Affinage

PTPRQ

Phosphatidylinositol phosphatase PTPRQ · UniProt Q9UMZ3

Length
2332 aa
Mass
260.9 kDa
Annotated
2026-06-10
31 papers in source corpus 10 papers cited in narrative 10 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 6/6 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

PTPRQ is a receptor-like phosphatase that acts at the interface of inositol lipid signalling and the structural maintenance of inner ear hair cell stereocilia (PMID:12837292, PMID:20715155). Unlike classical protein tyrosine phosphatases, it has very low activity against phosphotyrosine and instead functions as a phosphatidylinositol phosphatase; its catalytic domain has a flat active-site pocket that accommodates large phosphoinositide substrates and preferentially dephosphorylates PI(3,4,5)P3, thereby downregulating Akt/PKB signalling (PMID:23897475, PMID:19351528). It is expressed as either an alternatively spliced transmembrane receptor-like protein or a cytosolic protein, and the transmembrane form localizes to the basal membrane of podocytes (PMID:12837292). In the inner ear, PTPRQ is a chondroitin sulfate proteoglycan associated with the shaft connectors of hair bundles, with multiple developmentally regulated isoforms whose abundance correlates with shaft connector spacing (PMID:20715155). Loss of Ptprq in mice causes progressive stereocilia fusion and elongation, loss of vestibular evoked potentials, and behavioral defects, establishing it as required for maintaining hair bundle architecture and vestibular/auditory function, downstream of the miR-96 hair cell differentiation pathway (PMID:22357859, PMID:24446963). In humans, truncating PTPRQ variants cause autosomal dominant hearing loss (DFNA73): a nonsense mutation in the last coding exon (p.Trp2294*) yields a transcript that escapes nonsense-mediated decay, consistent with a dominant-negative truncated protein (PMID:29309402), and a knock-in mouse modelling a frameshift allele recapitulates progressive high-frequency hearing loss with disorganized stereocilia (PMID:39434500).

Mechanistic history

Synthesis pass · year-by-year structured walk · 9 steps
  1. 2003 High

    Established that despite its phosphatase classification, PTPRQ acts on phosphoinositide lipids rather than phosphotyrosine, and exists in distinct transmembrane and cytosolic isoforms with cell-type-specific localization.

    Evidence Enzyme activity assays, alternative promoter/splicing analysis, and immunolocalization in human kidney tissue and cell lines

    PMID:12837292

    Open questions at the time
    • Substrate preference among individual phosphoinositides not resolved
    • Functional role of the cytosolic versus transmembrane isoform unclear
  2. 2009 Medium

    Linked PTPRQ lipid phosphatase activity to a cellular outcome by showing it lowers phosphoinositide levels and dampens Akt signalling to restrain adipogenic differentiation.

    Evidence Overexpression in human mesenchymal stem cells with PI quantification, Akt phosphorylation Western blots, and adipogenesis assays

    PMID:19351528

    Open questions at the time
    • No mutagenesis or reconstitution to confirm catalytic dependence
    • Overexpression may not reflect endogenous activity
  3. 2011 High

    Defined PTPRQ as a chondroitin sulfate proteoglycan structural component of hair bundle shaft connectors, distinguishing a structural role from its enzymatic activity.

    Evidence Chondroitinase ABC treatment, electron microscopy, isoform-specific immunostaining, and wild-type versus Ptprq-null mouse inner ear comparison

    PMID:20715155

    Open questions at the time
    • Molecular partners forming the shaft connector not identified
    • Relationship between lipid phosphatase activity and proteoglycan function unresolved
  4. 2012 High

    Demonstrated through clean genetic knockout that Ptprq is required to maintain stereocilia integrity and vestibular function in vivo.

    Evidence Ptprq-null mouse analysis with scanning electron microscopy, vestibular evoked potentials, and swimming behavior across postnatal day 5 to 12 months

    PMID:22357859

    Open questions at the time
    • Mechanism connecting Ptprq loss to stereocilia fusion/elongation not defined
    • Distinct contributions of lipid phosphatase versus proteoglycan function not dissected
  5. 2014 Medium

    Placed Ptprq downstream of miR-96 in hair cell differentiation, integrating it into a regulatory pathway controlling the auditory phenotype.

    Evidence Microarray transcriptomics and single hair cell electrophysiology comparing Ptprq-null, diminuendo heterozygous, and diminuendo homozygous mice

    PMID:24446963

    Open questions at the time
    • Direct regulation of Ptprq by miR-96 not demonstrated
    • Other miR-96 targets contributing to phenotype not separated
  6. 2013 High

    Provided the structural and kinetic basis for PTPRQ phosphoinositide specificity, explaining how a flat active site accommodates bulky lipid substrates and selects PI(3,4,5)P3 to downregulate Akt.

    Evidence X-ray crystallography at 1.56 Å of the catalytic domain with kinetic assays across phosphatidylinositide substrates

    PMID:23897475

    Open questions at the time
    • Structure of full-length receptor-like protein not solved
    • In vivo relevance of PI(3,4,5)P3 dephosphorylation in hair cells not established
  7. 2017 Medium

    Identified a dominant disease mechanism (DFNA73), showing a last-exon nonsense mutation escapes NMD to produce a truncated protein consistent with dominant-negative action.

    Evidence NGS, linkage and exome analysis, and semi-quantitative RT-PCR demonstrating NMD escape in patient fibroblasts

    PMID:29309402

    Open questions at the time
    • Dominant-negative mechanism inferred but not functionally proven
    • Effect of the truncated protein on bundle structure not tested
  8. 2024 Medium

    Validated dominant truncating PTPRQ pathogenicity in an animal model, recapitulating progressive hearing loss and revealing affected downstream cochlear pathways.

    Evidence CRISPR-Cas9 knock-in mice with auditory brainstem responses, stereocilia electron microscopy, and cochlear proteomics

    PMID:39434500

    Open questions at the time
    • Causal role of oxidative phosphorylation/angiogenesis/synaptic pathway changes not established
    • Mechanism distinguishing heterozygous mild from homozygous profound phenotype unclear
  9. 2025 Medium

    Characterized the splicing consequences of intronic and splice-site PTPRQ variants, defining how they generate frameshifts and exon skipping that disrupt the protein.

    Evidence Minigene splicing assays with Sanger confirmation and computational structural/docking analysis

    PMID:40165225 PMID:41069440

    Open questions at the time
    • Functional consequences for protein activity shown only computationally
    • Quantitative effect on transcript levels in patient tissue not measured

Open questions

Synthesis pass · forward-looking unresolved questions
  • How PTPRQ's lipid phosphatase activity and its chondroitin sulfate proteoglycan structural role are mechanistically coupled at the stereocilia shaft connector remains unresolved.
  • No reconstitution linking catalytic activity to bundle maintenance
  • Direct binding partners at shaft connectors unidentified
  • Whether dominant-negative truncations act through enzymatic or structural disruption unknown

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0016787 hydrolase activity 3 GO:0008289 lipid binding 2 GO:0005198 structural molecule activity 1
Localization
GO:0005886 plasma membrane 2
Pathway
R-HSA-162582 Signal Transduction 2 R-HSA-9709957 Sensory Perception 1

Evidence

Reading pass · 10 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2003 PTPRQ (rPTP-GMC1) has very low activity against phosphotyrosine but is active as a phosphatidylinositol phosphatase against phosphatidylinositol phosphates involved in regulation of survival, proliferation, and subcellular architecture. It can be expressed as either a transmembrane receptor-like protein or a cytosolic protein, regulated by alternative promoter use and alternative splicing. The transmembrane form localizes to the basal membrane of human podocytes. Enzyme activity assays, alternative promoter/splicing analysis, subcellular localization by immunolocalization in human kidney tissue and cell lines Experimental cell research High 12837292
2013 The crystal structure of the PTPRQ catalytic domain was solved at 1.56 Å resolution, revealing a disordered M6 loop and flat active-site pocket that facilitates accommodation of large phosphatidylinositide substrates. Kinetic experiments demonstrated strong preference for PI(3,4,5)P3 over other PI substrates, suggesting PTPRQ downregulates Akt signalling. X-ray crystallography at 1.56 Å resolution, kinetic enzyme assays with phosphatidylinositide substrates Acta crystallographica. Section D, Biological crystallography High 23897475
2009 Overexpression of PTPRQ (PTP-RQ) in human mesenchymal stem cells reduced differentiation into adipocytes by decreasing intracellular phosphatidylinositol phosphate levels and consequently downregulating Akt/PKB phosphorylation. Overexpression in human MSCs, phosphatidylinositol phosphate quantification, Western blotting for Akt/PKB phosphorylation, adipogenesis assay Biochemical and biophysical research communications Medium 19351528
2011 Ptprq is a chondroitin sulfate proteoglycan associated with shaft connectors of hair bundles: chondroitinase ABC treatment caused loss of electron-dense particles at shaft connectors, increased electrophoretic mobility of Ptprq, and abolished DSD1 epitope staining in wild-type but not Ptprq-null mouse hair bundles. Multiple developmentally regulated isoforms of Ptprq are expressed on hair bundles, with isoform differences correlating with shaft connector spacing. Chondroitinase ABC treatment, electron microscopy, immunostaining with monoclonal antibodies (mAb 473-HD, mAb H10), comparison of wild-type vs. Ptprq(-/-) mouse inner ear Developmental neurobiology High 20715155
2012 Loss of Ptprq in mice causes progressive stereocilia fusion and elongation in vestibular hair bundles (extrastriolar utricle hair bundles up to 50% longer than controls), loss of vestibular evoked potentials in the majority of mutant mice, and subtle swimming behavior defects, establishing a direct role for Ptprq in maintaining vestibular hair bundle structure and function. Ptprq(-/-) mouse analysis, scanning electron microscopy of hair bundles, vestibular evoked potentials, behavioral swimming tests; longitudinal study from postnatal day 5 to 12 months The Journal of neuroscience High 22357859
2014 Reduction of Ptprq in the miR-96 mutant (diminuendo) mouse contributes substantially to its auditory phenotype: the morphological and electrophysiological phenotype of Ptprq-null mice resembles that of diminuendo heterozygotes, and transcriptome comparison showed broad similarity between diminuendo homozygotes and Ptprq-null mice, placing Ptprq downstream of miR-96 in the hair cell differentiation pathway. Microarray transcriptome analysis, scanning electron microscopy, single hair cell electrophysiology; comparison of Ptprq-null, diminuendo heterozygous, and diminuendo homozygous mice The European journal of neuroscience Medium 24446963
2017 A heterozygous nonsense mutation in the last coding exon of PTPRQ (p.Trp2294*) causes autosomal dominant hearing loss (DFNA73). The mutant transcript escapes nonsense-mediated decay (NMD) in patient fibroblasts, suggesting a dominant-negative mechanism from a truncated protein lacking only six C-terminal residues. Next-generation sequencing, Sanger sequencing, genome-wide linkage analysis, whole-exome sequencing, semi-quantitative RT-PCR for NMD escape in patient fibroblasts Genetics in medicine Medium 29309402
2024 A novel PTPRQ truncating variant (c.3697del, p.Leu1233Phefs*11) causes autosomal dominant progressive hearing loss. CRISPR-Cas9 knock-in mice heterozygous for the equivalent allele recapitulate mild progressive high-frequency hearing loss, while homozygous mice show profound hearing loss with disorganized stereocilia. Cochlear proteome analysis of homozygous mutants revealed differentially expressed pathways including oxidative phosphorylation, angiogenesis regulation, and synaptic vesicle cycling. CRISPR-Cas9 knock-in mouse generation, auditory brainstem response measurements, scanning electron microscopy of stereocilia, cochlear proteome analysis Clinical genetics Medium 39434500
2025 Minigene assays confirmed that a deep intronic PTPRQ variant and a splice variant cause aberrant splicing, including exon skipping leading to frameshift mutations. Protein 3D structure prediction and rigid ligand docking were used to assess pathogenicity of variants escaping nonsense-mediated decay. Minigene splicing assays, Sanger sequencing confirmation, protein 3D structure prediction, rigid ligand docking BMC medical genomics Medium 40165225
2025 Minigene assays confirmed that the PTPRQ splice variant c.6603-3 T>G causes exon 43 skipping, resulting in a frameshift mutation (p.Ser2201ArgfsTer112), establishing the molecular mechanism by which this variant disrupts PTPRQ function. Minigene splicing assay, Sanger sequencing, bioinformatics splicing prediction Journal of otology Medium 41069440

Source papers

Stage 0 corpus · 31 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2010 Mutations in PTPRQ are a cause of autosomal-recessive nonsyndromic hearing impairment DFNB84 and associated with vestibular dysfunction. American journal of human genetics 74 20346435
2012 Hair bundle defects and loss of function in the vestibular end organs of mice lacking the receptor-like inositol lipid phosphatase PTPRQ. The Journal of neuroscience : the official journal of the Society for Neuroscience 47 22357859
2010 Nonsense mutation of the stereociliar membrane protein gene PTPRQ in human hearing loss DFNB84. Journal of medical genetics 39 20472657
2003 PTPRQ is a novel phosphatidylinositol phosphatase that can be expressed as a cytoplasmic protein or as a subcellularly localized receptor-like protein. Experimental cell research 30 12837292
2017 A C-terminal nonsense mutation links PTPRQ with autosomal-dominant hearing loss, DFNA73. Genetics in medicine : official journal of the American College of Medical Genetics 28 29309402
2009 Involvement of PTP-RQ in differentiation during adipogenesis of human mesenchymal stem cells. Biochemical and biophysical research communications 26 19351528
2014 A reduction in Ptprq associated with specific features of the deafness phenotype of the miR-96 mutant mouse diminuendo. The European journal of neuroscience 22 24446963
2015 Novel PTPRQ mutations identified in three congenital hearing loss patients with various types of hearing loss. The Annals of otology, rhinology, and laryngology 16 25788564
2019 First confirmatory study on PTPRQ as an autosomal dominant non-syndromic hearing loss gene. Journal of translational medicine 15 31655630
2018 Autosomal Recessive Congenital Sensorineural Hearing Loss due to a Novel Compound Heterozygous PTPRQ Mutation in a Chinese Family. Neural plasticity 14 29849575
2015 Identification of a novel compound heterozygous mutation in PTPRQ in a DFNB84 family with prelingual sensorineural hearing impairment. Molecular genetics and genomics : MGG 14 25557914
2021 Identification of Hearing Loss-Associated Variants of PTPRQ, MYO15A, and SERPINB6 in Pakistani Families. BioMed research international 13 33997018
2015 Identification of Two Novel Compound Heterozygous PTPRQ Mutations Associated with Autosomal Recessive Hearing Loss in a Chinese Family. PloS one 13 25919374
2011 Evidence for multiple, developmentally regulated isoforms of Ptprq on hair cells of the inner ear. Developmental neurobiology 12 20715155
2021 Whole-exome sequencing identified a novel heterozygous mutation of SALL1 and a new homozygous mutation of PTPRQ in a Chinese family with Townes-Brocks syndrome and hearing loss. BMC medical genomics 11 33478437
2018 Deafness and vestibular dysfunction in a Doberman Pinscher puppy associated with a mutation in the PTPRQ gene. Journal of veterinary internal medicine 11 29460419
2017 Identification of Novel PTPRQ and MYO1A Mutations in An Iranian Pedigree with Autosomal Recessive Hearing Loss. Cell journal 11 29308629
2017 PTPRQ as a potential biomarker for idiopathic normal pressure hydrocephalus. Molecular medicine reports 9 28714010
2013 Structural basis for the dephosphorylating activity of PTPRQ towards phosphatidylinositide substrates. Acta crystallographica. Section D, Biological crystallography 9 23897475
2022 Targeted Next-Generation Sequencing Identified Novel Compound Heterozygous Variants in the PTPRQ Gene Causing Autosomal Recessive Hearing Loss in a Chinese Family. Frontiers in genetics 7 35899188
2016 High PTPRQ Expression and Its Relationship to Expression of PTPRZ1 and the Presence of KRAS Mutations in Colorectal Cancer Tissues. Anticancer research 7 26851024
2013 Identification of novel PTPRQ phosphatase inhibitors based on the virtual screening with docking simulations. Theoretical biology & medical modelling 6 23981594
2023 Delayed progressive sensorineural hearing loss due to a novel compound heterozygous PTPRQ mutation in a Chinese patient. Journal of clinical laboratory analysis 5 37106574
2017 The Tetraspanin-Associated Uroplakins Family (UPK2/3) Is Evolutionarily Related to PTPRQ, a Phosphotyrosine Phosphatase Receptor. PloS one 5 28099513
2024 Detailed Clinical Features of PTPRQ-Associated Hearing Loss Identified in a Large Japanese Hearing Loss Cohort. Genes 2 38674423
2025 Whole-genome sequencing, as a powerful diagnostic tool in hearing loss, reveals novel variants in PTPRQ missed by whole-exome sequencing. BMC medical genomics 1 40165225
2024 A Novel PTPRQ c.3697del Variant Causes Autosomal Dominant Progressive Hearing Loss in Both Humans and Mice. Clinical genetics 1 39434500
2025 Whole Exome Sequencing Identifies Novel Splicing Variants in the PTPRQ Gene and Their Mechanisms in Autosomal Recessive Non-Syndromic Hearing Loss. Journal of otology 0 41069440
2024 Novel PTPRQ variants associated with hearing loss in a Chinese family PTPRQ variants in Chinese hearing loss. Frontiers in genetics 0 39205941
2021 Novel FERMT3 and PTPRQ Mutations Associated with Leukocyte Adhesion Deficiency-III and Sensorineural Hearing Loss. Journal of pediatric genetics 0 38162163
2017 Correction: The Tetraspanin-Associated Uroplakins Family (UPK2/3) Is Evolutionarily Related to PTPRQ, a Phosphotyrosine Phosphatase Receptor. PloS one 0 28192514

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