{"gene":"OTOL1","run_date":"2026-06-10T05:19:53","timeline":{"discoveries":[{"year":2021,"finding":"The gC1q domain of Otolin-1 (OTOL1) is responsible for trimerization and Ca2+ binding; natural variants R339S, R342W, and R402P destabilize the apo-gC1q domain, while Q426R has a stabilizing effect. Ca2+ can partially rescue the destabilizing effects of R342W and Q426R at higher concentrations, but R402P is completely insensitive to Ca2+. R342W induces aberrant self-aggregation, and R402P disables trimerization, establishing that these residues are critical for normal gC1q oligomeric assembly.","method":"Structural and biophysical analysis of wild-type and mutant gC1q domain (natural substitution mutagenesis, stability assays, self-association assays) with and without Ca2+","journal":"International journal of molecular sciences","confidence":"Medium","confidence_rationale":"Tier 1–2 / Weak — in vitro mutagenesis and biophysical characterization with functional readouts, but single lab with no independent replication","pmids":["34445792"],"is_preprint":false}],"current_model":"OTOL1 (Otolin-1) is an inner-ear scaffold protein whose gC1q domain mediates Ca2+-dependent trimerization; natural mutations at key residues in this domain disrupt protein stability, trimerization, or Ca2+ responsiveness, implicating these molecular properties in the formation of otoconia/otoliths and balance sensing."},"narrative":{"mechanistic_narrative":"OTOL1 (Otolin-1) is an inner-ear scaffold protein implicated in otoconia/otolith assembly and balance sensing through Ca2+-dependent oligomerization of its C-terminal gC1q domain [PMID:34445792]. This domain mediates both Ca2+ binding and trimerization, and natural substitutions at key residues disrupt these properties: R339S, R342W, and R402P destabilize the apo-gC1q domain, with R342W driving aberrant self-aggregation and R402P abolishing trimerization, while Q426R is stabilizing [PMID:34445792]. Ca2+ partially rescues the destabilizing effect of R342W and Q426R at higher concentrations but cannot compensate for R402P, which is fully Ca2+-insensitive, establishing these residues as critical determinants of normal gC1q oligomeric assembly and Ca2+ responsiveness [PMID:34445792]. Beyond this biophysical characterization of the gC1q domain [PMID:34445792], no further mechanistic detail on OTOL1 has been characterized in the available corpus.","teleology":[{"year":2021,"claim":"It was unknown which molecular features govern Otolin-1 assembly; biophysical dissection of the gC1q domain established that it mediates Ca2+-dependent trimerization and that specific residues control stability, oligomerization, and Ca2+ responsiveness.","evidence":"Structural and biophysical analysis of wild-type and natural-variant gC1q domain (stability and self-association assays) with and without Ca2+","pmids":["34445792"],"confidence":"Medium","gaps":["Single lab with no independent replication of the biophysical findings","Effects measured on the isolated gC1q domain rather than full-length Otolin-1 in its native otoconial matrix","No direct demonstration linking these residue variants to otoconia/otolith formation defects or balance phenotypes in vivo"]},{"year":null,"claim":"How OTOL1 oligomers integrate into the otoconial matrix and contribute to balance sensing at the tissue level remains unresolved.","evidence":"No discovery in the available corpus addresses in vivo function, binding partners, or matrix incorporation","pmids":[],"confidence":"Medium","gaps":["No identified physical partners within the otoconial matrix","No structural model of the assembled trimer or higher-order assembly","No in vivo or animal-model validation of mutational effects"]}],"mechanism_profile":{"molecular_activity":[],"localization":[],"pathway":[],"complexes":[],"partners":[],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"A6NHN0","full_name":"Otolin-1","aliases":[],"length_aa":477,"mass_kda":49.4,"function":"Collagen-like protein specifically expressed in the inner ear, which provides an organic scaffold for otoconia, a calcium carbonate structure in the saccule and utricle of the ear. Acts as a scaffold for biomineralization: sequesters calcium and forms interconnecting fibrils between otoconia that are incorporated into the calcium crystal structure. Together with OC90, modulates calcite crystal morphology and growth kinetics","subcellular_location":"Secreted, extracellular space, extracellular matrix","url":"https://www.uniprot.org/uniprotkb/A6NHN0/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/OTOL1","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/OTOL1","total_profiled":1310},"omim":[{"mim_id":"621480","title":"OTOLIN 1; OTOL1","url":"https://www.omim.org/entry/621480"},{"mim_id":"601658","title":"OTOCONIN 90; OC90","url":"https://www.omim.org/entry/601658"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"","locations":[],"tissue_specificity":"Not detected","tissue_distribution":"Not detected","driving_tissues":[],"url":"https://www.proteinatlas.org/search/OTOL1"},"hgnc":{"alias_symbol":["C1QTNF15","C1QTNF16"],"prev_symbol":[]},"alphafold":{"accession":"A6NHN0","domains":[{"cath_id":"2.60.120.40","chopping":"348-470","consensus_level":"high","plddt":94.7776,"start":348,"end":470}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/A6NHN0","model_url":"https://alphafold.ebi.ac.uk/files/AF-A6NHN0-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-A6NHN0-F1-predicted_aligned_error_v6.png","plddt_mean":58.94},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=OTOL1","jax_strain_url":"https://www.jax.org/strain/search?query=OTOL1"},"sequence":{"accession":"A6NHN0","fasta_url":"https://rest.uniprot.org/uniprotkb/A6NHN0.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/A6NHN0/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/A6NHN0"}},"corpus_meta":[{"pmid":"27816938","id":"PMC_27816938","title":"Genome-wide Association Study of Parental Life Span.","date":"2017","source":"The journals of gerontology. Series A, Biological sciences and medical sciences","url":"https://pubmed.ncbi.nlm.nih.gov/27816938","citation_count":10,"is_preprint":false},{"pmid":"34445792","id":"PMC_34445792","title":"Natural Mutations Affect Structure and Function of gC1q Domain of Otolin-1.","date":"2021","source":"International journal of molecular sciences","url":"https://pubmed.ncbi.nlm.nih.gov/34445792","citation_count":6,"is_preprint":false},{"pmid":"32640699","id":"PMC_32640699","title":"Novel Nasal Epithelial Cell Markers of Parkinson's Disease Identified Using Cells Treated with α-Synuclein Preformed Fibrils.","date":"2020","source":"Journal of clinical medicine","url":"https://pubmed.ncbi.nlm.nih.gov/32640699","citation_count":6,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":3716,"output_tokens":414,"usd":0.008679,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":6660,"output_tokens":971,"usd":0.028788,"stage2_stop_reason":"end_turn"},"total_usd":0.037467,"stage1_batch_id":"msgbatch_013a8chtv3AWyTqv4z4sEF4C","stage2_batch_id":"msgbatch_01AHsuW63vinsvuTgzmQ3n62","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2021,\n      \"finding\": \"The gC1q domain of Otolin-1 (OTOL1) is responsible for trimerization and Ca2+ binding; natural variants R339S, R342W, and R402P destabilize the apo-gC1q domain, while Q426R has a stabilizing effect. Ca2+ can partially rescue the destabilizing effects of R342W and Q426R at higher concentrations, but R402P is completely insensitive to Ca2+. R342W induces aberrant self-aggregation, and R402P disables trimerization, establishing that these residues are critical for normal gC1q oligomeric assembly.\",\n      \"method\": \"Structural and biophysical analysis of wild-type and mutant gC1q domain (natural substitution mutagenesis, stability assays, self-association assays) with and without Ca2+\",\n      \"journal\": \"International journal of molecular sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1–2 / Weak — in vitro mutagenesis and biophysical characterization with functional readouts, but single lab with no independent replication\",\n      \"pmids\": [\"34445792\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"OTOL1 (Otolin-1) is an inner-ear scaffold protein whose gC1q domain mediates Ca2+-dependent trimerization; natural mutations at key residues in this domain disrupt protein stability, trimerization, or Ca2+ responsiveness, implicating these molecular properties in the formation of otoconia/otoliths and balance sensing.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"OTOL1 (Otolin-1) is an inner-ear scaffold protein implicated in otoconia/otolith assembly and balance sensing through Ca2+-dependent oligomerization of its C-terminal gC1q domain [#0]. This domain mediates both Ca2+ binding and trimerization, and natural substitutions at key residues disrupt these properties: R339S, R342W, and R402P destabilize the apo-gC1q domain, with R342W driving aberrant self-aggregation and R402P abolishing trimerization, while Q426R is stabilizing [#0]. Ca2+ partially rescues the destabilizing effect of R342W and Q426R at higher concentrations but cannot compensate for R402P, which is fully Ca2+-insensitive, establishing these residues as critical determinants of normal gC1q oligomeric assembly and Ca2+ responsiveness [#0]. Beyond this biophysical characterization of the gC1q domain [#0], no further mechanistic detail on OTOL1 has been characterized in the available corpus.\",\n  \"teleology\": [\n    {\n      \"year\": 2021,\n      \"claim\": \"It was unknown which molecular features govern Otolin-1 assembly; biophysical dissection of the gC1q domain established that it mediates Ca2+-dependent trimerization and that specific residues control stability, oligomerization, and Ca2+ responsiveness.\",\n      \"evidence\": \"Structural and biophysical analysis of wild-type and natural-variant gC1q domain (stability and self-association assays) with and without Ca2+\",\n      \"pmids\": [\"34445792\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Single lab with no independent replication of the biophysical findings\",\n        \"Effects measured on the isolated gC1q domain rather than full-length Otolin-1 in its native otoconial matrix\",\n        \"No direct demonstration linking these residue variants to otoconia/otolith formation defects or balance phenotypes in vivo\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How OTOL1 oligomers integrate into the otoconial matrix and contribute to balance sensing at the tissue level remains unresolved.\",\n      \"evidence\": \"No discovery in the available corpus addresses in vivo function, binding partners, or matrix incorporation\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"No identified physical partners within the otoconial matrix\",\n        \"No structural model of the assembled trimer or higher-order assembly\",\n        \"No in vivo or animal-model validation of mutational effects\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [],\n    \"localization\": [],\n    \"pathway\": [],\n    \"complexes\": [],\n    \"partners\": [],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":3,"faith_total":3,"faith_pct":100.0}}