{"gene":"PTPRQ","run_date":"2026-06-10T06:43:36","timeline":{"discoveries":[{"year":2003,"finding":"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.","method":"Enzyme activity assays, alternative promoter/splicing analysis, subcellular localization by immunolocalization in human kidney tissue and cell lines","journal":"Experimental cell research","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — direct enzymatic activity characterization combined with subcellular localization and alternative splicing analysis in multiple cell types; single lab but multiple orthogonal methods","pmids":["12837292"],"is_preprint":false},{"year":2013,"finding":"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.","method":"X-ray crystallography at 1.56 Å resolution, kinetic enzyme assays with phosphatidylinositide substrates","journal":"Acta crystallographica. Section D, Biological crystallography","confidence":"High","confidence_rationale":"Tier 1 / Moderate — crystal structure combined with kinetic biochemical assays in a single rigorous study; multiple orthogonal methods","pmids":["23897475"],"is_preprint":false},{"year":2009,"finding":"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.","method":"Overexpression in human MSCs, phosphatidylinositol phosphate quantification, Western blotting for Akt/PKB phosphorylation, adipogenesis assay","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — functional overexpression with PI measurement and downstream signaling readout; single lab, multiple methods but no mutagenesis or reconstitution","pmids":["19351528"],"is_preprint":false},{"year":2011,"finding":"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.","method":"Chondroitinase ABC treatment, electron microscopy, immunostaining with monoclonal antibodies (mAb 473-HD, mAb H10), comparison of wild-type vs. Ptprq(-/-) mouse inner ear","journal":"Developmental neurobiology","confidence":"High","confidence_rationale":"Tier 2 / Strong — three independent lines of biochemical and immunological evidence for proteoglycan nature, with genetic null controls; multiple orthogonal methods","pmids":["20715155"],"is_preprint":false},{"year":2012,"finding":"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.","method":"Ptprq(-/-) mouse analysis, scanning electron microscopy of hair bundles, vestibular evoked potentials, behavioral swimming tests; longitudinal study from postnatal day 5 to 12 months","journal":"The Journal of neuroscience","confidence":"High","confidence_rationale":"Tier 2 / Strong — clean genetic knockout with multiple orthogonal phenotypic readouts (morphology, electrophysiology, behavior) across multiple time points","pmids":["22357859"],"is_preprint":false},{"year":2014,"finding":"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.","method":"Microarray transcriptome analysis, scanning electron microscopy, single hair cell electrophysiology; comparison of Ptprq-null, diminuendo heterozygous, and diminuendo homozygous mice","journal":"The European journal of neuroscience","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — epistasis established by genetic comparison with null allele and transcriptomics; single lab, multiple methods","pmids":["24446963"],"is_preprint":false},{"year":2017,"finding":"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.","method":"Next-generation sequencing, Sanger sequencing, genome-wide linkage analysis, whole-exome sequencing, semi-quantitative RT-PCR for NMD escape in patient fibroblasts","journal":"Genetics in medicine","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — NMD escape demonstrated by RT-PCR in patient cells, supported by segregation and linkage; dominant-negative mechanism is inferred but NMD escape is directly shown","pmids":["29309402"],"is_preprint":false},{"year":2024,"finding":"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.","method":"CRISPR-Cas9 knock-in mouse generation, auditory brainstem response measurements, scanning electron microscopy of stereocilia, cochlear proteome analysis","journal":"Clinical genetics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — knock-in animal model with functional hearing measurements, morphological analysis, and proteomics; single lab, multiple methods","pmids":["39434500"],"is_preprint":false},{"year":2025,"finding":"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.","method":"Minigene splicing assays, Sanger sequencing confirmation, protein 3D structure prediction, rigid ligand docking","journal":"BMC medical genomics","confidence":"Medium","confidence_rationale":"Tier 2–3 / Weak — minigene assay directly demonstrates splicing consequence; structural analysis is computational; single lab","pmids":["40165225"],"is_preprint":false},{"year":2025,"finding":"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.","method":"Minigene splicing assay, Sanger sequencing, bioinformatics splicing prediction","journal":"Journal of otology","confidence":"Medium","confidence_rationale":"Tier 2–3 / Weak — minigene assay directly demonstrates exon skipping mechanism; single lab, limited to splicing characterization","pmids":["41069440"],"is_preprint":false}],"current_model":"PTPRQ is a receptor-like inositol lipid phosphatase with a flat active-site pocket (resolved by X-ray crystallography) that preferentially dephosphorylates PI(3,4,5)P3 over phosphotyrosine, thereby downregulating Akt signalling; it exists as alternatively spliced transmembrane or cytosolic isoforms, functions as a chondroitin sulfate proteoglycan at shaft connectors of inner ear hair cell stereocilia, and is required for maintaining normal hair bundle architecture and vestibular/auditory function in both mice and humans, with loss-of-function causing recessive hearing loss (DFNB84) and specific C-terminal truncations causing dominant hearing loss (DFNA73) via an NMD-escape dominant-negative mechanism."},"narrative":{"mechanistic_narrative":"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].","teleology":[{"year":2003,"claim":"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","pmids":["12837292"],"confidence":"High","gaps":["Substrate preference among individual phosphoinositides not resolved","Functional role of the cytosolic versus transmembrane isoform unclear"]},{"year":2009,"claim":"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","pmids":["19351528"],"confidence":"Medium","gaps":["No mutagenesis or reconstitution to confirm catalytic dependence","Overexpression may not reflect endogenous activity"]},{"year":2011,"claim":"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","pmids":["20715155"],"confidence":"High","gaps":["Molecular partners forming the shaft connector not identified","Relationship between lipid phosphatase activity and proteoglycan function unresolved"]},{"year":2012,"claim":"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","pmids":["22357859"],"confidence":"High","gaps":["Mechanism connecting Ptprq loss to stereocilia fusion/elongation not defined","Distinct contributions of lipid phosphatase versus proteoglycan function not dissected"]},{"year":2014,"claim":"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","pmids":["24446963"],"confidence":"Medium","gaps":["Direct regulation of Ptprq by miR-96 not demonstrated","Other miR-96 targets contributing to phenotype not separated"]},{"year":2013,"claim":"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","pmids":["23897475"],"confidence":"High","gaps":["Structure of full-length receptor-like protein not solved","In vivo relevance of PI(3,4,5)P3 dephosphorylation in hair cells not established"]},{"year":2017,"claim":"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","pmids":["29309402"],"confidence":"Medium","gaps":["Dominant-negative mechanism inferred but not functionally proven","Effect of the truncated protein on bundle structure not tested"]},{"year":2024,"claim":"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","pmids":["39434500"],"confidence":"Medium","gaps":["Causal role of oxidative phosphorylation/angiogenesis/synaptic pathway changes not established","Mechanism distinguishing heterozygous mild from homozygous profound phenotype unclear"]},{"year":2025,"claim":"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","pmids":["40165225","41069440"],"confidence":"Medium","gaps":["Functional consequences for protein activity shown only computationally","Quantitative effect on transcript levels in patient tissue not measured"]},{"year":null,"claim":"How PTPRQ's lipid phosphatase activity and its chondroitin sulfate proteoglycan structural role are mechanistically coupled at the stereocilia shaft connector remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["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":{"molecular_activity":[{"term_id":"GO:0016787","term_label":"hydrolase activity","supporting_discovery_ids":[0,1,2]},{"term_id":"GO:0005198","term_label":"structural molecule activity","supporting_discovery_ids":[3]},{"term_id":"GO:0008289","term_label":"lipid binding","supporting_discovery_ids":[0,1]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[0,3]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[1,2]},{"term_id":"R-HSA-9709957","term_label":"Sensory Perception","supporting_discovery_ids":[4]}],"complexes":[],"partners":[],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q9UMZ3","full_name":"Phosphatidylinositol phosphatase PTPRQ","aliases":["Receptor-type tyrosine-protein phosphatase Q","PTP-RQ","R-PTP-Q"],"length_aa":2332,"mass_kda":260.9,"function":"Dephosphorylates phosphatidylinositol phosphates, such as phosphatidylinositol 3,4,5-trisphosphate (PIP3) and phosphatidylinositol 3,5-diphosphates, with preference for PIP3 (PubMed:23897475). Phosphate can be hydrolyzed from the D3 and D5 positions in the inositol ring (PubMed:23897475). Has low tyrosine-protein phosphatase activity in vitro; however, the relevance of such activity in vivo is unclear (By similarity). Plays an important role in adipogenesis of mesenchymal stem cells (MSCs). Regulates the phosphorylation state of AKT1 by regulating the levels of PIP3 in MSCs and preadipocyte cells (PubMed:19351528). Required for hair bundle maturation, a process that enables hair cells to detect and transmit sound and balance signals effectively, therefore affecting auditory function (PubMed:20472657, PubMed:29309402). May act by regulating the level of phosphatidylinositol 4,5-bisphosphate (PIP2) level in the basal region of hair bundles (By similarity)","subcellular_location":"Cell projection, stereocilium; Apical cell membrane; Basal cell membrane","url":"https://www.uniprot.org/uniprotkb/Q9UMZ3/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/PTPRQ","classification":"Not Classified","n_dependent_lines":13,"n_total_lines":74,"dependency_fraction":0.17567567567567569},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/PTPRQ","total_profiled":1310},"omim":[{"mim_id":"617663","title":"DEAFNESS, AUTOSOMAL DOMINANT 73; DFNA73","url":"https://www.omim.org/entry/617663"},{"mim_id":"614944","title":"DEAFNESS, AUTOSOMAL RECESSIVE 84B; DFNB84B","url":"https://www.omim.org/entry/614944"},{"mim_id":"614925","title":"OTOGELIN-LIKE PROTEIN; OTOGL","url":"https://www.omim.org/entry/614925"},{"mim_id":"613391","title":"DEAFNESS, AUTOSOMAL RECESSIVE 84A; DFNB84A","url":"https://www.omim.org/entry/613391"},{"mim_id":"611606","title":"MICRO RNA 96; MIR96","url":"https://www.omim.org/entry/611606"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Cytosol","reliability":"Approved"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in some","driving_tissues":[{"tissue":"kidney","ntpm":7.8},{"tissue":"urinary bladder","ntpm":4.6}],"url":"https://www.proteinatlas.org/search/PTPRQ"},"hgnc":{"alias_symbol":[],"prev_symbol":["DFNB84"]},"alphafold":{"accession":"Q9UMZ3","domains":[{"cath_id":"2.60.40.10","chopping":"13-94","consensus_level":"high","plddt":78.9187,"start":13,"end":94},{"cath_id":"2.60.40.10","chopping":"103-256_311-335","consensus_level":"medium","plddt":76.5065,"start":103,"end":335},{"cath_id":"2.60.40.10","chopping":"356-435","consensus_level":"high","plddt":74.6116,"start":356,"end":435},{"cath_id":"2.60.40.10","chopping":"438-492_566-608","consensus_level":"medium","plddt":68.7903,"start":438,"end":608},{"cath_id":"2.60.40.10","chopping":"617-702","consensus_level":"medium","plddt":78.5486,"start":617,"end":702},{"cath_id":"2.60.40.10","chopping":"713-796","consensus_level":"medium","plddt":75.657,"start":713,"end":796},{"cath_id":"2.60.40.10","chopping":"806-892","consensus_level":"high","plddt":76.148,"start":806,"end":892},{"cath_id":"2.60.40.10","chopping":"903-969","consensus_level":"high","plddt":78.3043,"start":903,"end":969},{"cath_id":"2.60.40.10","chopping":"996-1090","consensus_level":"medium","plddt":73.6521,"start":996,"end":1090},{"cath_id":"2.60.40.10","chopping":"1099-1189","consensus_level":"medium","plddt":72.8862,"start":1099,"end":1189},{"cath_id":"2.60.40.10","chopping":"1200-1279","consensus_level":"medium","plddt":79.0104,"start":1200,"end":1279},{"cath_id":"2.60.40.10","chopping":"1290-1377","consensus_level":"medium","plddt":78.0395,"start":1290,"end":1377},{"cath_id":"-","chopping":"1398-1454","consensus_level":"high","plddt":74.264,"start":1398,"end":1454},{"cath_id":"2.60.40.10","chopping":"1472-1575","consensus_level":"high","plddt":80.3351,"start":1472,"end":1575},{"cath_id":"2.60.40.10","chopping":"1589-1640_1647-1678","consensus_level":"high","plddt":79.3548,"start":1589,"end":1678},{"cath_id":"2.60.40.10","chopping":"1681-1784","consensus_level":"medium","plddt":75.3536,"start":1681,"end":1784},{"cath_id":"2.60.40","chopping":"1812-1870_1886-1941","consensus_level":"high","plddt":79.739,"start":1812,"end":1941},{"cath_id":"3.90.190.10","chopping":"2016-2322","consensus_level":"high","plddt":81.0371,"start":2016,"end":2322}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9UMZ3","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q9UMZ3-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q9UMZ3-F1-predicted_aligned_error_v6.png","plddt_mean":74.94},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=PTPRQ","jax_strain_url":"https://www.jax.org/strain/search?query=PTPRQ"},"sequence":{"accession":"Q9UMZ3","fasta_url":"https://rest.uniprot.org/uniprotkb/Q9UMZ3.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q9UMZ3/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9UMZ3"}},"corpus_meta":[{"pmid":"20346435","id":"PMC_20346435","title":"Mutations in PTPRQ are a cause of autosomal-recessive nonsyndromic hearing impairment DFNB84 and associated with vestibular dysfunction.","date":"2010","source":"American journal of human genetics","url":"https://pubmed.ncbi.nlm.nih.gov/20346435","citation_count":74,"is_preprint":false},{"pmid":"22357859","id":"PMC_22357859","title":"Hair bundle defects and loss of function in the vestibular end organs of mice lacking the receptor-like inositol lipid phosphatase PTPRQ.","date":"2012","source":"The Journal of neuroscience : the official journal of the Society for Neuroscience","url":"https://pubmed.ncbi.nlm.nih.gov/22357859","citation_count":47,"is_preprint":false},{"pmid":"20472657","id":"PMC_20472657","title":"Nonsense mutation of the stereociliar membrane protein gene PTPRQ in human hearing loss DFNB84.","date":"2010","source":"Journal of medical genetics","url":"https://pubmed.ncbi.nlm.nih.gov/20472657","citation_count":39,"is_preprint":false},{"pmid":"12837292","id":"PMC_12837292","title":"PTPRQ is a novel phosphatidylinositol phosphatase that can be expressed as a cytoplasmic protein or as a subcellularly localized receptor-like protein.","date":"2003","source":"Experimental cell research","url":"https://pubmed.ncbi.nlm.nih.gov/12837292","citation_count":30,"is_preprint":false},{"pmid":"29309402","id":"PMC_29309402","title":"A C-terminal nonsense mutation links PTPRQ with autosomal-dominant hearing loss, DFNA73.","date":"2017","source":"Genetics in medicine : official journal of the American College of Medical Genetics","url":"https://pubmed.ncbi.nlm.nih.gov/29309402","citation_count":28,"is_preprint":false},{"pmid":"19351528","id":"PMC_19351528","title":"Involvement of PTP-RQ in differentiation during adipogenesis of human mesenchymal stem cells.","date":"2009","source":"Biochemical and biophysical research communications","url":"https://pubmed.ncbi.nlm.nih.gov/19351528","citation_count":26,"is_preprint":false},{"pmid":"24446963","id":"PMC_24446963","title":"A reduction in Ptprq associated with specific features of the deafness phenotype of the miR-96 mutant mouse diminuendo.","date":"2014","source":"The European journal of neuroscience","url":"https://pubmed.ncbi.nlm.nih.gov/24446963","citation_count":22,"is_preprint":false},{"pmid":"25788564","id":"PMC_25788564","title":"Novel PTPRQ mutations identified in three congenital hearing loss patients with various types of hearing loss.","date":"2015","source":"The Annals of otology, rhinology, and laryngology","url":"https://pubmed.ncbi.nlm.nih.gov/25788564","citation_count":16,"is_preprint":false},{"pmid":"31655630","id":"PMC_31655630","title":"First confirmatory study on PTPRQ as an autosomal dominant non-syndromic hearing loss gene.","date":"2019","source":"Journal of translational medicine","url":"https://pubmed.ncbi.nlm.nih.gov/31655630","citation_count":15,"is_preprint":false},{"pmid":"25557914","id":"PMC_25557914","title":"Identification of a novel compound heterozygous mutation in PTPRQ in a DFNB84 family with prelingual sensorineural hearing impairment.","date":"2015","source":"Molecular genetics and genomics : MGG","url":"https://pubmed.ncbi.nlm.nih.gov/25557914","citation_count":14,"is_preprint":false},{"pmid":"29849575","id":"PMC_29849575","title":"Autosomal Recessive Congenital Sensorineural Hearing Loss due to a Novel Compound Heterozygous PTPRQ Mutation in a Chinese Family.","date":"2018","source":"Neural plasticity","url":"https://pubmed.ncbi.nlm.nih.gov/29849575","citation_count":14,"is_preprint":false},{"pmid":"25919374","id":"PMC_25919374","title":"Identification of Two Novel Compound Heterozygous PTPRQ Mutations Associated with Autosomal Recessive Hearing Loss in a Chinese Family.","date":"2015","source":"PloS 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genomics","url":"https://pubmed.ncbi.nlm.nih.gov/33478437","citation_count":11,"is_preprint":false},{"pmid":"29460419","id":"PMC_29460419","title":"Deafness and vestibular dysfunction in a Doberman Pinscher puppy associated with a mutation in the PTPRQ gene.","date":"2018","source":"Journal of veterinary internal medicine","url":"https://pubmed.ncbi.nlm.nih.gov/29460419","citation_count":11,"is_preprint":false},{"pmid":"29308629","id":"PMC_29308629","title":"Identification of Novel PTPRQ and MYO1A Mutations in An Iranian Pedigree with Autosomal Recessive Hearing Loss.","date":"2017","source":"Cell journal","url":"https://pubmed.ncbi.nlm.nih.gov/29308629","citation_count":11,"is_preprint":false},{"pmid":"23897475","id":"PMC_23897475","title":"Structural basis for the dephosphorylating activity of PTPRQ towards phosphatidylinositide substrates.","date":"2013","source":"Acta crystallographica. Section D, Biological crystallography","url":"https://pubmed.ncbi.nlm.nih.gov/23897475","citation_count":9,"is_preprint":false},{"pmid":"28714010","id":"PMC_28714010","title":"PTPRQ as a potential biomarker for idiopathic normal pressure hydrocephalus.","date":"2017","source":"Molecular medicine reports","url":"https://pubmed.ncbi.nlm.nih.gov/28714010","citation_count":9,"is_preprint":false},{"pmid":"26851024","id":"PMC_26851024","title":"High PTPRQ Expression and Its Relationship to Expression of PTPRZ1 and the Presence of KRAS Mutations in Colorectal Cancer Tissues.","date":"2016","source":"Anticancer research","url":"https://pubmed.ncbi.nlm.nih.gov/26851024","citation_count":7,"is_preprint":false},{"pmid":"35899188","id":"PMC_35899188","title":"Targeted Next-Generation Sequencing Identified Novel Compound Heterozygous Variants in the PTPRQ Gene Causing Autosomal Recessive Hearing Loss in a Chinese Family.","date":"2022","source":"Frontiers in genetics","url":"https://pubmed.ncbi.nlm.nih.gov/35899188","citation_count":7,"is_preprint":false},{"pmid":"23981594","id":"PMC_23981594","title":"Identification of novel PTPRQ phosphatase inhibitors based on the virtual screening with docking simulations.","date":"2013","source":"Theoretical biology & medical modelling","url":"https://pubmed.ncbi.nlm.nih.gov/23981594","citation_count":6,"is_preprint":false},{"pmid":"37106574","id":"PMC_37106574","title":"Delayed progressive sensorineural hearing loss due to a novel compound heterozygous PTPRQ mutation in a Chinese patient.","date":"2023","source":"Journal of clinical laboratory analysis","url":"https://pubmed.ncbi.nlm.nih.gov/37106574","citation_count":5,"is_preprint":false},{"pmid":"28099513","id":"PMC_28099513","title":"The Tetraspanin-Associated Uroplakins Family (UPK2/3) Is Evolutionarily Related to PTPRQ, a Phosphotyrosine Phosphatase Receptor.","date":"2017","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/28099513","citation_count":5,"is_preprint":false},{"pmid":"38674423","id":"PMC_38674423","title":"Detailed Clinical Features of PTPRQ-Associated Hearing Loss Identified in a Large Japanese Hearing Loss Cohort.","date":"2024","source":"Genes","url":"https://pubmed.ncbi.nlm.nih.gov/38674423","citation_count":2,"is_preprint":false},{"pmid":"40165225","id":"PMC_40165225","title":"Whole-genome sequencing, as a powerful diagnostic tool in hearing loss, reveals novel variants in PTPRQ missed by whole-exome sequencing.","date":"2025","source":"BMC medical genomics","url":"https://pubmed.ncbi.nlm.nih.gov/40165225","citation_count":1,"is_preprint":false},{"pmid":"39434500","id":"PMC_39434500","title":"A Novel PTPRQ c.3697del Variant Causes Autosomal Dominant Progressive Hearing Loss in Both Humans and Mice.","date":"2024","source":"Clinical genetics","url":"https://pubmed.ncbi.nlm.nih.gov/39434500","citation_count":1,"is_preprint":false},{"pmid":"38162163","id":"PMC_38162163","title":"Novel FERMT3 and PTPRQ Mutations Associated with Leukocyte Adhesion Deficiency-III and Sensorineural Hearing Loss.","date":"2021","source":"Journal of pediatric genetics","url":"https://pubmed.ncbi.nlm.nih.gov/38162163","citation_count":0,"is_preprint":false},{"pmid":"39205941","id":"PMC_39205941","title":"Novel PTPRQ variants associated with hearing loss in a Chinese family PTPRQ variants in Chinese hearing loss.","date":"2024","source":"Frontiers in genetics","url":"https://pubmed.ncbi.nlm.nih.gov/39205941","citation_count":0,"is_preprint":false},{"pmid":"41069440","id":"PMC_41069440","title":"Whole Exome Sequencing Identifies Novel Splicing Variants in the PTPRQ Gene and Their Mechanisms in Autosomal Recessive Non-Syndromic Hearing Loss.","date":"2025","source":"Journal of otology","url":"https://pubmed.ncbi.nlm.nih.gov/41069440","citation_count":0,"is_preprint":false},{"pmid":"28192514","id":"PMC_28192514","title":"Correction: The Tetraspanin-Associated Uroplakins Family (UPK2/3) Is Evolutionarily Related to PTPRQ, a Phosphotyrosine Phosphatase Receptor.","date":"2017","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/28192514","citation_count":0,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":16065,"output_tokens":2683,"usd":0.04422,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":10064,"output_tokens":3186,"usd":0.064985,"stage2_stop_reason":"end_turn"},"total_usd":0.109205,"stage1_batch_id":"msgbatch_01CNoDbkChHEkgrJnL7BwtGJ","stage2_batch_id":"msgbatch_016Y4x9E9Wg5VQDANj9quSQD","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2003,\n      \"finding\": \"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.\",\n      \"method\": \"Enzyme activity assays, alternative promoter/splicing analysis, subcellular localization by immunolocalization in human kidney tissue and cell lines\",\n      \"journal\": \"Experimental cell research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — direct enzymatic activity characterization combined with subcellular localization and alternative splicing analysis in multiple cell types; single lab but multiple orthogonal methods\",\n      \"pmids\": [\"12837292\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"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.\",\n      \"method\": \"X-ray crystallography at 1.56 Å resolution, kinetic enzyme assays with phosphatidylinositide substrates\",\n      \"journal\": \"Acta crystallographica. Section D, Biological crystallography\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — crystal structure combined with kinetic biochemical assays in a single rigorous study; multiple orthogonal methods\",\n      \"pmids\": [\"23897475\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"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.\",\n      \"method\": \"Overexpression in human MSCs, phosphatidylinositol phosphate quantification, Western blotting for Akt/PKB phosphorylation, adipogenesis assay\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — functional overexpression with PI measurement and downstream signaling readout; single lab, multiple methods but no mutagenesis or reconstitution\",\n      \"pmids\": [\"19351528\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"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.\",\n      \"method\": \"Chondroitinase ABC treatment, electron microscopy, immunostaining with monoclonal antibodies (mAb 473-HD, mAb H10), comparison of wild-type vs. Ptprq(-/-) mouse inner ear\",\n      \"journal\": \"Developmental neurobiology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — three independent lines of biochemical and immunological evidence for proteoglycan nature, with genetic null controls; multiple orthogonal methods\",\n      \"pmids\": [\"20715155\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"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.\",\n      \"method\": \"Ptprq(-/-) mouse analysis, scanning electron microscopy of hair bundles, vestibular evoked potentials, behavioral swimming tests; longitudinal study from postnatal day 5 to 12 months\",\n      \"journal\": \"The Journal of neuroscience\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — clean genetic knockout with multiple orthogonal phenotypic readouts (morphology, electrophysiology, behavior) across multiple time points\",\n      \"pmids\": [\"22357859\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"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.\",\n      \"method\": \"Microarray transcriptome analysis, scanning electron microscopy, single hair cell electrophysiology; comparison of Ptprq-null, diminuendo heterozygous, and diminuendo homozygous mice\",\n      \"journal\": \"The European journal of neuroscience\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — epistasis established by genetic comparison with null allele and transcriptomics; single lab, multiple methods\",\n      \"pmids\": [\"24446963\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"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.\",\n      \"method\": \"Next-generation sequencing, Sanger sequencing, genome-wide linkage analysis, whole-exome sequencing, semi-quantitative RT-PCR for NMD escape in patient fibroblasts\",\n      \"journal\": \"Genetics in medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — NMD escape demonstrated by RT-PCR in patient cells, supported by segregation and linkage; dominant-negative mechanism is inferred but NMD escape is directly shown\",\n      \"pmids\": [\"29309402\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"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.\",\n      \"method\": \"CRISPR-Cas9 knock-in mouse generation, auditory brainstem response measurements, scanning electron microscopy of stereocilia, cochlear proteome analysis\",\n      \"journal\": \"Clinical genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — knock-in animal model with functional hearing measurements, morphological analysis, and proteomics; single lab, multiple methods\",\n      \"pmids\": [\"39434500\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"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.\",\n      \"method\": \"Minigene splicing assays, Sanger sequencing confirmation, protein 3D structure prediction, rigid ligand docking\",\n      \"journal\": \"BMC medical genomics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Weak — minigene assay directly demonstrates splicing consequence; structural analysis is computational; single lab\",\n      \"pmids\": [\"40165225\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"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.\",\n      \"method\": \"Minigene splicing assay, Sanger sequencing, bioinformatics splicing prediction\",\n      \"journal\": \"Journal of otology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Weak — minigene assay directly demonstrates exon skipping mechanism; single lab, limited to splicing characterization\",\n      \"pmids\": [\"41069440\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"PTPRQ is a receptor-like inositol lipid phosphatase with a flat active-site pocket (resolved by X-ray crystallography) that preferentially dephosphorylates PI(3,4,5)P3 over phosphotyrosine, thereby downregulating Akt signalling; it exists as alternatively spliced transmembrane or cytosolic isoforms, functions as a chondroitin sulfate proteoglycan at shaft connectors of inner ear hair cell stereocilia, and is required for maintaining normal hair bundle architecture and vestibular/auditory function in both mice and humans, with loss-of-function causing recessive hearing loss (DFNB84) and specific C-terminal truncations causing dominant hearing loss (DFNA73) via an NMD-escape dominant-negative mechanism.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"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 [#0, #3]. 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 [#1, #2]. 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 [#0]. 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 [#3]. 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 [#4, #5]. 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 [#6], and a knock-in mouse modelling a frameshift allele recapitulates progressive high-frequency hearing loss with disorganized stereocilia [#7].\",\n  \"teleology\": [\n    {\n      \"year\": 2003,\n      \"claim\": \"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.\",\n      \"evidence\": \"Enzyme activity assays, alternative promoter/splicing analysis, and immunolocalization in human kidney tissue and cell lines\",\n      \"pmids\": [\"12837292\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Substrate preference among individual phosphoinositides not resolved\", \"Functional role of the cytosolic versus transmembrane isoform unclear\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Linked PTPRQ lipid phosphatase activity to a cellular outcome by showing it lowers phosphoinositide levels and dampens Akt signalling to restrain adipogenic differentiation.\",\n      \"evidence\": \"Overexpression in human mesenchymal stem cells with PI quantification, Akt phosphorylation Western blots, and adipogenesis assays\",\n      \"pmids\": [\"19351528\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No mutagenesis or reconstitution to confirm catalytic dependence\", \"Overexpression may not reflect endogenous activity\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Defined PTPRQ as a chondroitin sulfate proteoglycan structural component of hair bundle shaft connectors, distinguishing a structural role from its enzymatic activity.\",\n      \"evidence\": \"Chondroitinase ABC treatment, electron microscopy, isoform-specific immunostaining, and wild-type versus Ptprq-null mouse inner ear comparison\",\n      \"pmids\": [\"20715155\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular partners forming the shaft connector not identified\", \"Relationship between lipid phosphatase activity and proteoglycan function unresolved\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Demonstrated through clean genetic knockout that Ptprq is required to maintain stereocilia integrity and vestibular function in vivo.\",\n      \"evidence\": \"Ptprq-null mouse analysis with scanning electron microscopy, vestibular evoked potentials, and swimming behavior across postnatal day 5 to 12 months\",\n      \"pmids\": [\"22357859\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism connecting Ptprq loss to stereocilia fusion/elongation not defined\", \"Distinct contributions of lipid phosphatase versus proteoglycan function not dissected\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Placed Ptprq downstream of miR-96 in hair cell differentiation, integrating it into a regulatory pathway controlling the auditory phenotype.\",\n      \"evidence\": \"Microarray transcriptomics and single hair cell electrophysiology comparing Ptprq-null, diminuendo heterozygous, and diminuendo homozygous mice\",\n      \"pmids\": [\"24446963\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct regulation of Ptprq by miR-96 not demonstrated\", \"Other miR-96 targets contributing to phenotype not separated\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"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.\",\n      \"evidence\": \"X-ray crystallography at 1.56 Å of the catalytic domain with kinetic assays across phosphatidylinositide substrates\",\n      \"pmids\": [\"23897475\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structure of full-length receptor-like protein not solved\", \"In vivo relevance of PI(3,4,5)P3 dephosphorylation in hair cells not established\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Identified a dominant disease mechanism (DFNA73), showing a last-exon nonsense mutation escapes NMD to produce a truncated protein consistent with dominant-negative action.\",\n      \"evidence\": \"NGS, linkage and exome analysis, and semi-quantitative RT-PCR demonstrating NMD escape in patient fibroblasts\",\n      \"pmids\": [\"29309402\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Dominant-negative mechanism inferred but not functionally proven\", \"Effect of the truncated protein on bundle structure not tested\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Validated dominant truncating PTPRQ pathogenicity in an animal model, recapitulating progressive hearing loss and revealing affected downstream cochlear pathways.\",\n      \"evidence\": \"CRISPR-Cas9 knock-in mice with auditory brainstem responses, stereocilia electron microscopy, and cochlear proteomics\",\n      \"pmids\": [\"39434500\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Causal role of oxidative phosphorylation/angiogenesis/synaptic pathway changes not established\", \"Mechanism distinguishing heterozygous mild from homozygous profound phenotype unclear\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Characterized the splicing consequences of intronic and splice-site PTPRQ variants, defining how they generate frameshifts and exon skipping that disrupt the protein.\",\n      \"evidence\": \"Minigene splicing assays with Sanger confirmation and computational structural/docking analysis\",\n      \"pmids\": [\"40165225\", \"41069440\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Functional consequences for protein activity shown only computationally\", \"Quantitative effect on transcript levels in patient tissue not measured\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How PTPRQ's lipid phosphatase activity and its chondroitin sulfate proteoglycan structural role are mechanistically coupled at the stereocilia shaft connector remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"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\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0016787\", \"supporting_discovery_ids\": [0, 1, 2]},\n      {\"term_id\": \"GO:0005198\", \"supporting_discovery_ids\": [3]},\n      {\"term_id\": \"GO:0008289\", \"supporting_discovery_ids\": [0, 1]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [0, 3]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [1, 2]},\n      {\"term_id\": \"R-HSA-9709957\", \"supporting_discovery_ids\": [4]}\n    ],\n    \"complexes\": [],\n    \"partners\": [],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":6,"faith_total":6,"faith_pct":100.0}}