Affinage

PDZD7

PDZ domain-containing protein 7 · UniProt Q9H5P4

Length
1033 aa
Mass
111.8 kDa
Annotated
2026-06-10
24 papers in source corpus 13 papers cited in narrative 13 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 8/8 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

PDZD7 is a multi-PDZ-domain scaffold protein that organizes the USH2 ankle-link complex at the base of inner ear hair cell stereocilia, where it is essential for stereocilia bundle development and mechanotransduction (PMID:24334608, PMID:31914662). It localizes to the ankle-link region overlapping with usherin (USH2A), GPR98/ADGRV1, and whirlin (WHRN), and directly binds all three; within this quaternary complex WHRN preferentially binds USH2A while PDZD7 preferentially binds GPR98, with the WHRN–PDZD7 interaction bridging the two subcomplexes (PMID:23055499, PMID:24334608, PMID:25406310). Membrane targeting is achieved through its harmonin homology domain, which adopts a five-helix fold and binds lipid to direct PDZD7 to the plasma membrane; a hearing-loss mutation in the HHD N-terminal extension abolishes lipid binding (PMID:33937240). Its N-terminal tandem PDZ domains form a binding supermodule that engages the C-terminal PDZ-binding motif of ADGRV1, and deafness-causing mutations in the PDZ binding grooves disrupt the stability and binding of this tandem (PMID:35836927). PDZD7 further couples the complex to actin cytoskeleton dynamics and motor-based transport, forming complexes with FCHSD2 (linking to CDC42/N-WASP) via PDZ3 and with the unconventional motor MYO7A in stereocilia membrane fractions (PMID:27525485, PMID:35695292). The long isoform specifically is required for ankle-link complex assembly and engages PIP5K1C as an isoform-specific partner (PMID:31914662). Functionally, PDZD7 modulates ADGRV1/VLGR1 Gαi-mediated adenylate cyclase signaling, relieving constitutive AC inhibition (PMID:24962568). Homozygous PDZD7 disruption causes non-syndromic congenital sensorineural hearing impairment, while it acts as a modifier and digenic contributor to Usher syndrome through effects on GPR98 localization in photoreceptors (PMID:20440071, PMID:19028668).

Mechanistic history

Synthesis pass · year-by-year structured walk · 11 steps
  1. 2008 Medium

    Establishing whether PDZD7 disruption causes human disease addressed whether this gene had a defined physiological role; the discovery linked it to hereditary hearing loss and the Usher protein network.

    Evidence FISH breakpoint mapping and junction sequencing of a human patient with a reciprocal translocation, plus protein-interaction assays and inner ear RT-PCR

    PMID:19028668

    Open questions at the time
    • Single family; causal mechanism not resolved beyond breakpoint disruption
    • Network integration shown by interaction assays without in vivo functional readout
  2. 2010 High

    Whether PDZD7 functionally interacts with known Usher genes was unknown; in vivo knockdown showed it modifies retinal disease and contributes to digenic Usher syndrome.

    Evidence Zebrafish morpholino knockdown with retinal cell death assay, genetic epistasis with ush2a/gpr98, and Gpr98 immunolocalization

    PMID:20440071

    Open questions at the time
    • Morpholino knockdown does not define molecular binding interfaces
    • Photoreceptor mechanism inferred from Gpr98 mislocalization only
  3. 2012 High

    The subcellular site and partners of PDZD7 in hair cells were undefined; localization and binding studies placed it at the ankle-link region with the USH2 proteins.

    Evidence Mass spectrometry of chick stereocilia, immunofluorescence with tagged proteins, and binding assays in LLC-PK1 cells

    PMID:23055499

    Open questions at the time
    • Binding shown in heterologous cells, not native stereocilia
    • Stoichiometry and complex architecture not resolved
  4. 2013 High

    Whether PDZD7 is required for hearing and complex assembly was untested; a knockout mouse demonstrated it is essential for ankle-link complex localization and mechanotransduction.

    Evidence Pdzd7 knockout mouse with ABR/DPOAE/cochlear microphonics, mechanotransduction current recordings, immunofluorescence, and co-IP/pull-down

    PMID:24334608

    Open questions at the time
    • Photoreceptor USH2 proteins remained largely unchanged in KO, leaving retinal role unresolved
    • Direct binding interfaces not structurally defined
  5. 2014 Medium

    How the four USH2 proteins assemble and whether PDZD7 has a signaling output was unclear; complementary studies defined the quaternary complex bridging architecture and a role in ADGRV1 Gαi/AC signaling.

    Evidence Yeast two-hybrid, pull-down, and colocalization for complex topology; cell-based cAMP/AC activity assays for VLGR1 signaling regulation

    PMID:24962568 PMID:25406310

    Open questions at the time
    • Variable stoichiometry not quantified
    • AC regulation shown in transfected cells only, single method/lab
  6. 2016 High

    Whether PDZD7 connects to the motor machinery of stereocilia was unknown; it was shown to form a complex with MYO7A dependent on functional MYO7A in vivo.

    Evidence Stereocilia membrane fractionation with mass spectrometry, Co-IP in tissue culture, and immunofluorescence in wild-type vs Myo7a mutant mice

    PMID:27525485

    Open questions at the time
    • Direct vs indirect MYO7A association not distinguished
    • Functional consequence of MYO7A–PDZD7 link not separately tested
  7. 2018 Low

    The full partner repertoire of PDZD7's PDZ domains was incompletely mapped; a screen expanded candidate interactors, though most lacked functional confirmation.

    Evidence Yeast two-hybrid using the first two PDZ domains as bait, expression analysis, and ABR in Cadm1 knockout mice

    PMID:29796015

    Open questions at the time
    • Yeast two-hybrid only for most interactions; not validated in inner ear
    • Cadm1 KO had normal hearing, leaving functional relevance unestablished
  8. 2019 High

    Which PDZD7 isoform mediates ankle-link assembly was unresolved; isoform-specific deletion showed the long isoform is uniquely required and identified PIP5K1C as its partner.

    Evidence Isoform-specific Pdzd7 mutant mice (exon 14 deletion), immunofluorescence, ABR, MET recordings, and yeast two-hybrid

    PMID:31914662

    Open questions at the time
    • PIP5K1C interaction not functionally validated in hair cells
    • Mechanism by which the long isoform anchors the complex not defined
  9. 2021 High

    How PDZD7 is targeted to the membrane was unknown; structural and functional work showed its HHD binds lipid to mediate plasma membrane localization, and a deafness mutation abolishes this.

    Evidence X-ray crystallography at 1.49 Å, lipid-binding assay, HEK293T localization, and disease-variant mutagenesis

    PMID:33937240

    Open questions at the time
    • Lipid specificity in native stereocilia membranes not defined
    • Membrane targeting tested in HEK293T, not hair cells
  10. 2022 High

    The structural basis of PDZD7's scaffolding interactions was undefined; structural studies resolved how the PDZ tandem engages ADGRV1 and how PDZ3 binds FCHSD2 to link the complex to cytoskeletal regulators.

    Evidence NMR/biophysical analysis of the PDZ tandem–ADGRV1 PBM, crystallography of the FCHSD2 tail–PDZ3 complex (2.0 Å), Co-IP, and deafness-variant mutagenesis

    PMID:35695292 PMID:35836927

    Open questions at the time
    • FCHSD2/CDC42/N-WASP coupling inferred, not demonstrated in hair cells
    • Higher-order assembly of multiple partners on the supermodule not resolved
  11. 2025 Medium

    The spatial and temporal organization of PDZD7 and ADGRV1 within stereocilia was unresolved; super-resolution imaging revealed asymmetric distribution and distinct temporal dynamics of ADGRV1 domains.

    Evidence STED super-resolution nanoscopy in juvenile mouse hair cells

    PMID:40836926

    Open questions at the time
    • Descriptive imaging without functional perturbation
    • Functional meaning of asymmetric/temporal patterns not tested

Open questions

Synthesis pass · forward-looking unresolved questions
  • How PDZD7-organized ankle-link signaling (ADGRV1 Gαi/AC and FCHSD2/cytoskeletal coupling) is integrated with mechanotransduction during stereocilia maturation, and the precise molecular basis of its photoreceptor/digenic Usher role, remain open.
  • Downstream effects of AC modulation on hair cell physiology not defined
  • Retinal disease mechanism beyond GPR98 mislocalization unestablished
  • No integrated model linking signaling outputs to mechanotransduction

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0060090 molecular adaptor activity 4 GO:0008289 lipid binding 1 GO:0098772 molecular function regulator activity 1
Localization
GO:0005856 cytoskeleton 3 GO:0005886 plasma membrane 2
Pathway
R-HSA-9709957 Sensory Perception 2 R-HSA-162582 Signal Transduction 1
Partners
ADGRV1CADM1FCHSD2GSNMYO7APIP5K1CUSH2AWHRN
Complex memberships
USH2 ankle-link complex (USH2A–ADGRV1/GPR98–WHRN–PDZD7)

Evidence

Reading pass · 13 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2010 PDZD7 knockdown in zebrafish produced an Usher-like phenotype, exacerbated retinal cell death in combination with ush2a or gpr98 knockdown (genetic epistasis), 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 functional interaction with USH2A and GPR98. Zebrafish morpholino knockdown, retinal cell death assay, immunolocalization of Gpr98 The Journal of clinical investigation High 20440071
2012 PDZD7 localizes to the ankle-link region of hair cell stereocilia, overlapping with usherin, whirlin, and GPR98, as shown by immunofluorescence and overexpression of tagged proteins. Mass spectrometry confirmed PDZD7 expression in chick stereocilia at comparable molecular abundance to GPR98. Cytosolic domains of usherin and GPR98 were shown to bind both whirlin and PDZD7 in LLC-PK1 cells. Mass spectrometry of chick stereocilia, immunofluorescence, tagged protein overexpression in rat/mouse hair cells, binding assay in LLC-PK1 cells The Journal of neuroscience : the official journal of the Society for Neuroscience High 23055499
2013 Knockout of Pdzd7 in mice causes congenital profound deafness, disorganization of stereocilia bundles, reduced mechanotransduction currents in outer hair cells, and loss of USH2 protein complex (USH2A, GPR98, WHRN) localization at ankle links in cochlear hair cells. PDZD7 directly interacts with USH2A, GPR98, and WHRN. In photoreceptors, the three USH2 proteins remain largely unchanged at the periciliary membrane complex in knockout mice. Pdzd7 knockout mouse, ABR/DPOAE/cochlear microphonics, immunofluorescence, mechanotransduction current recordings, co-immunoprecipitation/pull-down Human molecular genetics High 24334608
2014 Overexpression of PDZD7 decreases adenylate cyclase inhibition mediated by the VLGR1 (GPR98) β-subunit, which constitutively inhibits AC via Gαi coupling. PDZD7 had no effect on the pathogenic VLGR1 Y6236fsx1 mutant, indicating that PDZD7 regulates normal VLGR1 signaling through the Gαi/AC pathway. Cell-based cAMP/AC activity assay, co-expression in transfected cells The Journal of biological chemistry Medium 24962568
2014 PDZD7 and whirlin (WHRN) are both required for formation of the USH2 quaternary protein complex containing USH2A, GPR98, WHRN, and PDZD7. In this complex, WHRN preferentially binds USH2A while PDZD7 preferentially binds GPR98; WHRN–PDZD7 interaction bridges USH2A and GPR98. The complex has variable stoichiometry, multiple domains interact among the four proteins. Yeast two-hybrid, pull-down assay, colocalization in cell culture The Journal of biological chemistry Medium 25406310
2016 MYO7A (myosin VIIA) forms a protein complex with PDZD7 in enriched stereocilia membrane fractions, as identified by mass spectrometry. MYO7A and PDZD7 interact in tissue-culture cells and co-localize to the ankle-link region of stereocilia in wild-type but not Myo7a mutant mice, placing PDZD7 downstream of or in complex with MYO7A. Stereocilia membrane fractionation, mass spectrometry, co-immunoprecipitation in tissue culture cells, immunofluorescence in wild-type vs. Myo7a mutant mice eLife High 27525485
2019 The PDZD7 long isoform (but not short isoforms) localizes to the ankle region of stereocilia and is required for proper localization of other ankle-link complex components. Loss of the long isoform causes stereocilia development deficits, hearing loss, and reduced mechanotransduction currents in mice. Yeast two-hybrid screening identified PIP5K1C as a PDZD7 long isoform-specific binding partner. Isoform-specific Pdzd7 mutant mice (exon 14 deletion), immunofluorescence, ABR, MET current recordings, yeast two-hybrid FASEB journal : official publication of the Federation of American Societies for Experimental Biology High 31914662
2018 Novel PDZD7-binding partners identified by yeast two-hybrid screening using the first two PDZ domains as bait include ADGRV1, gelsolin, β-catenin, and CADM1, among others. Cadm1 knockout mice showed normal hearing thresholds. Yeast two-hybrid screening, expression analysis of CADM1 in mouse inner ear, ABR in Cadm1 knockout mice Neural plasticity Low 29796015
2021 The PDZD7 harmonin homology domain (HHD) structure was solved at 1.49 Å resolution, revealing a five-helix fold with a unique α1N helix occupying the canonical binding pocket. The HHD domain binds lipid and mediates localization of PDZD7 to the plasma membrane in HEK293T cells. A hearing-loss mutation in the N-terminal extension region of the HHD disrupts lipid-binding ability, suggesting HHD-mediated membrane targeting is required for hearing. X-ray crystallography (1.49 Å), lipid-binding assay, cell localization in HEK293T cells, mutagenesis of hearing-loss variant Frontiers in cell and developmental biology High 33937240
2022 The two N-terminal PDZ domains of PDZD7 bind to the C-terminal PDZ-binding motif (PBM) of ADGRV1, with critical contribution of atypical C-terminal β-extensions. The two PDZ domains form a supramodule in solution stabilized upon PBM binding. Deafness-causing mutations in the PDZ domain binding grooves affect the stability and binding properties of the PDZD7 PDZ tandem. NMR/structural analysis, biophysical binding assays, mutagenesis of deafness variants Frontiers in molecular biosciences High 35836927
2022 PDZD7 PDZ3 domain forms a complex with the C-terminal tail of FCHSD2, as identified by yeast two-hybrid and confirmed in COS-7 cells. Crystal structure of the FCHSD2 tail–PDZD7 PDZ3 complex solved at 2.0 Å shows the PDZ-binding motif of FCHSD2 stretching through the αB/βB groove of PDZD7 PDZ3, linking the ankle-link complex to cytoskeleton dynamics via FCHSD2/CDC42/N-WASP. Yeast two-hybrid, co-immunoprecipitation in COS-7 cells, X-ray crystallography (2.0 Å) The Biochemical journal High 35695292
2008 Homozygous disruption of PDZD7 by reciprocal translocation in a human patient causes non-syndromic congenital sensorineural hearing impairment. Protein-protein interaction assays showed PDZD7 integrates into the Usher syndrome protein network. PDZD7 expression was confirmed in human inner ear by RT-PCR. FISH mapping of chromosomal breakpoints, vector ligation and sequencing of junction fragments, RT-PCR for inner ear expression, protein-protein interaction assays Human molecular genetics Medium 19028668
2025 STED nanoscopy revealed that ADGRV1 and PDZD7 show highly asymmetric localization patterns within stereocilia rows and between inner and outer hair cells. The extracellular portion of ADGRV1 disappears after postnatal day 12, while the GPCR domain persists until P21, suggesting distinct temporal roles. ADGRV1 and PDZD7 show strong colocalization at the ankle-link region. STED (stimulated emission depletion) super-resolution nanoscopy in juvenile mouse hair cells iScience Medium 40836926

Source papers

Stage 0 corpus · 24 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2010 PDZD7 is a modifier of retinal disease and a contributor to digenic Usher syndrome. The Journal of clinical investigation 197 20440071
2012 Localization of PDZD7 to the stereocilia ankle-link associates this scaffolding protein with the Usher syndrome protein network. The Journal of neuroscience : the official journal of the Society for Neuroscience 63 23055499
2014 Constitutive Gαi coupling activity of very large G protein-coupled receptor 1 (VLGR1) and its regulation by PDZD7 protein. The Journal of biological chemistry 60 24962568
2013 Deletion of PDZD7 disrupts the Usher syndrome type 2 protein complex in cochlear hair cells and causes hearing loss in mice. Human molecular genetics 53 24334608
2014 Whirlin and PDZ domain-containing 7 (PDZD7) proteins are both required to form the quaternary protein complex associated with Usher syndrome type 2. The Journal of biological chemistry 52 25406310
2015 PDZD7 and hearing loss: More than just a modifier. American journal of medical genetics. Part A 51 26416264
2008 Homozygous disruption of PDZD7 by reciprocal translocation in a consanguineous family: a new member of the Usher syndrome protein interactome causing congenital hearing impairment. Human molecular genetics 46 19028668
2019 Lnc-PDZD7 contributes to stemness properties and chemosensitivity in hepatocellular carcinoma through EZH2-mediated ATOH8 transcriptional repression. Journal of experimental & clinical cancer research : CR 44 30786928
2016 PDZD7-MYO7A complex identified in enriched stereocilia membranes. eLife 44 27525485
2016 Confirmation of PDZD7 as a Nonsyndromic Hearing Loss Gene. Ear and hearing 26 26849169
2019 Identification of a Potential Founder Effect of a Novel PDZD7 Variant Involved in Moderate-to-Severe Sensorineural Hearing Loss in Koreans. International journal of molecular sciences 19 31454969
2019 Lack of PDZD7 long isoform disrupts ankle-link complex and causes hearing loss in mice. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 18 31914662
2017 Novel recessive PDZD7 biallelic mutations in two Chinese families with non-syndromic hearing loss. American journal of medical genetics. Part A 18 29048736
2018 Identification of Binding Partners of Deafness-Related Protein PDZD7. Neural plasticity 12 29796015
2021 A novel recessive PDZD7 bi-allelic mutation in an Iranian family with non-syndromic hearing loss. BMC medical genomics 8 33530996
2021 Structure and Membrane Targeting of the PDZD7 Harmonin Homology Domain (HHD) Associated With Hearing Loss. Frontiers in cell and developmental biology 7 33937240
2019 Novel recessive PDZD7 biallelic mutations associated with hereditary hearing loss in a Chinese pedigree. Gene 7 31129248
2022 Deciphering the Molecular Interaction Between the Adhesion G Protein-Coupled Receptor ADGRV1 and its PDZ-Containing Regulator PDZD7. Frontiers in molecular biosciences 4 35836927
2022 Novel homozygous variant in the PDZD7 gene in a family with nonsyndromic sensorineural hearing loss. BMC medical genomics 3 35715776
2022 Deafness-related protein PDZD7 forms complex with the C-terminal tail of FCHSD2. The Biochemical journal 2 35695292
2025 Super-resolution mapping of the ankle link proteins ADGRV1 and PDZD7 in developing auditory hair cells. iScience 1 40836926
2025 A newly discovered Lnc-PDZD7-3 increased metastatic and proliferative potential of lung adenocarcinoma cells via modulating FN1/fibronectin signaling. Frontiers in genetics 1 41199745
2024 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. BMC medical genomics 1 38956522
2025 First clinical report of a rare PDZD7 nonsense variant and recurrent mutations in Iranian families with autosomal recessive non-syndromic hearing loss. BMC medical genomics 0 41276803

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