphatase whose expression is restricted to the central nervous system. Molec. Brain Res. 56: 9-21, 1998. [PubMed: 9602027] [Full Text: https://doi.org/10.1016/s0169-328x(98)00014-x]
Schuurs-Hoeijmakers, J. H. M., Vulto-van Silfhout, A. T., Vissers, L. E. L. M., van de Vondervoort, I. I. G. M., van Bon, B. W. M., de Ligt, J., Gilissen, C., Hehir-Kwa, J. Y., Neveling, K., del Rosario, M., Hira, G., Reitano, S., and 19 others. Identification of pathogenic gene variants in small families with intellectually disabled siblings by exome sequencing. J. Med. Genet. 50: 802-811, 2013. Note: Erratum: J. Med. Genet. 55: 504 only, 2018. [PubMed: 24123876] [Full Text: https://doi.org/10.1136/jmedgenet-2013-101644]
Wang, Z., Shen, D., Parsons, D. W., Bardelli, A., Sager, J., Szabo, S., Ptak, J., Silliman, N., Peters, B. A., van der Heijden, M. S., Parmigiani, G., Yan, H., Wang, T.-L., Riggins, G., Powell, S. M., Willson, J. K. V., Markowitz, S., Kinzler, K. W., Vogelstein, B., Velculescu, V. E. Mutational analysis of the tyrosine phosphatome in colorectal cancers. Science 304: 1164-1166, 2004. [PubMed: 15155950] [Full Text: https://doi.org/10.1126/science.1096096]