{"gene":"PDZD7","run_date":"2026-04-29T11:37:58","timeline":{"discoveries":[{"year":2010,"finding":"PDZD7 knockdown in zebrafish produced an Usher-like phenotype, exacerbated retinal cell death in combination with ush2a or gpr98 knockdown, and reduced Gpr98 localization in the region of the photoreceptor connecting cilium, establishing PDZD7 as a modifier of retinal disease and contributor to digenic Usher syndrome through genetic interaction with USH2A and GPR98.","method":"Zebrafish morpholino knockdown, epistasis/double-knockdown, immunolocalization","journal":"The Journal of clinical investigation","confidence":"High","confidence_rationale":"Tier 2 — genetic epistasis in zebrafish with multiple combinations, replicated with localization data; highly cited foundational paper","pmids":["20440071"],"is_preprint":false},{"year":2012,"finding":"PDZD7 localizes to the ankle-link region of hair cell stereocilia, overlapping with usherin, whirlin, and GPR98; cytosolic domains of usherin and GPR98 can directly bind to both whirlin and PDZD7, establishing PDZD7 as a scaffolding component of the ankle-link complex.","method":"Mass spectrometry of chick stereocilia, immunofluorescence, overexpression of tagged proteins in rat/mouse hair cells, pull-down assays in LLC-PK1 cells","journal":"The Journal of neuroscience","confidence":"High","confidence_rationale":"Tier 2 — multiple orthogonal methods (MS, immunofluorescence, pull-down) in multiple model systems","pmids":["23055499"],"is_preprint":false},{"year":2013,"finding":"Pdzd7 knockout mice exhibit congenital profound deafness with disorganized stereocilia bundles, reduced mechanotransduction currents, and loss of USH2 protein complex (USH2A, GPR98, WHRN) localization at ankle links in cochlear hair cells, demonstrating that PDZD7 is essential for organizing the USH2 complex at ankle links through direct interactions with all three USH2 proteins.","method":"Knockout mouse model, ABR/DPOAE/cochlear microphonics, electron microscopy, immunolocalization, electrophysiology","journal":"Human molecular genetics","confidence":"High","confidence_rationale":"Tier 2 — complete KO mouse with multiple functional readouts and molecular pathway placement","pmids":["24334608"],"is_preprint":false},{"year":2014,"finding":"PDZD7 overexpression decreased the adenylate cyclase inhibition mediated by the VLGR1 (ADGRV1) β-subunit Gαi coupling, identifying PDZD7 as a negative regulator of VLGR1 constitutive Gαi signaling activity.","method":"cAMP assay, co-expression in cell lines, functional mutant analysis","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 — in vitro functional assay with defined signaling readout, single lab","pmids":["24962568"],"is_preprint":false},{"year":2014,"finding":"WHRN and PDZD7 are both required to form a quaternary USH2 protein complex with USH2A and GPR98; WHRN preferentially binds USH2A, PDZD7 preferentially binds GPR98, and WHRN-PDZD7 interaction bridges USH2A and GPR98 within the complex.","method":"Yeast two-hybrid, pull-down assays, colocalization in cell lines, systematic domain mapping","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 — multiple orthogonal methods (Y2H, pull-down, colocalization) with systematic domain-level analysis","pmids":["25406310"],"is_preprint":false},{"year":2016,"finding":"MYO7A forms a complex with PDZD7 in stereocilia membrane fractions; MYO7A and PDZD7 interact in tissue-culture cells, and PDZD7 co-localizes to the ankle-link region of stereocilia in wild-type but not Myo7a mutant mice, demonstrating that PDZD7 localization at ankle links depends on MYO7A.","method":"Stereocilia membrane fractionation, mass spectrometry, co-immunoprecipitation in tissue-culture cells, immunolocalization in Myo7a mutant mice","journal":"eLife","confidence":"High","confidence_rationale":"Tier 2 — enrichment from native tissue combined with cell-based interaction and in vivo localization in mutant model","pmids":["27525485"],"is_preprint":false},{"year":2018,"finding":"Yeast two-hybrid screening using the first two PDZ domains of PDZD7 as bait identified novel binding partners including ADGRV1, gelsolin, β-catenin, and CADM1, expanding the known PDZD7 interactome.","method":"Yeast two-hybrid screening, expression verification by RT-PCR/immunostaining, ABR measurement in Cadm1 KO mice","journal":"Neural plasticity","confidence":"Medium","confidence_rationale":"Tier 3 — yeast two-hybrid with limited biochemical confirmation of individual interactions","pmids":["29796015"],"is_preprint":false},{"year":2019,"finding":"The PDZD7 long isoform, but not short isoforms, localizes to the ankle region of stereocilia; selective disruption of the long isoform in mice impairs ankle-link complex localization, causes stereocilia development deficits, reduces MET currents, and causes hearing loss; yeast two-hybrid identified PIP5K1C as a long-isoform-specific binding partner.","method":"Isoform-selective mouse knockout (exon 14 deletion), ABR, immunolocalization, electrophysiology, yeast two-hybrid","journal":"FASEB journal","confidence":"High","confidence_rationale":"Tier 2 — isoform-specific KO mouse with multiple functional readouts plus identification of isoform-specific interactor","pmids":["31914662"],"is_preprint":false},{"year":2021,"finding":"The PDZD7 harmonin homology domain (HHD) adopts a five-helix fold and contains a unique α1N helix that occupies the canonical binding pocket; the HHD binds lipids and mediates localization of PDZD7 to the plasma membrane, and a hearing-loss mutation in the N-terminal extension of HHD disrupts lipid binding.","method":"X-ray crystallography (1.49 Å), lipid-binding assays, subcellular localization in HEK293T cells, disease mutation analysis","journal":"Frontiers in cell and developmental biology","confidence":"High","confidence_rationale":"Tier 1 — crystal structure plus functional lipid-binding assay and disease mutation validation","pmids":["33937240"],"is_preprint":false},{"year":2022,"finding":"Both N-terminal PDZ domains of PDZD7 bind the C-terminal PDZ-binding motif (PBM) of ADGRV1 via atypical C-terminal β extensions; the two PDZ domains form a supramodule in solution that is stabilized upon PBM binding; two deafness-causing mutations located in the binding grooves of these PDZ domains disrupt stability and binding.","method":"NMR, ITC, mutagenesis, structural biochemistry in solution","journal":"Frontiers in molecular biosciences","confidence":"High","confidence_rationale":"Tier 1 — NMR structure and biophysical binding assays with disease mutation validation","pmids":["35836927"],"is_preprint":false},{"year":2022,"finding":"PDZD7 PDZ3 domain binds the C-terminal tail of FCHSD2 (a CDC42/N-WASP regulator of cell protrusion); crystal structure at 2.0 Å resolution shows the FCHSD2 PDZ-binding motif stretching through the αB/βB groove of PDZD7 PDZ3, linking the ankle-link complex to cytoskeletal dynamics.","method":"Yeast two-hybrid, co-immunoprecipitation in COS-7 cells, X-ray crystallography (2.0 Å)","journal":"The Biochemical journal","confidence":"High","confidence_rationale":"Tier 1 — crystal structure of complex plus orthogonal biochemical validation","pmids":["35695292"],"is_preprint":false},{"year":2025,"finding":"Using STED super-resolution nanoscopy, ADGRV1 and PDZD7 show highly asymmetric colocalization within stereocilia rows at the ankle-link region, with distinct distributions between inner and outer hair cells; the ADGRV1 extracellular domain disappears after P12 while the GPCR domain persists until P21, suggesting a signaling role beyond scaffolding.","method":"STED nanoscopy on juvenile mouse cochlear hair cells","journal":"iScience","confidence":"Medium","confidence_rationale":"Tier 2 — high-resolution direct localization experiment in native tissue, single lab","pmids":["40836926"],"is_preprint":false},{"year":2008,"finding":"Homozygous disruption of PDZD7 by chromosomal translocation causes non-syndromic congenital hearing loss; protein-protein interaction assays showed PDZD7 integrates into the Usher syndrome protein network; PDZD7 shares homology with harmonin (USH1C) and whirlin (DFNB31).","method":"FISH, junction fragment cloning/sequencing, RT-PCR for inner ear expression, protein-protein interaction assays","journal":"Human molecular genetics","confidence":"Medium","confidence_rationale":"Tier 2 — natural human loss-of-function variant with molecular interaction assays","pmids":["19028668"],"is_preprint":false}],"current_model":"PDZD7 is a PDZ domain-containing scaffolding protein that localizes to the ankle-link region of inner ear hair cell stereocilia (dependent on MYO7A), where its long isoform organizes the quaternary USH2 protein complex (USH2A, ADGRV1/GPR98, WHRN) through direct PDZ-domain-mediated interactions—PDZD7 preferentially binding ADGRV1 while WHRN bridges to USH2A—and its HHD domain mediates membrane targeting via lipid binding; loss of PDZD7 disrupts ankle-link complex localization, impairs mechanotransduction currents, and causes deafness, while in the retina PDZD7 acts as a modifier of GPR98 localization at the photoreceptor connecting cilium in an oligogenic context with USH2A and GPR98."},"narrative":{"teleology":[{"year":2008,"claim":"Establishing that PDZD7 is a deafness gene: a homozygous chromosomal translocation disrupting PDZD7 was identified as the cause of congenital hearing loss in a human case, and interaction assays placed it within the Usher protein network, revealing it as a harmonin/whirlin paralog with a role in auditory function.","evidence":"FISH and junction sequencing of human translocation; protein-protein interaction assays; RT-PCR for inner ear expression","pmids":["19028668"],"confidence":"Medium","gaps":["Single family study without independent replication at that time","No localization in hair cells demonstrated","Mechanism of hearing loss not established"]},{"year":2010,"claim":"Demonstrating that PDZD7 functions as a modifier of retinal degeneration in the USH2 pathway: zebrafish knockdown showed PDZD7 loss reduces GPR98 localization at photoreceptor connecting cilia and synergizes with USH2A or GPR98 loss to exacerbate retinal cell death, establishing oligogenic disease contribution.","evidence":"Zebrafish morpholino knockdown with single and double knockdowns; immunolocalization of Gpr98","pmids":["20440071"],"confidence":"High","gaps":["Retinal modifier role not confirmed in mammalian models","Direct biochemical interaction between PDZD7 and GPR98 not yet shown","Mechanism of retinal localization control unknown"]},{"year":2012,"claim":"Defining PDZD7 as a physical scaffolding component of the ankle-link complex: mass spectrometry identified PDZD7 in stereocilia, immunofluorescence placed it at the ankle-link region co-localizing with usherin, GPR98, and whirlin, and pull-downs confirmed direct binding to usherin and GPR98 cytoplasmic domains.","evidence":"Mass spectrometry of chick stereocilia; immunofluorescence in rodent hair cells; pull-down assays in LLC-PK1 cells","pmids":["23055499"],"confidence":"High","gaps":["Functional consequence of PDZD7 loss on ankle-link integrity not yet tested in vivo","Binding specificity among USH2 complex members not resolved"]},{"year":2013,"claim":"Proving PDZD7 is required for hearing and USH2 complex assembly in vivo: Pdzd7 knockout mice are congenitally deaf with disorganized stereocilia, reduced mechanotransduction currents, and loss of USH2A/GPR98/WHRN from ankle links, establishing PDZD7 as essential for organizing the quaternary USH2 complex.","evidence":"Complete knockout mouse; ABR/DPOAE/cochlear microphonics; scanning electron microscopy; immunolocalization; electrophysiology","pmids":["24334608"],"confidence":"High","gaps":["Whether PDZD7 loss affects retinal function in mammals not addressed","Relative contributions of different PDZD7 isoforms unknown"]},{"year":2014,"claim":"Resolving the binding architecture of the quaternary USH2 complex: systematic domain mapping showed WHRN preferentially binds USH2A and PDZD7 preferentially binds GPR98, with WHRN–PDZD7 interaction bridging the two receptors; additionally, PDZD7 was found to negatively regulate ADGRV1 Gαi signaling activity.","evidence":"Yeast two-hybrid, pull-downs, colocalization in cell lines (complex architecture); cAMP assay in cell lines (signaling modulation)","pmids":["25406310","24962568"],"confidence":"High","gaps":["Signaling modulation shown only in heterologous cells, not in hair cells","Whether PDZD7-mediated signaling regulation is physiologically relevant in vivo is unknown"]},{"year":2016,"claim":"Establishing that MYO7A is required for PDZD7 localization at ankle links: PDZD7 co-fractionates and co-immunoprecipitates with MYO7A from stereocilia membranes, and PDZD7 fails to localize to ankle links in Myo7a mutant mice, revealing MYO7A-dependent transport as the mechanism of PDZD7 positioning.","evidence":"Stereocilia membrane fractionation and mass spectrometry; co-IP in tissue-culture cells; immunolocalization in Myo7a mutant mice","pmids":["27525485"],"confidence":"High","gaps":["Whether MYO7A directly transports PDZD7 or acts indirectly is unclear","No reconstitution of motor-cargo complex in vitro"]},{"year":2019,"claim":"Demonstrating isoform specificity: only the long PDZD7 isoform localizes to ankle links and is required for hearing; selective disruption of the long isoform phenocopied the full knockout, and PIP5K1C was identified as a long-isoform-specific binding partner, linking PDZD7 to phosphoinositide signaling.","evidence":"Isoform-selective mouse knockout (exon 14 deletion); ABR; immunolocalization; electrophysiology; yeast two-hybrid","pmids":["31914662"],"confidence":"High","gaps":["Functional role of PIP5K1C interaction in stereocilia not tested","Functions of short PDZD7 isoforms remain unknown"]},{"year":2021,"claim":"Structural elucidation of the HHD domain revealed how PDZD7 targets membranes: crystallography showed a five-helix fold with a unique α1N helix occluding the canonical binding pocket; the HHD binds lipids and mediates plasma membrane localization, and a deafness-causing mutation in this domain abolishes lipid binding.","evidence":"X-ray crystallography at 1.49 Å; lipid-binding assays; subcellular localization in HEK293T cells; disease mutation analysis","pmids":["33937240"],"confidence":"High","gaps":["Lipid species specificity in native stereocilia membranes not determined","No in vivo rescue experiments with lipid-binding-deficient mutants"]},{"year":2022,"claim":"Atomic-resolution mapping of PDZ-domain interactions: NMR and crystallography revealed that PDZD7 PDZ1–PDZ2 forms a supramodule stabilized upon ADGRV1 PBM binding via atypical β-extensions, while PDZ3 binds FCHSD2 to connect the ankle-link complex to CDC42/N-WASP–mediated actin dynamics; deafness mutations in PDZ binding grooves disrupt these interactions.","evidence":"NMR and ITC for PDZ1–PDZ2/ADGRV1 (solution biophysics); X-ray crystallography at 2.0 Å for PDZ3/FCHSD2; co-IP in COS-7 cells; mutagenesis","pmids":["35836927","35695292"],"confidence":"High","gaps":["Whether FCHSD2 interaction is functionally required for stereocilia development not tested in vivo","Full-length PDZD7 structure and domain arrangement remain undetermined"]},{"year":2025,"claim":"Nanoscale localization revealed unexpected spatial asymmetry: STED super-resolution showed ADGRV1 and PDZD7 have row-specific asymmetric distributions in stereocilia, differing between inner and outer hair cells, and the ADGRV1 extracellular domain is lost after P12 while the GPCR domain persists, suggesting a signaling function beyond structural scaffolding.","evidence":"STED nanoscopy on juvenile mouse cochlear hair cells","pmids":["40836926"],"confidence":"Medium","gaps":["Functional significance of row-specific asymmetry is unknown","Whether the persistent ADGRV1 GPCR domain signals through PDZD7 in mature hair cells not tested","Single-lab observation awaiting independent confirmation"]},{"year":null,"claim":"Key unresolved questions include whether PDZD7 has a direct role in mammalian retinal function, how the full-length multi-domain protein is spatially organized in the ankle-link complex, whether PDZD7-mediated regulation of ADGRV1 signaling is physiologically relevant in hair cells, and the functional roles of the short PDZD7 isoforms.","evidence":"","pmids":[],"confidence":"Low","gaps":["No mammalian retinal phenotype from PDZD7 loss reported","No full-length structure or in situ structural model","Short isoform functions completely uncharacterized"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[1,2,4]},{"term_id":"GO:0008289","term_label":"lipid binding","supporting_discovery_ids":[8]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[3]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[1,8,11]},{"term_id":"GO:0005929","term_label":"cilium","supporting_discovery_ids":[0,1,2,5,7,11]}],"pathway":[{"term_id":"R-HSA-9709957","term_label":"Sensory Perception","supporting_discovery_ids":[2,7,12]}],"complexes":["USH2 ankle-link complex (USH2A/ADGRV1/WHRN/PDZD7)"],"partners":["ADGRV1","USH2A","WHRN","MYO7A","FCHSD2","PIP5K1C"],"other_free_text":[]},"mechanistic_narrative":"PDZD7 is a multi-PDZ-domain scaffolding protein essential for organizing the Usher type 2 (USH2) protein complex at the ankle-link region of inner ear hair cell stereocilia. Its long isoform localizes to stereocilia ankle links in a MYO7A-dependent manner, where its N-terminal PDZ1–PDZ2 supramodule preferentially binds ADGRV1/GPR98 while its PDZ3 domain engages FCHSD2 to link the complex to actin cytoskeletal dynamics, and its harmonin homology domain (HHD) mediates plasma membrane targeting through lipid binding [PMID:23055499, PMID:25406310, PMID:35695292, PMID:33937240]. Loss of PDZD7 in mice causes congenital deafness with disorganized stereocilia bundles, loss of USH2A/GPR98/WHRN localization at ankle links, and reduced mechanotransduction currents, and homozygous PDZD7 disruption in humans causes non-syndromic congenital hearing loss [PMID:24334608, PMID:19028668]. In the retina, PDZD7 acts as a genetic modifier of the USH2 pathway by regulating GPR98 localization at photoreceptor connecting cilia and contributing to digenic Usher syndrome in combination with USH2A or GPR98 mutations [PMID:20440071]."},"prefetch_data":{"uniprot":{"accession":"Q9H5P4","full_name":"PDZ domain-containing protein 7","aliases":[],"length_aa":1033,"mass_kda":111.8,"function":"In cochlear developing hair cells, essential in organizing the USH2 complex at stereocilia ankle links. Blocks inhibition of adenylate cyclase activity mediated by ADGRV1","subcellular_location":"Cell projection, cilium; Nucleus; Cell projection, stereocilium","url":"https://www.uniprot.org/uniprotkb/Q9H5P4/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/PDZD7","classification":"Not Classified","n_dependent_lines":3,"n_total_lines":1208,"dependency_fraction":0.0024834437086092716},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/PDZD7","total_profiled":1310},"omim":[{"mim_id":"618003","title":"DEAFNESS, AUTOSOMAL RECESSIVE 57; DFNB57","url":"https://www.omim.org/entry/618003"},{"mim_id":"612971","title":"PDZ DOMAIN-CONTAINING 7; PDZD7","url":"https://www.omim.org/entry/612971"},{"mim_id":"608400","title":"USHERIN; USH2A","url":"https://www.omim.org/entry/608400"},{"mim_id":"605472","title":"USHER SYNDROME, TYPE IIC; USH2C","url":"https://www.omim.org/entry/605472"},{"mim_id":"602851","title":"ADHESION G PROTEIN-COUPLED RECEPTOR V1; ADGRV1","url":"https://www.omim.org/entry/602851"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Nucleoplasm","reliability":"Approved"},{"location":"Primary cilium","reliability":"Approved"},{"location":"Basal body","reliability":"Additional"}],"tissue_specificity":"Group enriched","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"brain","ntpm":21.2},{"tissue":"intestine","ntpm":18.8},{"tissue":"pituitary gland","ntpm":7.1}],"url":"https://www.proteinatlas.org/search/PDZD7"},"hgnc":{"alias_symbol":["FLJ23209","bA108L7.8"],"prev_symbol":["PDZK7","DFNB57"]},"alphafold":{"accession":"Q9H5P4","domains":[{"cath_id":"2.30.42.10","chopping":"85-167","consensus_level":"high","plddt":87.7634,"start":85,"end":167},{"cath_id":"2.30.42.10","chopping":"175-303","consensus_level":"high","plddt":80.8782,"start":175,"end":303},{"cath_id":"2.30.42.10","chopping":"861-949","consensus_level":"high","plddt":89.4072,"start":861,"end":949},{"cath_id":"1.20.1160","chopping":"549-645","consensus_level":"high","plddt":84.7703,"start":549,"end":645}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9H5P4","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q9H5P4-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q9H5P4-F1-predicted_aligned_error_v6.png","plddt_mean":56.72},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=PDZD7","jax_strain_url":"https://www.jax.org/strain/search?query=PDZD7"},"sequence":{"accession":"Q9H5P4","fasta_url":"https://rest.uniprot.org/uniprotkb/Q9H5P4.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q9H5P4/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9H5P4"}},"corpus_meta":[{"pmid":"20440071","id":"PMC_20440071","title":"PDZD7 is a modifier of retinal disease and a contributor to digenic Usher syndrome.","date":"2010","source":"The Journal of clinical investigation","url":"https://pubmed.ncbi.nlm.nih.gov/20440071","citation_count":196,"is_preprint":false},{"pmid":"23055499","id":"PMC_23055499","title":"Localization of PDZD7 to the stereocilia ankle-link associates this scaffolding protein with the Usher syndrome protein network.","date":"2012","source":"The Journal of neuroscience : the official journal of the Society for Neuroscience","url":"https://pubmed.ncbi.nlm.nih.gov/23055499","citation_count":63,"is_preprint":false},{"pmid":"24962568","id":"PMC_24962568","title":"Constitutive Gαi coupling activity of very large G protein-coupled receptor 1 (VLGR1) and its regulation by PDZD7 protein.","date":"2014","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/24962568","citation_count":60,"is_preprint":false},{"pmid":"24334608","id":"PMC_24334608","title":"Deletion of PDZD7 disrupts the Usher syndrome type 2 protein complex in cochlear hair cells and causes hearing loss in mice.","date":"2013","source":"Human molecular genetics","url":"https://pubmed.ncbi.nlm.nih.gov/24334608","citation_count":53,"is_preprint":false},{"pmid":"25406310","id":"PMC_25406310","title":"Whirlin and PDZ domain-containing 7 (PDZD7) proteins are both required to form the quaternary protein complex associated with Usher syndrome type 2.","date":"2014","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/25406310","citation_count":52,"is_preprint":false},{"pmid":"26416264","id":"PMC_26416264","title":"PDZD7 and hearing loss: More than just a modifier.","date":"2015","source":"American journal of medical genetics. Part A","url":"https://pubmed.ncbi.nlm.nih.gov/26416264","citation_count":50,"is_preprint":false},{"pmid":"19028668","id":"PMC_19028668","title":"Homozygous disruption of PDZD7 by reciprocal translocation in a consanguineous family: a new member of the Usher syndrome protein interactome causing congenital hearing impairment.","date":"2008","source":"Human molecular genetics","url":"https://pubmed.ncbi.nlm.nih.gov/19028668","citation_count":46,"is_preprint":false},{"pmid":"30786928","id":"PMC_30786928","title":"Lnc-PDZD7 contributes to stemness properties and chemosensitivity in hepatocellular carcinoma through EZH2-mediated ATOH8 transcriptional repression.","date":"2019","source":"Journal of experimental & clinical cancer research : CR","url":"https://pubmed.ncbi.nlm.nih.gov/30786928","citation_count":44,"is_preprint":false},{"pmid":"27525485","id":"PMC_27525485","title":"PDZD7-MYO7A complex identified in enriched stereocilia membranes.","date":"2016","source":"eLife","url":"https://pubmed.ncbi.nlm.nih.gov/27525485","citation_count":44,"is_preprint":false},{"pmid":"26849169","id":"PMC_26849169","title":"Confirmation of PDZD7 as a Nonsyndromic Hearing Loss Gene.","date":"2016","source":"Ear and hearing","url":"https://pubmed.ncbi.nlm.nih.gov/26849169","citation_count":25,"is_preprint":false},{"pmid":"31454969","id":"PMC_31454969","title":"Identification of a Potential Founder Effect of a Novel PDZD7 Variant Involved in Moderate-to-Severe Sensorineural Hearing Loss in Koreans.","date":"2019","source":"International journal of molecular sciences","url":"https://pubmed.ncbi.nlm.nih.gov/31454969","citation_count":19,"is_preprint":false},{"pmid":"29048736","id":"PMC_29048736","title":"Novel recessive PDZD7 biallelic mutations in two Chinese families with non-syndromic hearing loss.","date":"2017","source":"American journal of medical genetics. Part A","url":"https://pubmed.ncbi.nlm.nih.gov/29048736","citation_count":18,"is_preprint":false},{"pmid":"31914662","id":"PMC_31914662","title":"Lack of PDZD7 long isoform disrupts ankle-link complex and causes hearing loss in mice.","date":"2019","source":"FASEB journal : official publication of the Federation of American Societies for Experimental Biology","url":"https://pubmed.ncbi.nlm.nih.gov/31914662","citation_count":17,"is_preprint":false},{"pmid":"29796015","id":"PMC_29796015","title":"Identification of Binding Partners of Deafness-Related Protein PDZD7.","date":"2018","source":"Neural plasticity","url":"https://pubmed.ncbi.nlm.nih.gov/29796015","citation_count":12,"is_preprint":false},{"pmid":"33530996","id":"PMC_33530996","title":"A novel recessive PDZD7 bi-allelic mutation in an Iranian family with non-syndromic hearing loss.","date":"2021","source":"BMC medical genomics","url":"https://pubmed.ncbi.nlm.nih.gov/33530996","citation_count":8,"is_preprint":false},{"pmid":"33937240","id":"PMC_33937240","title":"Structure and Membrane Targeting of the PDZD7 Harmonin Homology Domain (HHD) Associated With Hearing Loss.","date":"2021","source":"Frontiers in cell and developmental biology","url":"https://pubmed.ncbi.nlm.nih.gov/33937240","citation_count":7,"is_preprint":false},{"pmid":"31129248","id":"PMC_31129248","title":"Novel recessive PDZD7 biallelic mutations associated with hereditary hearing loss in a Chinese pedigree.","date":"2019","source":"Gene","url":"https://pubmed.ncbi.nlm.nih.gov/31129248","citation_count":7,"is_preprint":false},{"pmid":"35836927","id":"PMC_35836927","title":"Deciphering the Molecular Interaction Between the Adhesion G Protein-Coupled Receptor ADGRV1 and its PDZ-Containing Regulator PDZD7.","date":"2022","source":"Frontiers in molecular biosciences","url":"https://pubmed.ncbi.nlm.nih.gov/35836927","citation_count":4,"is_preprint":false},{"pmid":"35715776","id":"PMC_35715776","title":"Novel homozygous variant in the PDZD7 gene in a family with nonsyndromic sensorineural hearing loss.","date":"2022","source":"BMC medical genomics","url":"https://pubmed.ncbi.nlm.nih.gov/35715776","citation_count":3,"is_preprint":false},{"pmid":"35695292","id":"PMC_35695292","title":"Deafness-related protein PDZD7 forms complex with the C-terminal tail of FCHSD2.","date":"2022","source":"The Biochemical journal","url":"https://pubmed.ncbi.nlm.nih.gov/35695292","citation_count":2,"is_preprint":false},{"pmid":"40836926","id":"PMC_40836926","title":"Super-resolution mapping of the ankle link proteins ADGRV1 and PDZD7 in developing auditory hair cells.","date":"2025","source":"iScience","url":"https://pubmed.ncbi.nlm.nih.gov/40836926","citation_count":1,"is_preprint":false},{"pmid":"41199745","id":"PMC_41199745","title":"A newly discovered Lnc-PDZD7-3 increased metastatic and proliferative potential of lung adenocarcinoma cells via modulating FN1/fibronectin signaling.","date":"2025","source":"Frontiers in genetics","url":"https://pubmed.ncbi.nlm.nih.gov/41199745","citation_count":1,"is_preprint":false},{"pmid":"38956522","id":"PMC_38956522","title":"Clinical characterizations and molecular genetic study of two co-segregating variants in PDZD7 and PDE6C genes leading simultaneously to non-syndromic hearing loss and achromatopsia.","date":"2024","source":"BMC medical genomics","url":"https://pubmed.ncbi.nlm.nih.gov/38956522","citation_count":1,"is_preprint":false},{"pmid":"41276803","id":"PMC_41276803","title":"First clinical report of a rare PDZD7 nonsense variant and recurrent mutations in Iranian families with autosomal recessive non-syndromic hearing loss.","date":"2025","source":"BMC medical genomics","url":"https://pubmed.ncbi.nlm.nih.gov/41276803","citation_count":0,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":13733,"output_tokens":3096,"usd":0.043819},"stage2":{"model":"claude-opus-4-6","input_tokens":6504,"output_tokens":3100,"usd":0.16503},"total_usd":0.208849,"stage1_batch_id":"msgbatch_012ZiiCUBfB62NCTQd4Bk1Jo","stage2_batch_id":"msgbatch_01Xuqq9aUHoQouS7UVGZNStZ","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2010,\n      \"finding\": \"PDZD7 knockdown in zebrafish produced an Usher-like phenotype, exacerbated retinal cell death in combination with ush2a or gpr98 knockdown, and reduced Gpr98 localization in the region of the photoreceptor connecting cilium, establishing PDZD7 as a modifier of retinal disease and contributor to digenic Usher syndrome through genetic interaction with USH2A and GPR98.\",\n      \"method\": \"Zebrafish morpholino knockdown, epistasis/double-knockdown, immunolocalization\",\n      \"journal\": \"The Journal of clinical investigation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — genetic epistasis in zebrafish with multiple combinations, replicated with localization data; highly cited foundational paper\",\n      \"pmids\": [\"20440071\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"PDZD7 localizes to the ankle-link region of hair cell stereocilia, overlapping with usherin, whirlin, and GPR98; cytosolic domains of usherin and GPR98 can directly bind to both whirlin and PDZD7, establishing PDZD7 as a scaffolding component of the ankle-link complex.\",\n      \"method\": \"Mass spectrometry of chick stereocilia, immunofluorescence, overexpression of tagged proteins in rat/mouse hair cells, pull-down assays in LLC-PK1 cells\",\n      \"journal\": \"The Journal of neuroscience\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods (MS, immunofluorescence, pull-down) in multiple model systems\",\n      \"pmids\": [\"23055499\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Pdzd7 knockout mice exhibit congenital profound deafness with disorganized stereocilia bundles, reduced mechanotransduction currents, and loss of USH2 protein complex (USH2A, GPR98, WHRN) localization at ankle links in cochlear hair cells, demonstrating that PDZD7 is essential for organizing the USH2 complex at ankle links through direct interactions with all three USH2 proteins.\",\n      \"method\": \"Knockout mouse model, ABR/DPOAE/cochlear microphonics, electron microscopy, immunolocalization, electrophysiology\",\n      \"journal\": \"Human molecular genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — complete KO mouse with multiple functional readouts and molecular pathway placement\",\n      \"pmids\": [\"24334608\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"PDZD7 overexpression decreased the adenylate cyclase inhibition mediated by the VLGR1 (ADGRV1) β-subunit Gαi coupling, identifying PDZD7 as a negative regulator of VLGR1 constitutive Gαi signaling activity.\",\n      \"method\": \"cAMP assay, co-expression in cell lines, functional mutant analysis\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — in vitro functional assay with defined signaling readout, single lab\",\n      \"pmids\": [\"24962568\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"WHRN and PDZD7 are both required to form a quaternary USH2 protein complex with USH2A and GPR98; WHRN preferentially binds USH2A, PDZD7 preferentially binds GPR98, and WHRN-PDZD7 interaction bridges USH2A and GPR98 within the complex.\",\n      \"method\": \"Yeast two-hybrid, pull-down assays, colocalization in cell lines, systematic domain mapping\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods (Y2H, pull-down, colocalization) with systematic domain-level analysis\",\n      \"pmids\": [\"25406310\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"MYO7A forms a complex with PDZD7 in stereocilia membrane fractions; MYO7A and PDZD7 interact in tissue-culture cells, and PDZD7 co-localizes to the ankle-link region of stereocilia in wild-type but not Myo7a mutant mice, demonstrating that PDZD7 localization at ankle links depends on MYO7A.\",\n      \"method\": \"Stereocilia membrane fractionation, mass spectrometry, co-immunoprecipitation in tissue-culture cells, immunolocalization in Myo7a mutant mice\",\n      \"journal\": \"eLife\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — enrichment from native tissue combined with cell-based interaction and in vivo localization in mutant model\",\n      \"pmids\": [\"27525485\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Yeast two-hybrid screening using the first two PDZ domains of PDZD7 as bait identified novel binding partners including ADGRV1, gelsolin, β-catenin, and CADM1, expanding the known PDZD7 interactome.\",\n      \"method\": \"Yeast two-hybrid screening, expression verification by RT-PCR/immunostaining, ABR measurement in Cadm1 KO mice\",\n      \"journal\": \"Neural plasticity\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — yeast two-hybrid with limited biochemical confirmation of individual interactions\",\n      \"pmids\": [\"29796015\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"The PDZD7 long isoform, but not short isoforms, localizes to the ankle region of stereocilia; selective disruption of the long isoform in mice impairs ankle-link complex localization, causes stereocilia development deficits, reduces MET currents, and causes hearing loss; yeast two-hybrid identified PIP5K1C as a long-isoform-specific binding partner.\",\n      \"method\": \"Isoform-selective mouse knockout (exon 14 deletion), ABR, immunolocalization, electrophysiology, yeast two-hybrid\",\n      \"journal\": \"FASEB journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — isoform-specific KO mouse with multiple functional readouts plus identification of isoform-specific interactor\",\n      \"pmids\": [\"31914662\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"The PDZD7 harmonin homology domain (HHD) adopts a five-helix fold and contains a unique α1N helix that occupies the canonical binding pocket; the HHD binds lipids and mediates localization of PDZD7 to the plasma membrane, and a hearing-loss mutation in the N-terminal extension of HHD disrupts lipid binding.\",\n      \"method\": \"X-ray crystallography (1.49 Å), lipid-binding assays, subcellular localization in HEK293T cells, disease mutation analysis\",\n      \"journal\": \"Frontiers in cell and developmental biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — crystal structure plus functional lipid-binding assay and disease mutation validation\",\n      \"pmids\": [\"33937240\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Both N-terminal PDZ domains of PDZD7 bind the C-terminal PDZ-binding motif (PBM) of ADGRV1 via atypical C-terminal β extensions; the two PDZ domains form a supramodule in solution that is stabilized upon PBM binding; two deafness-causing mutations located in the binding grooves of these PDZ domains disrupt stability and binding.\",\n      \"method\": \"NMR, ITC, mutagenesis, structural biochemistry in solution\",\n      \"journal\": \"Frontiers in molecular biosciences\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — NMR structure and biophysical binding assays with disease mutation validation\",\n      \"pmids\": [\"35836927\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"PDZD7 PDZ3 domain binds the C-terminal tail of FCHSD2 (a CDC42/N-WASP regulator of cell protrusion); crystal structure at 2.0 Å resolution shows the FCHSD2 PDZ-binding motif stretching through the αB/βB groove of PDZD7 PDZ3, linking the ankle-link complex to cytoskeletal dynamics.\",\n      \"method\": \"Yeast two-hybrid, co-immunoprecipitation in COS-7 cells, X-ray crystallography (2.0 Å)\",\n      \"journal\": \"The Biochemical journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — crystal structure of complex plus orthogonal biochemical validation\",\n      \"pmids\": [\"35695292\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Using STED super-resolution nanoscopy, ADGRV1 and PDZD7 show highly asymmetric colocalization within stereocilia rows at the ankle-link region, with distinct distributions between inner and outer hair cells; the ADGRV1 extracellular domain disappears after P12 while the GPCR domain persists until P21, suggesting a signaling role beyond scaffolding.\",\n      \"method\": \"STED nanoscopy on juvenile mouse cochlear hair cells\",\n      \"journal\": \"iScience\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — high-resolution direct localization experiment in native tissue, single lab\",\n      \"pmids\": [\"40836926\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"Homozygous disruption of PDZD7 by chromosomal translocation causes non-syndromic congenital hearing loss; protein-protein interaction assays showed PDZD7 integrates into the Usher syndrome protein network; PDZD7 shares homology with harmonin (USH1C) and whirlin (DFNB31).\",\n      \"method\": \"FISH, junction fragment cloning/sequencing, RT-PCR for inner ear expression, protein-protein interaction assays\",\n      \"journal\": \"Human molecular genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — natural human loss-of-function variant with molecular interaction assays\",\n      \"pmids\": [\"19028668\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"PDZD7 is a PDZ domain-containing scaffolding protein that localizes to the ankle-link region of inner ear hair cell stereocilia (dependent on MYO7A), where its long isoform organizes the quaternary USH2 protein complex (USH2A, ADGRV1/GPR98, WHRN) through direct PDZ-domain-mediated interactions—PDZD7 preferentially binding ADGRV1 while WHRN bridges to USH2A—and its HHD domain mediates membrane targeting via lipid binding; loss of PDZD7 disrupts ankle-link complex localization, impairs mechanotransduction currents, and causes deafness, while in the retina PDZD7 acts as a modifier of GPR98 localization at the photoreceptor connecting cilium in an oligogenic context with USH2A and GPR98.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"PDZD7 is a multi-PDZ-domain scaffolding protein essential for organizing the Usher type 2 (USH2) protein complex at the ankle-link region of inner ear hair cell stereocilia. Its long isoform localizes to stereocilia ankle links in a MYO7A-dependent manner, where its N-terminal PDZ1–PDZ2 supramodule preferentially binds ADGRV1/GPR98 while its PDZ3 domain engages FCHSD2 to link the complex to actin cytoskeletal dynamics, and its harmonin homology domain (HHD) mediates plasma membrane targeting through lipid binding [PMID:23055499, PMID:25406310, PMID:35695292, PMID:33937240]. Loss of PDZD7 in mice causes congenital deafness with disorganized stereocilia bundles, loss of USH2A/GPR98/WHRN localization at ankle links, and reduced mechanotransduction currents, and homozygous PDZD7 disruption in humans causes non-syndromic congenital hearing loss [PMID:24334608, PMID:19028668]. In the retina, PDZD7 acts as a genetic modifier of the USH2 pathway by regulating GPR98 localization at photoreceptor connecting cilia and contributing to digenic Usher syndrome in combination with USH2A or GPR98 mutations [PMID:20440071].\",\n  \"teleology\": [\n    {\n      \"year\": 2008,\n      \"claim\": \"Establishing that PDZD7 is a deafness gene: a homozygous chromosomal translocation disrupting PDZD7 was identified as the cause of congenital hearing loss in a human case, and interaction assays placed it within the Usher protein network, revealing it as a harmonin/whirlin paralog with a role in auditory function.\",\n      \"evidence\": \"FISH and junction sequencing of human translocation; protein-protein interaction assays; RT-PCR for inner ear expression\",\n      \"pmids\": [\"19028668\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single family study without independent replication at that time\", \"No localization in hair cells demonstrated\", \"Mechanism of hearing loss not established\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Demonstrating that PDZD7 functions as a modifier of retinal degeneration in the USH2 pathway: zebrafish knockdown showed PDZD7 loss reduces GPR98 localization at photoreceptor connecting cilia and synergizes with USH2A or GPR98 loss to exacerbate retinal cell death, establishing oligogenic disease contribution.\",\n      \"evidence\": \"Zebrafish morpholino knockdown with single and double knockdowns; immunolocalization of Gpr98\",\n      \"pmids\": [\"20440071\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Retinal modifier role not confirmed in mammalian models\", \"Direct biochemical interaction between PDZD7 and GPR98 not yet shown\", \"Mechanism of retinal localization control unknown\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Defining PDZD7 as a physical scaffolding component of the ankle-link complex: mass spectrometry identified PDZD7 in stereocilia, immunofluorescence placed it at the ankle-link region co-localizing with usherin, GPR98, and whirlin, and pull-downs confirmed direct binding to usherin and GPR98 cytoplasmic domains.\",\n      \"evidence\": \"Mass spectrometry of chick stereocilia; immunofluorescence in rodent hair cells; pull-down assays in LLC-PK1 cells\",\n      \"pmids\": [\"23055499\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Functional consequence of PDZD7 loss on ankle-link integrity not yet tested in vivo\", \"Binding specificity among USH2 complex members not resolved\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Proving PDZD7 is required for hearing and USH2 complex assembly in vivo: Pdzd7 knockout mice are congenitally deaf with disorganized stereocilia, reduced mechanotransduction currents, and loss of USH2A/GPR98/WHRN from ankle links, establishing PDZD7 as essential for organizing the quaternary USH2 complex.\",\n      \"evidence\": \"Complete knockout mouse; ABR/DPOAE/cochlear microphonics; scanning electron microscopy; immunolocalization; electrophysiology\",\n      \"pmids\": [\"24334608\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether PDZD7 loss affects retinal function in mammals not addressed\", \"Relative contributions of different PDZD7 isoforms unknown\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Resolving the binding architecture of the quaternary USH2 complex: systematic domain mapping showed WHRN preferentially binds USH2A and PDZD7 preferentially binds GPR98, with WHRN–PDZD7 interaction bridging the two receptors; additionally, PDZD7 was found to negatively regulate ADGRV1 Gαi signaling activity.\",\n      \"evidence\": \"Yeast two-hybrid, pull-downs, colocalization in cell lines (complex architecture); cAMP assay in cell lines (signaling modulation)\",\n      \"pmids\": [\"25406310\", \"24962568\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Signaling modulation shown only in heterologous cells, not in hair cells\", \"Whether PDZD7-mediated signaling regulation is physiologically relevant in vivo is unknown\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Establishing that MYO7A is required for PDZD7 localization at ankle links: PDZD7 co-fractionates and co-immunoprecipitates with MYO7A from stereocilia membranes, and PDZD7 fails to localize to ankle links in Myo7a mutant mice, revealing MYO7A-dependent transport as the mechanism of PDZD7 positioning.\",\n      \"evidence\": \"Stereocilia membrane fractionation and mass spectrometry; co-IP in tissue-culture cells; immunolocalization in Myo7a mutant mice\",\n      \"pmids\": [\"27525485\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether MYO7A directly transports PDZD7 or acts indirectly is unclear\", \"No reconstitution of motor-cargo complex in vitro\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Demonstrating isoform specificity: only the long PDZD7 isoform localizes to ankle links and is required for hearing; selective disruption of the long isoform phenocopied the full knockout, and PIP5K1C was identified as a long-isoform-specific binding partner, linking PDZD7 to phosphoinositide signaling.\",\n      \"evidence\": \"Isoform-selective mouse knockout (exon 14 deletion); ABR; immunolocalization; electrophysiology; yeast two-hybrid\",\n      \"pmids\": [\"31914662\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Functional role of PIP5K1C interaction in stereocilia not tested\", \"Functions of short PDZD7 isoforms remain unknown\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Structural elucidation of the HHD domain revealed how PDZD7 targets membranes: crystallography showed a five-helix fold with a unique α1N helix occluding the canonical binding pocket; the HHD binds lipids and mediates plasma membrane localization, and a deafness-causing mutation in this domain abolishes lipid binding.\",\n      \"evidence\": \"X-ray crystallography at 1.49 Å; lipid-binding assays; subcellular localization in HEK293T cells; disease mutation analysis\",\n      \"pmids\": [\"33937240\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Lipid species specificity in native stereocilia membranes not determined\", \"No in vivo rescue experiments with lipid-binding-deficient mutants\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Atomic-resolution mapping of PDZ-domain interactions: NMR and crystallography revealed that PDZD7 PDZ1–PDZ2 forms a supramodule stabilized upon ADGRV1 PBM binding via atypical β-extensions, while PDZ3 binds FCHSD2 to connect the ankle-link complex to CDC42/N-WASP–mediated actin dynamics; deafness mutations in PDZ binding grooves disrupt these interactions.\",\n      \"evidence\": \"NMR and ITC for PDZ1–PDZ2/ADGRV1 (solution biophysics); X-ray crystallography at 2.0 Å for PDZ3/FCHSD2; co-IP in COS-7 cells; mutagenesis\",\n      \"pmids\": [\"35836927\", \"35695292\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether FCHSD2 interaction is functionally required for stereocilia development not tested in vivo\", \"Full-length PDZD7 structure and domain arrangement remain undetermined\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Nanoscale localization revealed unexpected spatial asymmetry: STED super-resolution showed ADGRV1 and PDZD7 have row-specific asymmetric distributions in stereocilia, differing between inner and outer hair cells, and the ADGRV1 extracellular domain is lost after P12 while the GPCR domain persists, suggesting a signaling function beyond structural scaffolding.\",\n      \"evidence\": \"STED nanoscopy on juvenile mouse cochlear hair cells\",\n      \"pmids\": [\"40836926\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Functional significance of row-specific asymmetry is unknown\", \"Whether the persistent ADGRV1 GPCR domain signals through PDZD7 in mature hair cells not tested\", \"Single-lab observation awaiting independent confirmation\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"Key unresolved questions include whether PDZD7 has a direct role in mammalian retinal function, how the full-length multi-domain protein is spatially organized in the ankle-link complex, whether PDZD7-mediated regulation of ADGRV1 signaling is physiologically relevant in hair cells, and the functional roles of the short PDZD7 isoforms.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No mammalian retinal phenotype from PDZD7 loss reported\", \"No full-length structure or in situ structural model\", \"Short isoform functions completely uncharacterized\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [1, 2, 4]},\n      {\"term_id\": \"GO:0008289\", \"supporting_discovery_ids\": [8]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [3]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [1, 8, 11]},\n      {\"term_id\": \"GO:0005929\", \"supporting_discovery_ids\": [0, 1, 2, 5, 7, 11]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-9709957\", \"supporting_discovery_ids\": [2, 7, 12]}\n    ],\n    \"complexes\": [\n      \"USH2 ankle-link complex (USH2A/ADGRV1/WHRN/PDZD7)\"\n    ],\n    \"partners\": [\n      \"ADGRV1\",\n      \"USH2A\",\n      \"WHRN\",\n      \"MYO7A\",\n      \"FCHSD2\",\n      \"PIP5K1C\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}