{"gene":"STRC","run_date":"2026-06-10T10:51:54","timeline":{"discoveries":[{"year":2001,"finding":"Stereocilin (STRC) is a protein of 1,809 amino acids containing a putative signal peptide and several hydrophobic segments, encoded by a gene expressed almost exclusively in the inner ear; immunohistolabeling demonstrated that stereocilin is expressed only in sensory hair cells and is associated with the stereocilia (stiff microvilli forming the mechanoreception structure) in the mouse inner ear.","method":"Immunohistolabeling of mouse inner ear tissue; genomic and cDNA cloning","journal":"Nature genetics","confidence":"High","confidence_rationale":"Tier 2 / Strong — direct immunolocalization with functional context (deafness mutations), replicated by subsequent studies, foundational characterization paper","pmids":["11687802"],"is_preprint":false},{"year":2001,"finding":"Loss-of-function mutations in STRC (frameshift and large deletion) cause autosomal recessive non-syndromic sensorineural deafness (DFNB16), establishing stereocilin as essential for hearing.","method":"Mutation identification by sequencing in affected families; genetic linkage to DFNB16 locus","journal":"Nature genetics","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple independent families, replicated across many subsequent cohort studies","pmids":["11687802"],"is_preprint":false},{"year":2018,"finding":"Stereocilin is expressed in the vestibular organ where it ensheathes the kinocilium of otolithic membranes, and biallelic loss-of-function STRC variants cause not only cochlear hearing loss but also pathological vestibular responses (episodic vertigo), demonstrating a functional role for stereocilin in sensing balance and spatial orientation.","method":"Clinical vestibular testing in DFNB16 patients with confirmed biallelic STRC variants (nonsense mutation and deletion); correlation with known localization of stereocilin at vestibular kinocilia","journal":"European journal of human genetics : EJHG","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct vestibular phenotyping in genetically confirmed patients, supported by known protein localization, single study","pmids":["30250054"],"is_preprint":false},{"year":2021,"finding":"Dual-AAV-mediated delivery of full-length STRC to outer hair cells of Strc-deficient mice restored exogenous stereocilin expression, hair bundle morphology, cochlear amplification, and auditory sensitivity, demonstrating that stereocilin is specifically required for outer hair cell amplifier function.","method":"Targeted gene deletion mouse model (Strc knockout); dual AAV9-PHP.B vector transduction of outer hair cells; DPOAE and ABR functional measurements; immunofluorescence for protein expression; hair bundle morphology analysis","journal":"Science advances","confidence":"High","confidence_rationale":"Tier 1 / Strong — loss-of-function mouse model with rescue by exogenous protein, multiple orthogonal functional readouts (DPOAEs, ABR, morphology, protein expression)","pmids":["34910522"],"is_preprint":false},{"year":2023,"finding":"Loss of stereocilin function in humans results in loss of connection between outer hair cells and the tectorial membrane, selectively impairing cochlear amplification (OHC function) while preserving inner hair cell function, leading to deficits in spectral processing and speech-in-noise perception but preserved temporal resolution.","method":"Psychoacoustic testing (spectral and temporal modulation transfer functions, speech-in-noise) in subjects with confirmed homozygous or compound heterozygous STRC loss-of-function mutations","journal":"Hearing research","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — direct functional characterization in genetically confirmed human subjects, single study, no molecular mechanism experiment but establishes OHC-specific functional consequence","pmids":["37890241"],"is_preprint":false},{"year":2026,"finding":"Dual AAV9-PHP.eB-mediated delivery of full-length Strc cDNA to Strc-/- mice restored stereocilin expression, OHC bundle architecture, OHC attachment to the tectorial membrane, cochlear amplification (DPOAEs), hearing thresholds (ABR), and behavioral frequency discrimination, demonstrating that stereocilin is required for OHC-tectorial membrane coupling and higher-order auditory processing.","method":"Strc knockout mouse model; dual AAV gene therapy; immunofluorescence; DPOAE and ABR measurements; Go/No-Go behavioral testing with psychometric analysis","journal":"Clinical and translational medicine","confidence":"High","confidence_rationale":"Tier 1 / Strong — loss-of-function model with full molecular and functional rescue, multiple orthogonal readouts including behavioral testing","pmids":["41508981"],"is_preprint":false},{"year":2005,"finding":"Strc mRNA is detectable in mouse cochlear explants cultured from embryonic day 15, with expression levels in explanted tissue equivalent to in vivo cochleae after 48 h, confirming inner-ear-specific expression is maintained ex vivo.","method":"RT-PCR quantification of Strc expression in cochlear explants vs. in vivo cochleae","journal":"Neuroreport","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single RT-PCR expression study, no functional or mechanistic follow-up, single lab","pmids":["15729138"],"is_preprint":false}],"current_model":"Stereocilin (STRC) is a hair-bundle-associated protein expressed exclusively in inner ear sensory hair cells, where it physically links outer hair cell (OHC) stereocilia to the tectorial membrane; loss of stereocilin disrupts this OHC–tectorial membrane coupling, abolishes cochlear amplification while leaving inner hair cell function intact, causes mild-to-moderate autosomal recessive sensorineural hearing loss (DFNB16), and also impairs vestibular function by disrupting the kinocilium–otoconial membrane connection, as demonstrated by mouse knockout models rescued by AAV-mediated gene replacement and confirmed in human patients."},"narrative":{"mechanistic_narrative":"Stereocilin (STRC) is a hair-cell-specific protein that structurally couples sensory stereocilia to overlying accessory membranes in the inner ear, enabling mechanotransduction and cochlear amplification [PMID:11687802, PMID:34910522]. It is expressed almost exclusively in inner ear sensory hair cells, where it localizes to the stereocilia of the hair bundle [PMID:11687802], and in the vestibular organ it ensheathes the kinocilium of otolithic membranes [PMID:30250054]. Functionally, stereocilin links outer hair cell (OHC) stereocilia to the tectorial membrane: loss of stereocilin abolishes this OHC–tectorial membrane connection and selectively impairs cochlear amplification while preserving inner hair cell function, producing deficits in spectral processing and speech-in-noise perception with preserved temporal resolution [PMID:37890241]. Dual-AAV delivery of full-length STRC to OHCs of Strc-deficient mice restores hair bundle architecture, OHC–tectorial membrane attachment, cochlear amplification, hearing thresholds, and behavioral frequency discrimination, establishing that stereocilin is specifically required for the OHC amplifier [PMID:34910522, PMID:41508981]. Biallelic loss-of-function mutations in STRC cause autosomal recessive non-syndromic sensorineural deafness (DFNB16) and additionally produce pathological vestibular responses [PMID:11687802, PMID:30250054]. Beyond its structural linking role, no enzymatic activity or direct binding partners have been characterized in the available corpus.","teleology":[{"year":2001,"claim":"Established that stereocilin is a hair-cell-specific protein physically associated with the mechanosensory stereocilia, defining where it acts and that it could plausibly contribute to mechanoreception.","evidence":"Genomic/cDNA cloning and immunohistolabeling of mouse inner ear tissue","pmids":["11687802"],"confidence":"High","gaps":["No direct binding partner or molecular mechanism identified","Subcellular sublocalization within the stereocilium not resolved"]},{"year":2001,"claim":"Showed that loss-of-function STRC mutations cause autosomal recessive deafness (DFNB16), proving stereocilin is essential for hearing rather than merely correlated with hair cells.","evidence":"Mutation identification by sequencing and genetic linkage in affected families","pmids":["11687802"],"confidence":"High","gaps":["Did not resolve which cell type (OHC vs IHC) drives the phenotype","Molecular consequence of mutations on hair bundle structure not yet defined"]},{"year":2005,"claim":"Confirmed that inner-ear-specific Strc expression is maintained in cochlear explants, validating an ex vivo model for studying its expression.","evidence":"RT-PCR of Strc in mouse cochlear explants vs in vivo cochleae","pmids":["15729138"],"confidence":"Low","gaps":["Single RT-PCR expression study with no functional follow-up","Does not address protein function or localization"]},{"year":2018,"claim":"Extended stereocilin's role beyond hearing by showing it ensheathes the vestibular kinocilium and that biallelic loss causes vestibular dysfunction, broadening its function to balance and spatial orientation.","evidence":"Clinical vestibular testing in DFNB16 patients with confirmed biallelic STRC variants","pmids":["30250054"],"confidence":"Medium","gaps":["Single clinical study","Vestibular structural defect not directly visualized in patients","Penetrance of vestibular phenotype unresolved"]},{"year":2021,"claim":"Demonstrated that stereocilin is specifically required for outer hair cell amplifier function by rescuing Strc-deficient mice with AAV-delivered full-length protein.","evidence":"Strc knockout mouse with dual AAV9-PHP.B OHC transduction; DPOAE, ABR, immunofluorescence, hair bundle morphology","pmids":["34910522"],"confidence":"High","gaps":["Molecular partners mediating OHC linkage not identified","Mechanism of stereocilia bundle organization unresolved"]},{"year":2023,"claim":"Defined the cell-type-specific functional consequence in humans, showing loss of OHC–tectorial membrane coupling selectively impairs cochlear amplification and spectral processing while sparing inner hair cell-dependent temporal resolution.","evidence":"Psychoacoustic testing in subjects with confirmed STRC loss-of-function mutations","pmids":["37890241"],"confidence":"Medium","gaps":["No molecular mechanism experiment","Single study","Does not establish biochemical nature of the OHC-tectorial membrane link"]},{"year":2026,"claim":"Confirmed stereocilin is required for OHC-tectorial membrane coupling and higher-order auditory processing by achieving full molecular, functional, and behavioral rescue in knockout mice.","evidence":"Strc knockout mouse; dual AAV9-PHP.eB gene therapy; immunofluorescence, DPOAE, ABR, Go/No-Go behavioral testing","pmids":["41508981"],"confidence":"High","gaps":["Direct molecular interactions with tectorial membrane components not identified","Structural basis of the linkage remains undefined"]},{"year":null,"claim":"The biochemical mechanism by which stereocilin physically tethers stereocilia to the tectorial and otoconial membranes, including its direct binding partners and structural organization, remains undefined.","evidence":"","pmids":[],"confidence":"High","gaps":["No direct physical interaction partner identified","No structural model of the stereocilin-mediated linkage","Enzymatic or non-structural activities, if any, uncharacterized"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0005198","term_label":"structural molecule activity","supporting_discovery_ids":[0,3,5]}],"localization":[{"term_id":"GO:0005929","term_label":"cilium","supporting_discovery_ids":[0,2]}],"pathway":[{"term_id":"R-HSA-9709957","term_label":"Sensory Perception","supporting_discovery_ids":[3,4,5]}],"complexes":[],"partners":[],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q7RTU9","full_name":"Stereocilin","aliases":[],"length_aa":1775,"mass_kda":193.0,"function":"Essential to the formation of horizontal top connectors between outer hair cell stereocilia","subcellular_location":"Cell surface; Cell projection, kinocilium; Cell projection, stereocilium","url":"https://www.uniprot.org/uniprotkb/Q7RTU9/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/STRC","classification":"Not Classified","n_dependent_lines":49,"n_total_lines":1208,"dependency_fraction":0.04056291390728477},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/STRC","total_profiled":1310},"omim":[{"mim_id":"621527","title":"TRANSMEMBRANE PROTEIN 145; TMEM145","url":"https://www.omim.org/entry/621527"},{"mim_id":"611102","title":"DEAFNESS-INFERTILITY SYNDROME; DIS","url":"https://www.omim.org/entry/611102"},{"mim_id":"607465","title":"CODANIN 1; CDAN1","url":"https://www.omim.org/entry/607465"},{"mim_id":"607249","title":"CATION CHANNEL, SPERM-ASSOCIATED, 2; CATSPER2","url":"https://www.omim.org/entry/607249"},{"mim_id":"606440","title":"STEREOCILIN; STRC","url":"https://www.omim.org/entry/606440"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"","locations":[],"tissue_specificity":"Tissue enriched","tissue_distribution":"Detected in some","driving_tissues":[{"tissue":"brain","ntpm":40.6}],"url":"https://www.proteinatlas.org/search/STRC"},"hgnc":{"alias_symbol":[],"prev_symbol":["DFNB16"]},"alphafold":{"accession":"Q7RTU9","domains":[{"cath_id":"-","chopping":"390-450","consensus_level":"medium","plddt":70.88,"start":390,"end":450},{"cath_id":"-","chopping":"948-1029","consensus_level":"medium","plddt":86.0227,"start":948,"end":1029},{"cath_id":"-","chopping":"1033-1103_1130-1138","consensus_level":"medium","plddt":82.9016,"start":1033,"end":1138},{"cath_id":"-","chopping":"1139-1240","consensus_level":"medium","plddt":80.3578,"start":1139,"end":1240}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q7RTU9","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q7RTU9-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q7RTU9-F1-predicted_aligned_error_v6.png","plddt_mean":68.75},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=STRC","jax_strain_url":"https://www.jax.org/strain/search?query=STRC"},"sequence":{"accession":"Q7RTU9","fasta_url":"https://rest.uniprot.org/uniprotkb/Q7RTU9.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q7RTU9/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q7RTU9"}},"corpus_meta":[{"pmid":"11687802","id":"PMC_11687802","title":"Mutations in a new gene encoding a protein of the hair bundle cause non-syndromic deafness at the DFNB16 locus.","date":"2001","source":"Nature genetics","url":"https://pubmed.ncbi.nlm.nih.gov/11687802","citation_count":145,"is_preprint":false},{"pmid":"22147502","id":"PMC_22147502","title":"Genome-wide SNP genotyping identifies the Stereocilin (STRC) gene as a major contributor to pediatric bilateral sensorineural hearing impairment.","date":"2011","source":"American journal of medical genetics. Part A","url":"https://pubmed.ncbi.nlm.nih.gov/22147502","citation_count":89,"is_preprint":false},{"pmid":"26011646","id":"PMC_26011646","title":"DFNB16 is a frequent cause of congenital hearing impairment: implementation of STRC mutation analysis in routine diagnostics.","date":"2014","source":"Clinical genetics","url":"https://pubmed.ncbi.nlm.nih.gov/26011646","citation_count":86,"is_preprint":false},{"pmid":"30867468","id":"PMC_30867468","title":"Frequency and clinical features of hearing loss caused by STRC deletions.","date":"2019","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/30867468","citation_count":67,"is_preprint":false},{"pmid":"34910522","id":"PMC_34910522","title":"Dual-vector gene therapy restores cochlear amplification and auditory sensitivity in a mouse model of DFNB16 hearing loss.","date":"2021","source":"Science advances","url":"https://pubmed.ncbi.nlm.nih.gov/34910522","citation_count":58,"is_preprint":false},{"pmid":"12829032","id":"PMC_12829032","title":"Regulation of human short-term repopulating cell (STRC) engraftment in NOD/SCID mice by host CD122+ cells.","date":"2003","source":"Experimental hematology","url":"https://pubmed.ncbi.nlm.nih.gov/12829032","citation_count":44,"is_preprint":false},{"pmid":"9429146","id":"PMC_9429146","title":"A new locus for non-syndromal, autosomal recessive, sensorineural hearing loss (DFNB16) maps to human chromosome 15q21-q22.","date":"1997","source":"Journal of medical genetics","url":"https://pubmed.ncbi.nlm.nih.gov/9429146","citation_count":32,"is_preprint":false},{"pmid":"27469136","id":"PMC_27469136","title":"Detection and Confirmation of Deafness-Causing Copy Number Variations in the STRC Gene by Massively Parallel Sequencing and Comparative Genomic Hybridization.","date":"2016","source":"The Annals of otology, rhinology, and laryngology","url":"https://pubmed.ncbi.nlm.nih.gov/27469136","citation_count":29,"is_preprint":false},{"pmid":"28984810","id":"PMC_28984810","title":"STRC Deletion is a Frequent Cause of Slight to Moderate Congenital Hearing Impairment in the Czech Republic.","date":"2017","source":"Otology & neurotology : official publication of the American Otological Society, American Neurotology Society [and] European Academy of Otology and Neurotology","url":"https://pubmed.ncbi.nlm.nih.gov/28984810","citation_count":28,"is_preprint":false},{"pmid":"31645979","id":"PMC_31645979","title":"Rapid screening of copy number variations in STRC by droplet digital PCR in patients with mild-to-moderate hearing loss.","date":"2019","source":"Human genome variation","url":"https://pubmed.ncbi.nlm.nih.gov/31645979","citation_count":26,"is_preprint":false},{"pmid":"35022556","id":"PMC_35022556","title":"Frequency of the STRC-CATSPER2 deletion in STRC-associated hearing loss patients.","date":"2022","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/35022556","citation_count":24,"is_preprint":false},{"pmid":"34621290","id":"PMC_34621290","title":"Prevalence and Characteristics of STRC Gene Mutations (DFNB16): A Systematic Review and Meta-Analysis.","date":"2021","source":"Frontiers in genetics","url":"https://pubmed.ncbi.nlm.nih.gov/34621290","citation_count":20,"is_preprint":false},{"pmid":"29425068","id":"PMC_29425068","title":"STRC Gene Mutations, Mainly Large Deletions, are a Very Important Cause of Early-Onset Hereditary Hearing Loss in the Czech Population.","date":"2018","source":"Genetic testing and molecular biomarkers","url":"https://pubmed.ncbi.nlm.nih.gov/29425068","citation_count":20,"is_preprint":false},{"pmid":"31552524","id":"PMC_31552524","title":"Moderate sensorineural hearing loss is typical for DFNB16 caused by various types of mutations affecting the STRC gene.","date":"2019","source":"European archives of oto-rhino-laryngology : official journal of the European Federation of Oto-Rhino-Laryngological Societies (EUFOS) : affiliated with the German Society for Oto-Rhino-Laryngology - Head and Neck Surgery","url":"https://pubmed.ncbi.nlm.nih.gov/31552524","citation_count":15,"is_preprint":false},{"pmid":"30250054","id":"PMC_30250054","title":"Stereocilin gene variants associated with episodic vertigo: expansion of the DFNB16 phenotype.","date":"2018","source":"European journal of human genetics : EJHG","url":"https://pubmed.ncbi.nlm.nih.gov/30250054","citation_count":15,"is_preprint":false},{"pmid":"34111299","id":"PMC_34111299","title":"Audiologic Phenotype and Progression in Pediatric STRC-Related Autosomal Recessive Hearing Loss.","date":"2021","source":"The Laryngoscope","url":"https://pubmed.ncbi.nlm.nih.gov/34111299","citation_count":14,"is_preprint":false},{"pmid":"32705992","id":"PMC_32705992","title":"Clinical features of hearing loss caused by STRC gene deletions/mutations in Russian population.","date":"2020","source":"International journal of pediatric otorhinolaryngology","url":"https://pubmed.ncbi.nlm.nih.gov/32705992","citation_count":13,"is_preprint":false},{"pmid":"30531641","id":"PMC_30531641","title":"Phenotypic Characterization of DFNB16-associated Hearing Loss.","date":"2019","source":"Otology & neurotology : official publication of the American Otological Society, American Neurotology Society [and] European Academy of Otology and Neurotology","url":"https://pubmed.ncbi.nlm.nih.gov/30531641","citation_count":12,"is_preprint":false},{"pmid":"26746617","id":"PMC_26746617","title":"Identification of a nonsense mutation in the STRC gene in a Korean family with moderate hearing loss.","date":"2015","source":"International journal of pediatric otorhinolaryngology","url":"https://pubmed.ncbi.nlm.nih.gov/26746617","citation_count":9,"is_preprint":false},{"pmid":"36764706","id":"PMC_36764706","title":"Recurrent Benign Paroxysmal Positional Vertigo in DFNB16 Patients with Biallelic STRC Gene Deletions.","date":"2023","source":"Otology & neurotology : official publication of the American Otological Society, American Neurotology Society [and] European Academy of Otology and Neurotology","url":"https://pubmed.ncbi.nlm.nih.gov/36764706","citation_count":8,"is_preprint":false},{"pmid":"30758234","id":"PMC_30758234","title":"Clinical Exome Sequencing Identifies a Frameshift Mutation Within the STRC Gene in a United Arab Emirates Family with Profound Nonsyndromic Hearing Loss.","date":"2019","source":"Genetic testing and molecular biomarkers","url":"https://pubmed.ncbi.nlm.nih.gov/30758234","citation_count":8,"is_preprint":false},{"pmid":"37207672","id":"PMC_37207672","title":"The Next Generation of Population-Based DFNB16 Carrier Screening and Diagnosis: STRC Copy-Number Variant Analysis from Genome Sequencing Data.","date":"2023","source":"Clinical chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/37207672","citation_count":6,"is_preprint":false},{"pmid":"31218851","id":"PMC_31218851","title":"Prenatal cytogenomic identification and molecular refinement of compound heterozygous STRC deletion breakpoints.","date":"2019","source":"Molecular genetics & genomic medicine","url":"https://pubmed.ncbi.nlm.nih.gov/31218851","citation_count":5,"is_preprint":false},{"pmid":"38001944","id":"PMC_38001944","title":"Novel Pathogenic Variants in the Gene Encoding Stereocilin (STRC) Causing Non-Syndromic Moderate Hearing Loss in Spanish and Argentinean Subjects.","date":"2023","source":"Biomedicines","url":"https://pubmed.ncbi.nlm.nih.gov/38001944","citation_count":4,"is_preprint":false},{"pmid":"37890241","id":"PMC_37890241","title":"Behavioral characterization of the cochlear amplifier lesion due to loss of function of stereocilin (STRC) in human subjects.","date":"2023","source":"Hearing research","url":"https://pubmed.ncbi.nlm.nih.gov/37890241","citation_count":3,"is_preprint":false},{"pmid":"41508981","id":"PMC_41508981","title":"Dual AAV gene therapy achieves recovery of hearing and auditory processing in a DFNB16 mouse model.","date":"2026","source":"Clinical and translational medicine","url":"https://pubmed.ncbi.nlm.nih.gov/41508981","citation_count":2,"is_preprint":false},{"pmid":"40341240","id":"PMC_40341240","title":"Refining the detection of complex rearrangements in 15q15.3 region involving the STRC gene in hereditary hearing loss patients.","date":"2025","source":"Journal of human genetics","url":"https://pubmed.ncbi.nlm.nih.gov/40341240","citation_count":2,"is_preprint":false},{"pmid":"36526540","id":"PMC_36526540","title":"Recurrent benign paroxysmal positional vertigo in two DFNB16 siblings: A CARE case report.","date":"2022","source":"European annals of otorhinolaryngology, head and neck diseases","url":"https://pubmed.ncbi.nlm.nih.gov/36526540","citation_count":2,"is_preprint":false},{"pmid":"15729138","id":"PMC_15729138","title":"RT-PCR analysis of Tecta, Coch, Eya4 and Strc in mouse cochlear explants.","date":"2005","source":"Neuroreport","url":"https://pubmed.ncbi.nlm.nih.gov/15729138","citation_count":2,"is_preprint":false},{"pmid":"40886188","id":"PMC_40886188","title":"Prevalence and spectrum of STRC variants in 1015 sensorineural hearing loss patients: insights from the Chinese population.","date":"2025","source":"Molecular genetics and genomics : MGG","url":"https://pubmed.ncbi.nlm.nih.gov/40886188","citation_count":1,"is_preprint":false},{"pmid":"41461707","id":"PMC_41461707","title":"Auditory genotype-phenotype correlation of patients with variants in STRC.","date":"2025","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/41461707","citation_count":1,"is_preprint":false},{"pmid":"41696978","id":"PMC_41696978","title":"Characterization of STRC Gene Conversions by Nanopore Sequencing.","date":"2026","source":"Clinical chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/41696978","citation_count":0,"is_preprint":false},{"pmid":"40122168","id":"PMC_40122168","title":"A look at DFNB16 markers and their application in the genetic study of hearing loss in Iranian deaf families.","date":"2025","source":"Acta otorrinolaringologica espanola","url":"https://pubmed.ncbi.nlm.nih.gov/40122168","citation_count":0,"is_preprint":false},{"pmid":"39734283","id":"PMC_39734283","title":"[Genetic analysis of children with nonsyndromic sensorineural hearing loss due to novel mutations/deletions of STRC bialleles].","date":"2024","source":"Zhonghua er bi yan hou tou jing wai ke za zhi = Chinese journal of otorhinolaryngology head and neck surgery","url":"https://pubmed.ncbi.nlm.nih.gov/39734283","citation_count":0,"is_preprint":false},{"pmid":"41430084","id":"PMC_41430084","title":"Targeted long-read nanopore sequencing as a complementary approach for detecting STRC variants and distinguishing the STRCP1 pseudogene.","date":"2025","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/41430084","citation_count":0,"is_preprint":false},{"pmid":"41623227","id":"PMC_41623227","title":"Natural History of Sensorineural Hearing Loss in Children With STRC Mutations.","date":"2026","source":"The Laryngoscope","url":"https://pubmed.ncbi.nlm.nih.gov/41623227","citation_count":0,"is_preprint":false},{"pmid":"41884524","id":"PMC_41884524","title":"Vestibular Profile of Patients with Hearing Loss Caused by Pathogenic Variants of the STRC Gene.","date":"2026","source":"Otology & neurotology open","url":"https://pubmed.ncbi.nlm.nih.gov/41884524","citation_count":0,"is_preprint":false},{"pmid":null,"id":"bio_10.1101_2024.11.05.24316795","title":"Comprehensive genetic analysis of<i>STRC</i>variants in hereditary hearing impairment using long-read sequencing","date":"2024-11-07","source":"bioRxiv","url":"https://doi.org/10.1101/2024.11.05.24316795","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2024.09.30.24314377","title":"Long-Read Sequencing Increases Diagnostic Yield for Pediatric Sensorineural Hearing Loss","date":"2024-09-30","source":"bioRxiv","url":"https://doi.org/10.1101/2024.09.30.24314377","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":21999,"output_tokens":1713,"usd":0.045846,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":8640,"output_tokens":2398,"usd":0.051575,"stage2_stop_reason":"end_turn"},"total_usd":0.097421,"stage1_batch_id":"msgbatch_017qqVz33Ga63SCDwzb35XPb","stage2_batch_id":"msgbatch_01Scr2Ei9x4HJMiRGxwrmvLK","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2001,\n      \"finding\": \"Stereocilin (STRC) is a protein of 1,809 amino acids containing a putative signal peptide and several hydrophobic segments, encoded by a gene expressed almost exclusively in the inner ear; immunohistolabeling demonstrated that stereocilin is expressed only in sensory hair cells and is associated with the stereocilia (stiff microvilli forming the mechanoreception structure) in the mouse inner ear.\",\n      \"method\": \"Immunohistolabeling of mouse inner ear tissue; genomic and cDNA cloning\",\n      \"journal\": \"Nature genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — direct immunolocalization with functional context (deafness mutations), replicated by subsequent studies, foundational characterization paper\",\n      \"pmids\": [\"11687802\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"Loss-of-function mutations in STRC (frameshift and large deletion) cause autosomal recessive non-syndromic sensorineural deafness (DFNB16), establishing stereocilin as essential for hearing.\",\n      \"method\": \"Mutation identification by sequencing in affected families; genetic linkage to DFNB16 locus\",\n      \"journal\": \"Nature genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple independent families, replicated across many subsequent cohort studies\",\n      \"pmids\": [\"11687802\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Stereocilin is expressed in the vestibular organ where it ensheathes the kinocilium of otolithic membranes, and biallelic loss-of-function STRC variants cause not only cochlear hearing loss but also pathological vestibular responses (episodic vertigo), demonstrating a functional role for stereocilin in sensing balance and spatial orientation.\",\n      \"method\": \"Clinical vestibular testing in DFNB16 patients with confirmed biallelic STRC variants (nonsense mutation and deletion); correlation with known localization of stereocilin at vestibular kinocilia\",\n      \"journal\": \"European journal of human genetics : EJHG\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct vestibular phenotyping in genetically confirmed patients, supported by known protein localization, single study\",\n      \"pmids\": [\"30250054\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Dual-AAV-mediated delivery of full-length STRC to outer hair cells of Strc-deficient mice restored exogenous stereocilin expression, hair bundle morphology, cochlear amplification, and auditory sensitivity, demonstrating that stereocilin is specifically required for outer hair cell amplifier function.\",\n      \"method\": \"Targeted gene deletion mouse model (Strc knockout); dual AAV9-PHP.B vector transduction of outer hair cells; DPOAE and ABR functional measurements; immunofluorescence for protein expression; hair bundle morphology analysis\",\n      \"journal\": \"Science advances\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — loss-of-function mouse model with rescue by exogenous protein, multiple orthogonal functional readouts (DPOAEs, ABR, morphology, protein expression)\",\n      \"pmids\": [\"34910522\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Loss of stereocilin function in humans results in loss of connection between outer hair cells and the tectorial membrane, selectively impairing cochlear amplification (OHC function) while preserving inner hair cell function, leading to deficits in spectral processing and speech-in-noise perception but preserved temporal resolution.\",\n      \"method\": \"Psychoacoustic testing (spectral and temporal modulation transfer functions, speech-in-noise) in subjects with confirmed homozygous or compound heterozygous STRC loss-of-function mutations\",\n      \"journal\": \"Hearing research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — direct functional characterization in genetically confirmed human subjects, single study, no molecular mechanism experiment but establishes OHC-specific functional consequence\",\n      \"pmids\": [\"37890241\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"Dual AAV9-PHP.eB-mediated delivery of full-length Strc cDNA to Strc-/- mice restored stereocilin expression, OHC bundle architecture, OHC attachment to the tectorial membrane, cochlear amplification (DPOAEs), hearing thresholds (ABR), and behavioral frequency discrimination, demonstrating that stereocilin is required for OHC-tectorial membrane coupling and higher-order auditory processing.\",\n      \"method\": \"Strc knockout mouse model; dual AAV gene therapy; immunofluorescence; DPOAE and ABR measurements; Go/No-Go behavioral testing with psychometric analysis\",\n      \"journal\": \"Clinical and translational medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — loss-of-function model with full molecular and functional rescue, multiple orthogonal readouts including behavioral testing\",\n      \"pmids\": [\"41508981\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"Strc mRNA is detectable in mouse cochlear explants cultured from embryonic day 15, with expression levels in explanted tissue equivalent to in vivo cochleae after 48 h, confirming inner-ear-specific expression is maintained ex vivo.\",\n      \"method\": \"RT-PCR quantification of Strc expression in cochlear explants vs. in vivo cochleae\",\n      \"journal\": \"Neuroreport\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single RT-PCR expression study, no functional or mechanistic follow-up, single lab\",\n      \"pmids\": [\"15729138\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"Stereocilin (STRC) is a hair-bundle-associated protein expressed exclusively in inner ear sensory hair cells, where it physically links outer hair cell (OHC) stereocilia to the tectorial membrane; loss of stereocilin disrupts this OHC–tectorial membrane coupling, abolishes cochlear amplification while leaving inner hair cell function intact, causes mild-to-moderate autosomal recessive sensorineural hearing loss (DFNB16), and also impairs vestibular function by disrupting the kinocilium–otoconial membrane connection, as demonstrated by mouse knockout models rescued by AAV-mediated gene replacement and confirmed in human patients.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"Stereocilin (STRC) is a hair-cell-specific protein that structurally couples sensory stereocilia to overlying accessory membranes in the inner ear, enabling mechanotransduction and cochlear amplification [#0, #3]. It is expressed almost exclusively in inner ear sensory hair cells, where it localizes to the stereocilia of the hair bundle [#0], and in the vestibular organ it ensheathes the kinocilium of otolithic membranes [#2]. Functionally, stereocilin links outer hair cell (OHC) stereocilia to the tectorial membrane: loss of stereocilin abolishes this OHC\\u2013tectorial membrane connection and selectively impairs cochlear amplification while preserving inner hair cell function, producing deficits in spectral processing and speech-in-noise perception with preserved temporal resolution [#4]. Dual-AAV delivery of full-length STRC to OHCs of Strc-deficient mice restores hair bundle architecture, OHC\\u2013tectorial membrane attachment, cochlear amplification, hearing thresholds, and behavioral frequency discrimination, establishing that stereocilin is specifically required for the OHC amplifier [#3, #5]. Biallelic loss-of-function mutations in STRC cause autosomal recessive non-syndromic sensorineural deafness (DFNB16) and additionally produce pathological vestibular responses [#1, #2]. Beyond its structural linking role, no enzymatic activity or direct binding partners have been characterized in the available corpus.\",\n  \"teleology\": [\n    {\n      \"year\": 2001,\n      \"claim\": \"Established that stereocilin is a hair-cell-specific protein physically associated with the mechanosensory stereocilia, defining where it acts and that it could plausibly contribute to mechanoreception.\",\n      \"evidence\": \"Genomic/cDNA cloning and immunohistolabeling of mouse inner ear tissue\",\n      \"pmids\": [\"11687802\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No direct binding partner or molecular mechanism identified\", \"Subcellular sublocalization within the stereocilium not resolved\"]\n    },\n    {\n      \"year\": 2001,\n      \"claim\": \"Showed that loss-of-function STRC mutations cause autosomal recessive deafness (DFNB16), proving stereocilin is essential for hearing rather than merely correlated with hair cells.\",\n      \"evidence\": \"Mutation identification by sequencing and genetic linkage in affected families\",\n      \"pmids\": [\"11687802\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not resolve which cell type (OHC vs IHC) drives the phenotype\", \"Molecular consequence of mutations on hair bundle structure not yet defined\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Confirmed that inner-ear-specific Strc expression is maintained in cochlear explants, validating an ex vivo model for studying its expression.\",\n      \"evidence\": \"RT-PCR of Strc in mouse cochlear explants vs in vivo cochleae\",\n      \"pmids\": [\"15729138\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Single RT-PCR expression study with no functional follow-up\", \"Does not address protein function or localization\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Extended stereocilin's role beyond hearing by showing it ensheathes the vestibular kinocilium and that biallelic loss causes vestibular dysfunction, broadening its function to balance and spatial orientation.\",\n      \"evidence\": \"Clinical vestibular testing in DFNB16 patients with confirmed biallelic STRC variants\",\n      \"pmids\": [\"30250054\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single clinical study\", \"Vestibular structural defect not directly visualized in patients\", \"Penetrance of vestibular phenotype unresolved\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Demonstrated that stereocilin is specifically required for outer hair cell amplifier function by rescuing Strc-deficient mice with AAV-delivered full-length protein.\",\n      \"evidence\": \"Strc knockout mouse with dual AAV9-PHP.B OHC transduction; DPOAE, ABR, immunofluorescence, hair bundle morphology\",\n      \"pmids\": [\"34910522\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular partners mediating OHC linkage not identified\", \"Mechanism of stereocilia bundle organization unresolved\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Defined the cell-type-specific functional consequence in humans, showing loss of OHC\\u2013tectorial membrane coupling selectively impairs cochlear amplification and spectral processing while sparing inner hair cell-dependent temporal resolution.\",\n      \"evidence\": \"Psychoacoustic testing in subjects with confirmed STRC loss-of-function mutations\",\n      \"pmids\": [\"37890241\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No molecular mechanism experiment\", \"Single study\", \"Does not establish biochemical nature of the OHC-tectorial membrane link\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Confirmed stereocilin is required for OHC-tectorial membrane coupling and higher-order auditory processing by achieving full molecular, functional, and behavioral rescue in knockout mice.\",\n      \"evidence\": \"Strc knockout mouse; dual AAV9-PHP.eB gene therapy; immunofluorescence, DPOAE, ABR, Go/No-Go behavioral testing\",\n      \"pmids\": [\"41508981\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct molecular interactions with tectorial membrane components not identified\", \"Structural basis of the linkage remains undefined\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The biochemical mechanism by which stereocilin physically tethers stereocilia to the tectorial and otoconial membranes, including its direct binding partners and structural organization, remains undefined.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No direct physical interaction partner identified\", \"No structural model of the stereocilin-mediated linkage\", \"Enzymatic or non-structural activities, if any, uncharacterized\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0005198\", \"supporting_discovery_ids\": [0, 3, 5]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005929\", \"supporting_discovery_ids\": [0, 2]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-9709957\", \"supporting_discovery_ids\": [3, 4, 5]}\n    ],\n    \"complexes\": [],\n    \"partners\": [],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":5,"faith_total":5,"faith_pct":100.0}}