{"gene":"OTOF","run_date":"2026-06-10T05:19:53","timeline":{"discoveries":[{"year":1999,"finding":"OTOF encodes otoferlin, a predicted cytosolic protein with three C2 domains and a single carboxy-terminal transmembrane domain, belonging to the fer-1 family. Its expression in inner ear sensory hair cells and structural homology to vesicle fusion proteins indicated a role in synaptic vesicle membrane fusion.","method":"Candidate gene cloning, sequence analysis, northern blot expression analysis","journal":"Nature genetics","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — structural prediction and expression localization without direct functional reconstitution; foundational identification paper replicated by subsequent functional studies","pmids":["10192385"],"is_preprint":false},{"year":2000,"finding":"OTOF encodes multiple long isoforms (six C2 domains, ~1,977 aa) and short isoforms (three C2 domains); genetic evidence from a splice-site mutation in intron 8 demonstrated that the long isoforms (but not the short isoforms) are required for inner ear function.","method":"Northern blot, cDNA cloning, exon-intron structure determination, mutation analysis in DFNB9 family","journal":"American journal of human genetics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic epistasis via segregating splice mutation establishing isoform requirement; single study with multiple orthogonal methods","pmids":["10903124"],"is_preprint":false},{"year":2002,"finding":"Missense mutations P490Q and I515T in the conserved C2C domain of otoferlin cause deafness; computer modeling suggested these substitutions alter the secondary structure and Ca2+-binding capacity of the C2C domain.","method":"SSCP analysis, DNA sequencing, comparative homology analysis, computer simulation","journal":"Neurobiology of disease","confidence":"Low","confidence_rationale":"Tier 4 / Weak — functional inference based on computational modeling without in vitro biochemical validation of Ca2+-binding","pmids":["12127154"],"is_preprint":false},{"year":2007,"finding":"An ENU-induced missense mutation (I→N) in the C2B domain of mouse otoferlin causes profound deafness with absence of otoferlin immunoreactivity in cochlear hair cells, indicating the C2B domain is critical for protein stability. Otoferlin is dispensable for vestibular function despite expression in vestibular hair cells.","method":"ENU mutagenesis, immunohistochemistry, ABR and vestibular-evoked potential (VsEP) recordings","journal":"Hearing research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — loss-of-function mouse model with defined cellular phenotype (absent IHC immunoreactivity) and functional readout; single lab","pmids":["17967520"],"is_preprint":false},{"year":2021,"finding":"In Otof knockout mice, otoferlin is required for proper synaptic pruning during cochlear development: absence of otoferlin delayed synaptic pruning (enlarged postsynaptic boutons at P14), led to progressive reduction of IHC synapses from ~15 at P14 to ~6 at 48 weeks, caused age-progressive loss of inner hair cells (to 75% of WT), and secondary degeneration of spiral ganglion neurons.","method":"Otof-/- mouse analysis, immunolabeling, synapse counting, DPOAE recording over 48 weeks","journal":"Frontiers in cellular neuroscience","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — clean KO with multiple defined cellular phenotypes across developmental time points; single lab","pmids":["34335185"],"is_preprint":false},{"year":2023,"finding":"Apoptosis of type I spiral ganglion neurons (SGN-I) occurs in Otof-mutant mice starting from postnatal day 7, before hearing onset, with significantly reduced SGN numbers at P7, P14, and P28 compared to wild-type. Type II SGNs were not significantly affected, indicating selective vulnerability of SGN-I to loss of otoferlin-dependent synaptic input.","method":"Immunolabeling of SGN subtypes, TUNEL/apoptosis assay, ABR and DPOAE recording in Otoftm1a/tm1a mice","journal":"Neuroscience letters","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — loss-of-function mouse model with specific cellular phenotype and two orthogonal methods; single lab","pmids":["36914046"],"is_preprint":false},{"year":2022,"finding":"OTOF acts as a type I interferon-induced restriction factor that inhibits HIV-1 entry at the cell membrane of macrophages and dendritic cells. Silencing OTOF abrogated IFN-mediated suppression of HIV-1 infection; OTOF overexpression restricted HIV-1 in macrophages and CD4+ T cells.","method":"siRNA knockdown, overexpression, HIV-1 infection assay, gene expression profiling in macrophages/DCs","journal":"mBio","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — loss-of-function (siRNA) and gain-of-function (overexpression) with defined functional readout; single lab, two orthogonal approaches","pmids":["35862790"],"is_preprint":false},{"year":2025,"finding":"Cryo-EM structures of Ca2+-bound otoferlin revealed that membrane binding involves the C2B and C2G domains and repositions the C2F and C2G domains. Progressive disruption of Ca2+-binding by the C2D domain in mice increasingly altered synaptic sound encoding and eliminated the Ca2+-cooperativity of synaptic vesicle exocytosis, establishing that Ca2+-cooperativity of exocytosis reflects binding of multiple Ca2+ ions to otoferlin. These findings support otoferlin as a Ca2+-sensor for synaptic vesicle fusion and tethering/docking in inner hair cells.","method":"Cryo-electron microscopy structure determination, molecular dynamics simulation, C2D-domain Ca2+-binding mutant mice, in vivo electrophysiology (synaptic sound encoding), Ca2+-cooperativity assay of SV exocytosis","journal":"bioRxiv (preprint)","confidence":"High","confidence_rationale":"Tier 1 / Strong — cryo-EM structure combined with mutagenesis in vivo and functional exocytosis assay in a single study; multiple orthogonal methods","pmids":[],"is_preprint":true},{"year":2019,"finding":"Dual AAV-mediated delivery of split OTOF cDNA (5' and 3' halves) into the mature cochlea of Otof-/- mice reconstituted full-length otoferlin coding sequence through recombination, restored otoferlin expression in transduced hair cells, and reversed profound deafness durably.","method":"Dual AAV cochlear injection in Otof-/- mice, immunofluorescence, ABR testing","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 / Strong — loss-of-function rescue with defined molecular reconstitution, multiple orthogonal methods, replicated subsequently by multiple labs","pmids":["30782832"],"is_preprint":false},{"year":2022,"finding":"Protein trans-splicing-based dual AAV system expressed exogenous human otoferlin in inner hair cells and restored synaptic vesicle release, reversing bilateral profound deafness in Otof-/- mice for at least 6 months after a single unilateral injection.","method":"Dual AAV trans-splicing, immunofluorescence, synaptic vesicle release assay (capacitance), ABR recording","journal":"Human genetics","confidence":"High","confidence_rationale":"Tier 2 / Strong — gain-of-function with direct measurement of synaptic vesicle exocytosis restoration and hearing recovery; multiple orthogonal methods in single study","pmids":["36383253"],"is_preprint":false},{"year":2025,"finding":"An E1799del knock-in mouse model (mirroring human E1804del DFNB9 variant) exhibits abnormal otoferlin distribution and failure of synaptic transmission in inner hair cells, demonstrating that this variant causes profound hearing loss by disrupting otoferlin's presynaptic function.","method":"Homologous recombination knock-in mouse, immunofluorescence for otoferlin localization, IHC synaptic transmission assay, ABR recording, AAV gene therapy rescue","journal":"Communications medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — knock-in model with direct subcellular localization and synaptic transmission phenotype; single study","pmids":["40506483"],"is_preprint":false},{"year":2025,"finding":"A minigene assay confirmed that the OTOF splice variant c.898-18G>A causes skipping of exon 10, establishing the molecular mechanism of this founder pathogenic allele.","method":"Minigene splicing assay","journal":"Human genomics","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — direct in vitro functional splicing assay; single lab, single method","pmids":["41053850"],"is_preprint":false},{"year":2021,"finding":"An intronic OTOF mutation (c.2406+4A>G), four nucleotides from the canonical splice site, causes exon 20 skipping as confirmed by mRNA analysis, establishing a splicing defect mechanism for ANSD in this family.","method":"Whole-exome sequencing, RNA extraction and mRNA analysis (RT-PCR)","journal":"Journal of genetics","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — direct mRNA functional validation of splicing defect; single lab, single method","pmids":["36988134"],"is_preprint":false},{"year":2021,"finding":"A splice site variant c.3289-1G>T in OTOF causes deletion of 10 or 13 bp from exon 27, resulting in two truncated otoferlin proteins (1141 and 1140 aa), as demonstrated by minigene assay and RT-PCR.","method":"Minigene assay, RT-PCR","journal":"BMC medical genomics","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — direct functional splicing validation; single lab, two methods","pmids":["33397372"],"is_preprint":false},{"year":2024,"finding":"AAV-mediated delivery of OTOF using a hair cell-specific Myo15 promoter in Otof-/- mice restored otoferlin expression specifically in hair cells, improved exocytosis function of inner hair cells (measured by membrane capacitance), and rescued hearing.","method":"AAV cochlear injection with Myo15 promoter, immunofluorescence, membrane capacitance (exocytosis assay), ABR recording","journal":"Molecular therapy. Nucleic acids","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct functional exocytosis measurement linked to otoferlin expression; single lab, multiple methods","pmids":["38404504"],"is_preprint":false}],"current_model":"Otoferlin (OTOF) is a multi-C2-domain Ca2+-sensing synaptic protein expressed in cochlear inner hair cells (IHCs) that is essential for Ca2+-dependent synaptic vesicle tethering, docking, and fusion at the IHC ribbon synapse; cryo-EM structures show membrane binding is mediated by the C2B and C2G domains, the C2D domain confers Ca2+-cooperativity of exocytosis, and loss-of-function causes failure of neurotransmitter release leading to profound prelingual deafness (DFNB9/auditory neuropathy) with progressive secondary degeneration of IHCs and type I spiral ganglion neurons."},"narrative":{"mechanistic_narrative":"Otoferlin (OTOF) is a multi-C2-domain, Ca2+-sensing presynaptic protein of cochlear inner hair cells (IHCs) that mediates Ca2+-dependent synaptic vesicle tethering, docking, and fusion at the IHC ribbon synapse [PMID:10192385, PMID:36383253]. Originally identified as a fer-1-family protein with multiple C2 domains and a single C-terminal transmembrane anchor, its hair-cell expression and homology to vesicle-fusion proteins placed it in the synaptic vesicle fusion machinery [PMID:10192385], and genetic analysis established that the long six-C2-domain isoforms, not the short three-C2-domain isoforms, are required for inner ear function [PMID:10903124]. Cryo-EM of Ca2+-bound otoferlin shows that membrane binding is mediated by the C2B and C2G domains with repositioning of the C2F and C2G domains, while graded disruption of Ca2+-binding by the C2D domain progressively degrades synaptic sound encoding and eliminates the Ca2+-cooperativity of vesicle exocytosis, establishing otoferlin as a multi-ion Ca2+ sensor for fusion. Loss of otoferlin in mice abolishes IHC neurotransmitter release and triggers a developmental and progressive degenerative cascade: delayed synaptic pruning and progressive loss of IHC synapses and inner hair cells [PMID:34335185], together with selective apoptosis of type I spiral ganglion neurons beginning before hearing onset [PMID:36914046]. In humans, OTOF mutations cause profound prelingual deafness (DFNB9/auditory neuropathy), demonstrated by a knock-in of the E1804del variant that disrupts otoferlin distribution and IHC synaptic transmission [PMID:40506483], and recurrent pathogenic alleles act through splicing defects [PMID:41053850, PMID:36988134, PMID:33397372]. Restoration of otoferlin in IHCs by dual-AAV reconstitution of the oversized coding sequence rescues exocytosis and durably reverses deafness, defining the protein's cell-autonomous presynaptic role [PMID:30782832, PMID:36383253, PMID:38404504]. Separately, OTOF has been reported as a type I interferon-induced restriction factor inhibiting HIV-1 entry in macrophages and dendritic cells [PMID:35862790].","teleology":[{"year":1999,"claim":"Established the molecular identity of otoferlin and its candidate role, answering what kind of protein OTOF encodes and where it acts.","evidence":"Candidate gene cloning, sequence analysis, and northern blot expression in inner ear hair cells","pmids":["10192385"],"confidence":"Medium","gaps":["No direct functional reconstitution of membrane fusion","C2-domain Ca2+-binding not biochemically tested","Subcellular synaptic localization not resolved"]},{"year":2000,"claim":"Resolved which otoferlin isoforms matter for hearing, showing the long six-C2-domain isoforms are functionally required.","evidence":"cDNA cloning, exon-intron mapping, and segregating intron-8 splice mutation in a DFNB9 family","pmids":["10903124"],"confidence":"Medium","gaps":["Functional role of short isoforms unresolved","Mechanistic contribution of the extra C2 domains not defined"]},{"year":2002,"claim":"First linked specific C2-domain missense variants to deafness, implicating C2C in Ca2+-binding function.","evidence":"SSCP, sequencing, and computational structural modeling of P490Q and I515T","pmids":["12127154"],"confidence":"Low","gaps":["Inference rests on computer modeling without in vitro Ca2+-binding validation","No cellular or animal confirmation of the effect"]},{"year":2007,"claim":"Defined the C2B domain as critical for protein stability and showed otoferlin is dispensable for vestibular function, narrowing its functional requirement to the auditory periphery.","evidence":"ENU-induced C2B missense mouse with immunohistochemistry, ABR, and VsEP recordings","pmids":["17967520"],"confidence":"Medium","gaps":["Mechanism of C2B-dependent stabilization unknown","Why vestibular hair cells tolerate loss not explained"]},{"year":2019,"claim":"Demonstrated that restoring otoferlin in mature cochlea reverses deafness, proving its loss is the causal and cell-autonomous defect and establishing therapeutic feasibility.","evidence":"Dual-AAV split-cDNA recombination delivery in Otof-/- mice with immunofluorescence and ABR","pmids":["30782832"],"confidence":"High","gaps":["Did not directly measure exocytosis restoration","Durability and degenerative reversal across older ages not fully addressed"]},{"year":2021,"claim":"Identified a developmental role for otoferlin in synaptic maturation and a progressive degenerative cascade, distinguishing its acute transmission role from long-term tissue maintenance.","evidence":"Otof-/- mouse synapse counting, immunolabeling, and DPOAE over 48 weeks","pmids":["34335185"],"confidence":"Medium","gaps":["Whether pruning defect is cell-autonomous to IHCs or activity-dependent unclear","Molecular link between absent release and IHC loss undefined"]},{"year":2021,"claim":"Confirmed splicing-defect mechanisms for intronic OTOF alleles, expanding the molecular spectrum of pathogenic variation beyond missense.","evidence":"Minigene assay and RT-PCR for c.3289-1G>T (exon 27) and mRNA analysis for c.2406+4A>G (exon 20 skipping)","pmids":["33397372","36988134"],"confidence":"Medium","gaps":["Protein-level consequences of truncated products not characterized","Quantitative effect on residual function not measured"]},{"year":2022,"claim":"Provided trans-splicing dual-AAV evidence that human otoferlin restores synaptic vesicle release and durably reverses bilateral deafness, directly tying rescue to exocytosis recovery.","evidence":"Dual-AAV trans-splicing in Otof-/- mice with membrane capacitance and ABR over 6 months","pmids":["36383253"],"confidence":"High","gaps":["Long-term durability beyond 6 months not assessed","Whether degenerative SGN/IHC loss is prevented not addressed"]},{"year":2022,"claim":"Reported an unexpected immune function for OTOF as an interferon-induced HIV-1 restriction factor, raising a distinct role outside the cochlea.","evidence":"siRNA knockdown and overexpression with HIV-1 infection assays in macrophages, DCs, and CD4+ T cells","pmids":["35862790"],"confidence":"Medium","gaps":["Molecular mechanism of entry inhibition undefined","Relationship to the cochlear C2-domain fusion function unknown","No structural or biochemical link to the synaptic role"]},{"year":2024,"claim":"Showed hair-cell-specific promoter-driven AAV restores otoferlin and IHC exocytosis, confirming the cell type in which otoferlin function must be reconstituted.","evidence":"AAV-Myo15 promoter delivery in Otof-/- mice with membrane capacitance and ABR","pmids":["38404504"],"confidence":"Medium","gaps":["Comparative efficacy versus broad promoters not resolved","Effect on downstream neuronal degeneration not measured"]},{"year":2025,"claim":"Defined the structural and Ca2+-sensing mechanism, showing membrane binding via C2B/C2G and C2D-mediated multi-ion Ca2+-cooperativity of vesicle fusion.","evidence":"Cryo-EM of Ca2+-bound otoferlin, MD simulation, C2D Ca2+-binding mutant mice, and in vivo electrophysiology with SV exocytosis cooperativity assay (preprint)","pmids":[],"confidence":"High","gaps":["Preprint, not peer reviewed","Identity of in vivo membrane and SNARE partners during fusion not resolved","How structural rearrangement couples to docking versus fusion steps not fully defined"]},{"year":2025,"claim":"Modeled a recurrent human DFNB9 variant in vivo, linking abnormal otoferlin distribution to failed IHC synaptic transmission and demonstrating rescue.","evidence":"E1799del (human E1804del) knock-in mouse with localization, IHC synaptic transmission assay, ABR, and AAV rescue; plus minigene confirmation of c.898-18G>A exon-10 skipping","pmids":["40506483","41053850"],"confidence":"Medium","gaps":["How mislocalization mechanistically impairs release not dissected","Generalizability of rescue across variant classes unclear"]},{"year":null,"claim":"How otoferlin's Ca2+-driven structural cycle coordinates vesicle tethering, docking, and fusion at the molecular level, and how its cochlear synaptic role relates to its reported interferon-induced antiviral activity, remain unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No defined molecular fusion partners at the IHC ribbon synapse in the corpus","Mechanism of HIV-1 entry restriction by OTOF undefined","Whether the two functions share a common biochemical basis unknown"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140299","term_label":"molecular sensor activity","supporting_discovery_ids":[7]},{"term_id":"GO:0008289","term_label":"lipid binding","supporting_discovery_ids":[7]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[7,0]},{"term_id":"GO:0031410","term_label":"cytoplasmic vesicle","supporting_discovery_ids":[9]}],"pathway":[{"term_id":"R-HSA-112316","term_label":"Neuronal System","supporting_discovery_ids":[9,7]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[4]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[10]}],"complexes":[],"partners":[],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q9HC10","full_name":"Otoferlin","aliases":["Fer-1-like protein 2"],"length_aa":1997,"mass_kda":226.8,"function":"Key calcium ion sensor involved in the Ca(2+)-triggered synaptic vesicle-plasma membrane fusion and in the control of neurotransmitter release at these output synapses. Interacts in a calcium-dependent manner to the presynaptic SNARE proteins at ribbon synapses of cochlear inner hair cells (IHCs) to trigger exocytosis of neurotransmitter. Also essential to synaptic exocytosis in immature outer hair cells (OHCs). May also play a role within the recycling of endosomes (By similarity)","subcellular_location":"Cytoplasmic vesicle, secretory vesicle, synaptic vesicle membrane; Basolateral cell membrane; Endoplasmic reticulum membrane; Golgi apparatus membrane; Presynaptic cell membrane; Cell membrane; Golgi apparatus, trans-Golgi network","url":"https://www.uniprot.org/uniprotkb/Q9HC10/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/OTOF","classification":"Not Classified","n_dependent_lines":0,"n_total_lines":1208,"dependency_fraction":0.0},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/OTOF","total_profiled":1310},"omim":[{"mim_id":"613532","title":"RAS-ASSOCIATED PROTEIN RAB8B; RAB8B","url":"https://www.omim.org/entry/613532"},{"mim_id":"605646","title":"SOLUTE CARRIER FAMILY 26, MEMBER 4; SLC26A4","url":"https://www.omim.org/entry/605646"},{"mim_id":"603681","title":"OTOFERLIN; OTOF","url":"https://www.omim.org/entry/603681"},{"mim_id":"603009","title":"DYSFERLIN; DYSF","url":"https://www.omim.org/entry/603009"},{"mim_id":"601071","title":"DEAFNESS, AUTOSOMAL RECESSIVE 9; DFNB9","url":"https://www.omim.org/entry/601071"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"","locations":[],"tissue_specificity":"Group enriched","tissue_distribution":"Detected in some","driving_tissues":[{"tissue":"bone marrow","ntpm":6.1},{"tissue":"brain","ntpm":20.8}],"url":"https://www.proteinatlas.org/search/OTOF"},"hgnc":{"alias_symbol":["FER1L2","DFNB6"],"prev_symbol":["DFNB9"]},"alphafold":{"accession":"Q9HC10","domains":[{"cath_id":"2.60.40.150","chopping":"3-120","consensus_level":"high","plddt":89.7535,"start":3,"end":120},{"cath_id":"2.60.40.150","chopping":"253-382","consensus_level":"high","plddt":86.8862,"start":253,"end":382},{"cath_id":"2.60.40.150","chopping":"416-596","consensus_level":"high","plddt":82.7001,"start":416,"end":596},{"cath_id":"2.60.40.150","chopping":"608-648_684-722_845-933","consensus_level":"high","plddt":86.6398,"start":608,"end":933},{"cath_id":"-","chopping":"727-821","consensus_level":"high","plddt":85.8585,"start":727,"end":821},{"cath_id":"2.60.40.150","chopping":"957-1107","consensus_level":"medium","plddt":86.0443,"start":957,"end":1107},{"cath_id":"2.60.40.150","chopping":"1129-1235_1406-1488","consensus_level":"medium","plddt":82.9349,"start":1129,"end":1488},{"cath_id":"2.60.40.150","chopping":"1489-1713","consensus_level":"medium","plddt":88.5784,"start":1489,"end":1713},{"cath_id":"2.60.40.150","chopping":"1731-1922","consensus_level":"medium","plddt":84.522,"start":1731,"end":1922}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9HC10","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q9HC10-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q9HC10-F1-predicted_aligned_error_v6.png","plddt_mean":76.38},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=OTOF","jax_strain_url":"https://www.jax.org/strain/search?query=OTOF"},"sequence":{"accession":"Q9HC10","fasta_url":"https://rest.uniprot.org/uniprotkb/Q9HC10.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q9HC10/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9HC10"}},"corpus_meta":[{"pmid":"10192385","id":"PMC_10192385","title":"A mutation in OTOF, encoding otoferlin, a FER-1-like protein, causes DFNB9, a nonsyndromic form of deafness.","date":"1999","source":"Nature genetics","url":"https://pubmed.ncbi.nlm.nih.gov/10192385","citation_count":439,"is_preprint":false},{"pmid":"30782832","id":"PMC_30782832","title":"Dual AAV-mediated gene therapy restores hearing in a DFNB9 mouse model.","date":"2019","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/30782832","citation_count":235,"is_preprint":false},{"pmid":"14635104","id":"PMC_14635104","title":"Auditory neuropathy in patients carrying mutations in the otoferlin gene (OTOF).","date":"2003","source":"Human mutation","url":"https://pubmed.ncbi.nlm.nih.gov/14635104","citation_count":167,"is_preprint":false},{"pmid":"38189623","id":"PMC_38189623","title":"AAV-Mediated Gene Therapy Restores Hearing in Patients with DFNB9 Deafness.","date":"2024","source":"Advanced science (Weinheim, Baden-Wurttemberg, Germany)","url":"https://pubmed.ncbi.nlm.nih.gov/38189623","citation_count":161,"is_preprint":false},{"pmid":"10903124","id":"PMC_10903124","title":"OTOF encodes multiple long and short isoforms: genetic evidence that the long ones underlie recessive deafness DFNB9.","date":"2000","source":"American journal of human genetics","url":"https://pubmed.ncbi.nlm.nih.gov/10903124","citation_count":161,"is_preprint":false},{"pmid":"18381613","id":"PMC_18381613","title":"A multicenter study on the prevalence and spectrum of mutations in the otoferlin gene (OTOF) in subjects with nonsyndromic hearing impairment and auditory neuropathy.","date":"2008","source":"Human mutation","url":"https://pubmed.ncbi.nlm.nih.gov/18381613","citation_count":156,"is_preprint":false},{"pmid":"16371502","id":"PMC_16371502","title":"OTOF mutations revealed by genetic analysis of hearing loss families including a potential temperature sensitive auditory neuropathy 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Its expression in inner ear sensory hair cells and structural homology to vesicle fusion proteins indicated a role in synaptic vesicle membrane fusion.\",\n      \"method\": \"Candidate gene cloning, sequence analysis, northern blot expression analysis\",\n      \"journal\": \"Nature genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — structural prediction and expression localization without direct functional reconstitution; foundational identification paper replicated by subsequent functional studies\",\n      \"pmids\": [\"10192385\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"OTOF encodes multiple long isoforms (six C2 domains, ~1,977 aa) and short isoforms (three C2 domains); genetic evidence from a splice-site mutation in intron 8 demonstrated that the long isoforms (but not the short isoforms) are required for inner ear function.\",\n      \"method\": \"Northern blot, cDNA cloning, exon-intron structure determination, mutation analysis in DFNB9 family\",\n      \"journal\": \"American journal of human genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic epistasis via segregating splice mutation establishing isoform requirement; single study with multiple orthogonal methods\",\n      \"pmids\": [\"10903124\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"Missense mutations P490Q and I515T in the conserved C2C domain of otoferlin cause deafness; computer modeling suggested these substitutions alter the secondary structure and Ca2+-binding capacity of the C2C domain.\",\n      \"method\": \"SSCP analysis, DNA sequencing, comparative homology analysis, computer simulation\",\n      \"journal\": \"Neurobiology of disease\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 4 / Weak — functional inference based on computational modeling without in vitro biochemical validation of Ca2+-binding\",\n      \"pmids\": [\"12127154\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"An ENU-induced missense mutation (I→N) in the C2B domain of mouse otoferlin causes profound deafness with absence of otoferlin immunoreactivity in cochlear hair cells, indicating the C2B domain is critical for protein stability. Otoferlin is dispensable for vestibular function despite expression in vestibular hair cells.\",\n      \"method\": \"ENU mutagenesis, immunohistochemistry, ABR and vestibular-evoked potential (VsEP) recordings\",\n      \"journal\": \"Hearing research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — loss-of-function mouse model with defined cellular phenotype (absent IHC immunoreactivity) and functional readout; single lab\",\n      \"pmids\": [\"17967520\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"In Otof knockout mice, otoferlin is required for proper synaptic pruning during cochlear development: absence of otoferlin delayed synaptic pruning (enlarged postsynaptic boutons at P14), led to progressive reduction of IHC synapses from ~15 at P14 to ~6 at 48 weeks, caused age-progressive loss of inner hair cells (to 75% of WT), and secondary degeneration of spiral ganglion neurons.\",\n      \"method\": \"Otof-/- mouse analysis, immunolabeling, synapse counting, DPOAE recording over 48 weeks\",\n      \"journal\": \"Frontiers in cellular neuroscience\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — clean KO with multiple defined cellular phenotypes across developmental time points; single lab\",\n      \"pmids\": [\"34335185\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Apoptosis of type I spiral ganglion neurons (SGN-I) occurs in Otof-mutant mice starting from postnatal day 7, before hearing onset, with significantly reduced SGN numbers at P7, P14, and P28 compared to wild-type. Type II SGNs were not significantly affected, indicating selective vulnerability of SGN-I to loss of otoferlin-dependent synaptic input.\",\n      \"method\": \"Immunolabeling of SGN subtypes, TUNEL/apoptosis assay, ABR and DPOAE recording in Otoftm1a/tm1a mice\",\n      \"journal\": \"Neuroscience letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — loss-of-function mouse model with specific cellular phenotype and two orthogonal methods; single lab\",\n      \"pmids\": [\"36914046\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"OTOF acts as a type I interferon-induced restriction factor that inhibits HIV-1 entry at the cell membrane of macrophages and dendritic cells. Silencing OTOF abrogated IFN-mediated suppression of HIV-1 infection; OTOF overexpression restricted HIV-1 in macrophages and CD4+ T cells.\",\n      \"method\": \"siRNA knockdown, overexpression, HIV-1 infection assay, gene expression profiling in macrophages/DCs\",\n      \"journal\": \"mBio\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — loss-of-function (siRNA) and gain-of-function (overexpression) with defined functional readout; single lab, two orthogonal approaches\",\n      \"pmids\": [\"35862790\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Cryo-EM structures of Ca2+-bound otoferlin revealed that membrane binding involves the C2B and C2G domains and repositions the C2F and C2G domains. Progressive disruption of Ca2+-binding by the C2D domain in mice increasingly altered synaptic sound encoding and eliminated the Ca2+-cooperativity of synaptic vesicle exocytosis, establishing that Ca2+-cooperativity of exocytosis reflects binding of multiple Ca2+ ions to otoferlin. These findings support otoferlin as a Ca2+-sensor for synaptic vesicle fusion and tethering/docking in inner hair cells.\",\n      \"method\": \"Cryo-electron microscopy structure determination, molecular dynamics simulation, C2D-domain Ca2+-binding mutant mice, in vivo electrophysiology (synaptic sound encoding), Ca2+-cooperativity assay of SV exocytosis\",\n      \"journal\": \"bioRxiv (preprint)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — cryo-EM structure combined with mutagenesis in vivo and functional exocytosis assay in a single study; multiple orthogonal methods\",\n      \"pmids\": [],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Dual AAV-mediated delivery of split OTOF cDNA (5' and 3' halves) into the mature cochlea of Otof-/- mice reconstituted full-length otoferlin coding sequence through recombination, restored otoferlin expression in transduced hair cells, and reversed profound deafness durably.\",\n      \"method\": \"Dual AAV cochlear injection in Otof-/- mice, immunofluorescence, ABR testing\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — loss-of-function rescue with defined molecular reconstitution, multiple orthogonal methods, replicated subsequently by multiple labs\",\n      \"pmids\": [\"30782832\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Protein trans-splicing-based dual AAV system expressed exogenous human otoferlin in inner hair cells and restored synaptic vesicle release, reversing bilateral profound deafness in Otof-/- mice for at least 6 months after a single unilateral injection.\",\n      \"method\": \"Dual AAV trans-splicing, immunofluorescence, synaptic vesicle release assay (capacitance), ABR recording\",\n      \"journal\": \"Human genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — gain-of-function with direct measurement of synaptic vesicle exocytosis restoration and hearing recovery; multiple orthogonal methods in single study\",\n      \"pmids\": [\"36383253\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"An E1799del knock-in mouse model (mirroring human E1804del DFNB9 variant) exhibits abnormal otoferlin distribution and failure of synaptic transmission in inner hair cells, demonstrating that this variant causes profound hearing loss by disrupting otoferlin's presynaptic function.\",\n      \"method\": \"Homologous recombination knock-in mouse, immunofluorescence for otoferlin localization, IHC synaptic transmission assay, ABR recording, AAV gene therapy rescue\",\n      \"journal\": \"Communications medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — knock-in model with direct subcellular localization and synaptic transmission phenotype; single study\",\n      \"pmids\": [\"40506483\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"A minigene assay confirmed that the OTOF splice variant c.898-18G>A causes skipping of exon 10, establishing the molecular mechanism of this founder pathogenic allele.\",\n      \"method\": \"Minigene splicing assay\",\n      \"journal\": \"Human genomics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — direct in vitro functional splicing assay; single lab, single method\",\n      \"pmids\": [\"41053850\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"An intronic OTOF mutation (c.2406+4A>G), four nucleotides from the canonical splice site, causes exon 20 skipping as confirmed by mRNA analysis, establishing a splicing defect mechanism for ANSD in this family.\",\n      \"method\": \"Whole-exome sequencing, RNA extraction and mRNA analysis (RT-PCR)\",\n      \"journal\": \"Journal of genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — direct mRNA functional validation of splicing defect; single lab, single method\",\n      \"pmids\": [\"36988134\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"A splice site variant c.3289-1G>T in OTOF causes deletion of 10 or 13 bp from exon 27, resulting in two truncated otoferlin proteins (1141 and 1140 aa), as demonstrated by minigene assay and RT-PCR.\",\n      \"method\": \"Minigene assay, RT-PCR\",\n      \"journal\": \"BMC medical genomics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — direct functional splicing validation; single lab, two methods\",\n      \"pmids\": [\"33397372\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"AAV-mediated delivery of OTOF using a hair cell-specific Myo15 promoter in Otof-/- mice restored otoferlin expression specifically in hair cells, improved exocytosis function of inner hair cells (measured by membrane capacitance), and rescued hearing.\",\n      \"method\": \"AAV cochlear injection with Myo15 promoter, immunofluorescence, membrane capacitance (exocytosis assay), ABR recording\",\n      \"journal\": \"Molecular therapy. Nucleic acids\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct functional exocytosis measurement linked to otoferlin expression; single lab, multiple methods\",\n      \"pmids\": [\"38404504\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"Otoferlin (OTOF) is a multi-C2-domain Ca2+-sensing synaptic protein expressed in cochlear inner hair cells (IHCs) that is essential for Ca2+-dependent synaptic vesicle tethering, docking, and fusion at the IHC ribbon synapse; cryo-EM structures show membrane binding is mediated by the C2B and C2G domains, the C2D domain confers Ca2+-cooperativity of exocytosis, and loss-of-function causes failure of neurotransmitter release leading to profound prelingual deafness (DFNB9/auditory neuropathy) with progressive secondary degeneration of IHCs and type I spiral ganglion neurons.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"Otoferlin (OTOF) is a multi-C2-domain, Ca2+-sensing presynaptic protein of cochlear inner hair cells (IHCs) that mediates Ca2+-dependent synaptic vesicle tethering, docking, and fusion at the IHC ribbon synapse [#0, #9]. Originally identified as a fer-1-family protein with multiple C2 domains and a single C-terminal transmembrane anchor, its hair-cell expression and homology to vesicle-fusion proteins placed it in the synaptic vesicle fusion machinery [#0], and genetic analysis established that the long six-C2-domain isoforms, not the short three-C2-domain isoforms, are required for inner ear function [#1]. Cryo-EM of Ca2+-bound otoferlin shows that membrane binding is mediated by the C2B and C2G domains with repositioning of the C2F and C2G domains, while graded disruption of Ca2+-binding by the C2D domain progressively degrades synaptic sound encoding and eliminates the Ca2+-cooperativity of vesicle exocytosis, establishing otoferlin as a multi-ion Ca2+ sensor for fusion [#7]. Loss of otoferlin in mice abolishes IHC neurotransmitter release and triggers a developmental and progressive degenerative cascade: delayed synaptic pruning and progressive loss of IHC synapses and inner hair cells [#4], together with selective apoptosis of type I spiral ganglion neurons beginning before hearing onset [#5]. In humans, OTOF mutations cause profound prelingual deafness (DFNB9/auditory neuropathy), demonstrated by a knock-in of the E1804del variant that disrupts otoferlin distribution and IHC synaptic transmission [#10], and recurrent pathogenic alleles act through splicing defects [#11, #12, #13]. Restoration of otoferlin in IHCs by dual-AAV reconstitution of the oversized coding sequence rescues exocytosis and durably reverses deafness, defining the protein's cell-autonomous presynaptic role [#8, #9, #14]. Separately, OTOF has been reported as a type I interferon-induced restriction factor inhibiting HIV-1 entry in macrophages and dendritic cells [#6].\",\n  \"teleology\": [\n    {\n      \"year\": 1999,\n      \"claim\": \"Established the molecular identity of otoferlin and its candidate role, answering what kind of protein OTOF encodes and where it acts.\",\n      \"evidence\": \"Candidate gene cloning, sequence analysis, and northern blot expression in inner ear hair cells\",\n      \"pmids\": [\"10192385\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No direct functional reconstitution of membrane fusion\", \"C2-domain Ca2+-binding not biochemically tested\", \"Subcellular synaptic localization not resolved\"]\n    },\n    {\n      \"year\": 2000,\n      \"claim\": \"Resolved which otoferlin isoforms matter for hearing, showing the long six-C2-domain isoforms are functionally required.\",\n      \"evidence\": \"cDNA cloning, exon-intron mapping, and segregating intron-8 splice mutation in a DFNB9 family\",\n      \"pmids\": [\"10903124\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Functional role of short isoforms unresolved\", \"Mechanistic contribution of the extra C2 domains not defined\"]\n    },\n    {\n      \"year\": 2002,\n      \"claim\": \"First linked specific C2-domain missense variants to deafness, implicating C2C in Ca2+-binding function.\",\n      \"evidence\": \"SSCP, sequencing, and computational structural modeling of P490Q and I515T\",\n      \"pmids\": [\"12127154\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Inference rests on computer modeling without in vitro Ca2+-binding validation\", \"No cellular or animal confirmation of the effect\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Defined the C2B domain as critical for protein stability and showed otoferlin is dispensable for vestibular function, narrowing its functional requirement to the auditory periphery.\",\n      \"evidence\": \"ENU-induced C2B missense mouse with immunohistochemistry, ABR, and VsEP recordings\",\n      \"pmids\": [\"17967520\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism of C2B-dependent stabilization unknown\", \"Why vestibular hair cells tolerate loss not explained\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Demonstrated that restoring otoferlin in mature cochlea reverses deafness, proving its loss is the causal and cell-autonomous defect and establishing therapeutic feasibility.\",\n      \"evidence\": \"Dual-AAV split-cDNA recombination delivery in Otof-/- mice with immunofluorescence and ABR\",\n      \"pmids\": [\"30782832\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not directly measure exocytosis restoration\", \"Durability and degenerative reversal across older ages not fully addressed\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Identified a developmental role for otoferlin in synaptic maturation and a progressive degenerative cascade, distinguishing its acute transmission role from long-term tissue maintenance.\",\n      \"evidence\": \"Otof-/- mouse synapse counting, immunolabeling, and DPOAE over 48 weeks\",\n      \"pmids\": [\"34335185\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether pruning defect is cell-autonomous to IHCs or activity-dependent unclear\", \"Molecular link between absent release and IHC loss undefined\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Confirmed splicing-defect mechanisms for intronic OTOF alleles, expanding the molecular spectrum of pathogenic variation beyond missense.\",\n      \"evidence\": \"Minigene assay and RT-PCR for c.3289-1G>T (exon 27) and mRNA analysis for c.2406+4A>G (exon 20 skipping)\",\n      \"pmids\": [\"33397372\", \"36988134\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Protein-level consequences of truncated products not characterized\", \"Quantitative effect on residual function not measured\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Provided trans-splicing dual-AAV evidence that human otoferlin restores synaptic vesicle release and durably reverses bilateral deafness, directly tying rescue to exocytosis recovery.\",\n      \"evidence\": \"Dual-AAV trans-splicing in Otof-/- mice with membrane capacitance and ABR over 6 months\",\n      \"pmids\": [\"36383253\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Long-term durability beyond 6 months not assessed\", \"Whether degenerative SGN/IHC loss is prevented not addressed\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Reported an unexpected immune function for OTOF as an interferon-induced HIV-1 restriction factor, raising a distinct role outside the cochlea.\",\n      \"evidence\": \"siRNA knockdown and overexpression with HIV-1 infection assays in macrophages, DCs, and CD4+ T cells\",\n      \"pmids\": [\"35862790\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Molecular mechanism of entry inhibition undefined\", \"Relationship to the cochlear C2-domain fusion function unknown\", \"No structural or biochemical link to the synaptic role\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Showed hair-cell-specific promoter-driven AAV restores otoferlin and IHC exocytosis, confirming the cell type in which otoferlin function must be reconstituted.\",\n      \"evidence\": \"AAV-Myo15 promoter delivery in Otof-/- mice with membrane capacitance and ABR\",\n      \"pmids\": [\"38404504\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Comparative efficacy versus broad promoters not resolved\", \"Effect on downstream neuronal degeneration not measured\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Defined the structural and Ca2+-sensing mechanism, showing membrane binding via C2B/C2G and C2D-mediated multi-ion Ca2+-cooperativity of vesicle fusion.\",\n      \"evidence\": \"Cryo-EM of Ca2+-bound otoferlin, MD simulation, C2D Ca2+-binding mutant mice, and in vivo electrophysiology with SV exocytosis cooperativity assay (preprint)\",\n      \"pmids\": [],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Preprint, not peer reviewed\", \"Identity of in vivo membrane and SNARE partners during fusion not resolved\", \"How structural rearrangement couples to docking versus fusion steps not fully defined\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Modeled a recurrent human DFNB9 variant in vivo, linking abnormal otoferlin distribution to failed IHC synaptic transmission and demonstrating rescue.\",\n      \"evidence\": \"E1799del (human E1804del) knock-in mouse with localization, IHC synaptic transmission assay, ABR, and AAV rescue; plus minigene confirmation of c.898-18G>A exon-10 skipping\",\n      \"pmids\": [\"40506483\", \"41053850\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"How mislocalization mechanistically impairs release not dissected\", \"Generalizability of rescue across variant classes unclear\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How otoferlin's Ca2+-driven structural cycle coordinates vesicle tethering, docking, and fusion at the molecular level, and how its cochlear synaptic role relates to its reported interferon-induced antiviral activity, remain unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No defined molecular fusion partners at the IHC ribbon synapse in the corpus\", \"Mechanism of HIV-1 entry restriction by OTOF undefined\", \"Whether the two functions share a common biochemical basis unknown\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140299\", \"supporting_discovery_ids\": [7]},\n      {\"term_id\": \"GO:0008289\", \"supporting_discovery_ids\": [7]},\n      {\"term_id\": \"GO:0005509\", \"supporting_discovery_ids\": [7]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [7, 0]},\n      {\"term_id\": \"GO:0031410\", \"supporting_discovery_ids\": [9]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-112316\", \"supporting_discovery_ids\": [9, 7]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [4]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [10]}\n    ],\n    \"complexes\": [],\n    \"partners\": [],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":6,"faith_total":6,"faith_pct":100.0}}