Alternative titles; symbols
HGNC Approved Gene Symbol: PTPRQ
Cytogenetic location: 12q21.31 Genomic coordinates (GRCh38): 12:80,444,235-80,680,273 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 12q21.31 | Deafness, autosomal dominant 73 | 617663 | Autosomal dominant | 3 |
| Deafness, autosomal recessive 84A | 613391 | Autosomal recessive | 3 |
PTPRQ belongs to the type III receptor-like protein-tyrosine phosphatase (PTPase) family. PTPRQ has low activity against phosphotyrosine, but is active against phosphatidylinositol phosphates that are involved in regulation of survival, proliferation, and subcellular architecture (Seifert et al., 2003).
Using degenerate PCR to identify novel PTPases expressed in glomerular mesangial cells from rats with experimentally-induced glomerulonephritis, Wright et al. (1998) cloned Ptprq, which they called Ptpgmc1. The Ptpgmc1 protein contains a signal peptide, 18 fibronectin (135600) type III-like adhesion domains, a transmembrane domain, and a single cytosolic PTPase domain. It also has putative sites for phosphorylation and N-linked glycosylation. Wright et al. (1998) also cloned a human partial PTPGMC1 cDNA. Northern blot analysis of rat tissues demonstrated Ptpgmc1 expression only in proliferating mesangial cells.
Seifert et al. (2003) presented evidence that cytoplasmic and receptor-like forms of rat and human PTPRQ are produced by alternative splicing and the use of alternative promoters. Northern blot analysis detected PTPRQ transcripts of 1.8 to 7.5 kb in human tissues and rat mesangial cells. The 1.8-kb transcript, which encodes a soluble protein containing only the catalytic domain, was predominant in human testis and rat mesangial cells, in which it was upregulated 7- to 8-fold following induction of glomerular injury. The 7.5-kb transcript, which encodes a protein containing both catalytic and extracellular domains, was predominant in human adult lung and adult and fetal kidney. In situ hybridization detected PTPRQ on the basal membrane of adult and fetal human glomerular podocytes, but not elsewhere in the kidney.
Schraders et al. (2010) reported complete characterization of the human PTPRQ gene and identified 4 different splice variants (I-IV). Alternative splicing occurred at the 5-prime end of the gene, and exon 49 was also alternatively spliced in both testes and retina. The splice variants differed in the number of FN3 domains, which are known to bind extracellular ligands, with variant I containing 2,200 amino acids and 15 FN3 domains, variant II containing 2,587 amino acids and 19 FN3 domains, variant III containing 2,517 amino acids and 19 FN3 domains, and variant IV containing 2,501 amino acids and 18 FN3 domains. Quantitative PCR analysis using a fragment encoding the intracellular region of PTPRQ detected expression in all but 2 human fetal tissues tested, with highest expression in fetal kidney, followed by fetal lung and fetal cochlea. Transcript levels were below detection level in fetal liver and fetal colon. In all adult human tissues tested, the highest transcript levels were in lung and heart.
Schraders et al. (2010) determined that the PTPRQ gene contains 58 exons.
By fluorescence in situ hybridization, Wright et al. (1998) mapped the PTPRQ gene to chromosome 12q15. Schraders et al. (2010) noted that the PTPRQ gene mapped to chromosome 12q21.31.
Oganesian et al. (2003) found that rat Ptprq had both protein-tyrosine phosphatase activity and phosphatidylinositol (PtdIns) phosphatase activity. In vitro, the recombinant catalytic domain of Ptprq had low tyrosine phosphatase activity against tyrosine-phosphorylated peptides and protein substrates, but it could dephosphorylate a broad range of PtdIns phosphates, including PtdIns 2,3,4-trisphosphate and most PtdIns monophosphates and diphosphates. Phosphate was hydrolyzed from the D3 and D5 positions in the inositol ring. Overexpression of Ptprq in cultured cells inhibited proliferation and induced apoptosis. A mutation that had no effect on protein-tyrosine phosphatase activity but eliminated PtdIns phosphatase activity eliminated the inhibitory effects on proliferation and apoptosis.
Deafness, Autosomal Recessive 84A
In affected members of 2 unrelated families with autosomal recessive nonsyndromic sensorineural hearing loss with vestibular dysfunction (DFNB84A; 613391), Schraders et al. (2010) identified respective homozygous mutations in the PTPRQ gene (603317.0001 and 603317.0002).
Deafness, Autosomal Dominant 73
By whole-exome sequencing in a 4-generation German family segregating autosomal dominant hearing loss (DFNA73; 617663), Eisenberger et al. (2017) identified a heterozygous nonsense mutation in the last coding exon (exon 45) of the PTPRQ gene (W2294X; 603317.0003).
Goodyear et al. (2003) showed that Ptprq localized to inner-ear hair bundles in chick inner ear and to kidney glomeruli. In early postnatal mice, Ptprq stained hair bundles in the cochlea and the vestibule in the inner ear and was also expressed during embryonic development. The distribution of staining on hair bundles differed according to the type of hair cell and its location. Two different transgenic mouse strains with different mutations in the Ptprq gene had absence of shaft connectors in mutant vestibular hair bundles and misaligned or absent stereocilia. Mutant mice showed rapid postnatal deterioration in cochlear hair-bundle structure, associated with smaller than normal transducer currents, progressive loss of basal-coil cochlear hair cells, and deafness. Goodyear et al. (2003) suggested that Ptprq is required for formation of the shaft connectors of the hair bundle, the normal maturation of cochlear hair bundles, and the long-term survival of high-frequency auditory hair cells.
In 2 Dutch adult sibs with autosomal recessive nonsyndromic hearing loss with vestibular dysfunction (DFNB84A; 613391), Schraders et al. (2010) identified a homozygous 1491T-A transversion in exon 19 of the PTPRQ gene, resulting in a tyr497-to-ter (Y497X) substitution, and a truncated protein lacking the transmembrane and phosphatase domains. The nomenclature of the mutation was based on splice variant III. The mutation was not found in 125 ethnically matched controls. Measurements of autozygosity indicated that the parents had a common ancestor who lived at least 5 generations ago. The hearing loss was bilateral, symmetric, sensorineural, and likely congenital. Neither patient developed normal speech, and both reported progression of hearing loss from severe to profound from 30 and 45 years of age and after, respectively. In addition, both reported delayed motor development, and electronystagmography in caloric and rotary testing demonstrated impaired vestibular function.
In 2 Moroccan sibs, born of consanguineous parents, with autosomal recessive nonsyndromic hearing loss with vestibular dysfunction (DFNB84A; 613391), Schraders et al. (2010) identified a homozygous 1369A-G transition in exon 19 of the PTPRQ gene, resulting in an arg457-to-gly (A457G) substitution in a highly conserved residue in the fifth FN3 domain, which is an extracellular domain known to bind ligands. The nomenclature of the mutation was based on splice variant III. The mutation was not found in 125 ethnically matched controls. The hearing loss was bilateral, symmetric, sensorineural, progressive, and likely congenital. Electronystagmography in caloric and rotary testing demonstrated impaired vestibular function. The phenotype was slightly less severe than that observed in a Dutch family with a truncating mutation (Y497X; 603317.0001), suggesting that the R457G mutant retains residual function.
By whole-exome sequencing in a 4-generation German family segregating autosomal dominant nonsyndromic hearing loss (DFNA73; 617663), Eisenberger et al. (2017) identified a heterozygous c.6881G-A transition (c.6881G-A, NM_001145026.1) in the last coding exon (exon 45) of the PTPRQ gene, resulting in a trp2294-to-ter (W2294X) substitution, in affected members. The age of onset of hearing loss ranged from early childhood to the third decade. The proband's 4-year-old brother, who was heterozygous for the mutation, had not yet manifested hearing loss, but the mutation otherwise segregated with the phenotype. The mutation was not present in the ExAC or the gnomAD databases. PTPRQ expression in patient fibroblasts indicated that the mutant allele escapes nonsense-mediated decay.
Eisenberger, T., Di Donato, N., Decker, C., Delle Vedove, A, Neuhaus, C., Nurnberg, G., Toliat, M., Nurnberg, P., Murbe, D., Bolz, H. J. B. A C-terminal nonsense mutation links PTPRQ with autosomal-dominant hearing loss. Genet. Med. 20: 614-621, 2017. [PubMed: 29309402] [Full Text: https://doi.org/10.1038/gim.2017.155]
Goodyear, R. J., Legan, P. K., Wright, M. B., Marcotti, W., Oganesian, A., Coats, S. A., Booth, C. J., Kros, C. J., Seifert, R. A., Bowen-Pope, D. F., Richardson, G. P. A receptor-like inositol lipid phosphatase is required for the maturation of developing cochlear hair bundles. J. Neurosci. 23: 9208-9219, 2003. [PubMed: 14534255] [Full Text: https://doi.org/10.1523/JNEUROSCI.23-27-09208.2003]
Oganesian, A., Poot, M., Daum, G., Coats, S. A., Wright, M. B., Seifert, R. A., Bowen-Pope, D. F. Protein tyrosine phosphatase RQ is a phosphatidylinositol phosphatase that can regulate cell survival and proliferation. Proc. Nat. Acad. Sci. 100: 7563-7568, 2003. [PubMed: 12802008] [Full Text: https://doi.org/10.1073/pnas.1336511100]
Schraders, M., Oostrik, J., Huygen, P. L. M., Strom, T. M., van Wijk, E., Kunst, H. P. M., Hoefsloot, L. H., Cremers, C. W. R. J., Admiraal, R. J. C., Kremer, H. Mutations in PTPRQ are a cause of autosomal-recessive nonsyndromic hearing impairment DFNB84 and associated with vestibular dysfunction. Am. J. Hum. Genet. 86: 604-610, 2010. [PubMed: 20346435] [Full Text: https://doi.org/10.1016/j.ajhg.2010.02.015]
Seifert, R. A., Coats, S. A., Oganesian, A., Wright, M. B., Dishmon, M., Booth, C. J., Johnson, R. J., Alpers, C. E., Bowen-Pope, D. F. PTPRQ is a novel phosphatidylinositol phosphatase that can be expressed as a cytoplasmic protein or as a subcellularly localized receptor-like protein. Exp. Cell Res. 287: 374-386, 2003. [PubMed: 12837292] [Full Text: https://doi.org/10.1016/s0014-4827(03)00121-6]
Wright, M. B., Hugo, C., Seifert, R., Disteche, C. M., Bowen-Pope, D. F. Proliferating and migrating mesangial cells responding to injury express a novel receptor protein-tyrosine phosphatase in experimental mesangial proliferative glomerulonephritis. J. Biol. Chem. 273: 23929-23937, 1998. [PubMed: 9727007] [Full Text: https://doi.org/10.1074/jbc.273.37.23929]