{"gene":"CABCOCO1","run_date":"2026-06-09T22:57:17","timeline":{"discoveries":[{"year":2016,"finding":"CABCOCO1 (calcium-binding coiled-coil protein 1) is a novel protein with demonstrated calcium-binding activity, localized in the sperm flagellum. Recombinant CABCOCO1 showed calcium-binding activity via Stains-all, ruthenium red staining, and direct terbium-binding measurement. Immunohistochemical analyses showed localization in spermatogenic cells, initially in the cytoplasm of spermatocytes, concentrated around centrioles of spermatids, co-localizing with the centrosomal protein pericentrin. During spermiogenesis, CABCOCO1 relocalized from the centrosome to the sperm flagellum. In porcine sperm (where the proximal centriole is retained), CABCOCO1 localized to both the basal body and flagellum.","method":"In vitro calcium-binding assay (Stains-all, ruthenium red, terbium binding of recombinant protein); immunohistochemistry; subcellular fractionation/localization","journal":"Molecular reproduction and development","confidence":"Medium","confidence_rationale":"Tier 1–2 / Weak — in vitro calcium-binding assay with recombinant protein and multiple staining methods, plus direct immunolocalization, but single lab, single study","pmids":["26990073"],"is_preprint":false},{"year":2023,"finding":"CABCOCO1 physically interacts with CCDC189, a radial-spoke-associated protein of the sperm axoneme. CCDC189 was localized to the radial spoke of the first peripheral microtubule doublet by immunoelectron microscopy. Co-immunoprecipitation and mass spectrometry identified CABCOCO1 as a CCDC189-interacting protein. Inactivation of Cabcoco1 caused malformation of sperm flagella (MMAF phenotype). Inactivation of CCDC189 caused downregulation of CABCOCO1 protein expression. Both CCDC189 and CABCOCO1 were found to interact with the radial-spoke-specific protein RSPH1 and intraflagellar transport proteins.","method":"Co-immunoprecipitation, mass spectrometry, Cabcoco1 knockout mouse (loss-of-function with MMAF phenotype readout), immunoelectron microscopy, immunoblotting","journal":"National science review","confidence":"High","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP with MS identification, knockout phenotype with defined cellular readout, immunoelectron microscopy localization, multiple orthogonal methods in a single study","pmids":["37601242"],"is_preprint":false},{"year":2025,"finding":"C10ORF107 (CABCOCO1) was identified as a candidate gene variant in patients with congenital heart disease presenting with laterality defects (situs ambiguus), suggesting a role in left-right axis determination, potentially through ciliary function.","method":"Whole-exome sequencing of CHD patients with laterality defects","journal":"Journal of human genetics","confidence":"Low","confidence_rationale":"Tier 4 / Weak — genomic sequencing/variant association only, no functional mechanistic experiment performed on CABCOCO1 itself","pmids":["40467998"],"is_preprint":false}],"current_model":"CABCOCO1 (ciliary-associated calcium-binding coiled-coil protein 1) is a calcium-binding protein that localizes to the sperm flagellum and centrosome/basal body during spermiogenesis; it physically interacts with the radial-spoke-associated protein CCDC189 and with RSPH1 and intraflagellar transport proteins at the axoneme, and loss of CABCOCO1 causes multiple morphological abnormalities of the sperm flagella (MMAF), establishing its role in sperm flagellum formation."},"narrative":{"mechanistic_narrative":"CABCOCO1 is a calcium-binding protein that functions in sperm flagellum formation during spermiogenesis [PMID:26990073, PMID:37601242]. It exhibits direct calcium-binding activity and undergoes a developmentally programmed relocalization, concentrating around centrioles and co-localizing with pericentrin in spermatids before redistributing to the sperm flagellum; in species retaining the proximal centriole it localizes to both the basal body and the flagellum [PMID:26990073]. At the axoneme, CABCOCO1 physically interacts with the radial-spoke-associated protein CCDC189 and engages the radial-spoke-specific protein RSPH1 and intraflagellar transport proteins, with CCDC189 required to maintain CABCOCO1 protein levels [PMID:37601242]. Loss of CABCOCO1 causes multiple morphological abnormalities of the sperm flagella (MMAF), establishing it as essential for normal flagellar architecture [PMID:37601242]. Beyond its role in sperm flagellum assembly, no further mechanistic detail has been characterized in the available corpus.","teleology":[{"year":2016,"claim":"Established CABCOCO1 as a genuine calcium-binding protein with a spermatogenic localization pattern, raising the question of how a calcium sensor participates in centriole and flagellum biology.","evidence":"In vitro calcium-binding assays (Stains-all, ruthenium red, terbium binding) on recombinant protein plus immunohistochemical localization across spermatogenic stages","pmids":["26990073"],"confidence":"Medium","gaps":["Functional consequence of calcium binding not tested","Single lab, single study without loss-of-function validation","Molecular partners at the centriole or flagellum not identified"]},{"year":2023,"claim":"Defined CABCOCO1's molecular context at the axoneme and its functional requirement, showing it acts within the radial-spoke/IFT machinery and is needed for sperm flagellum integrity.","evidence":"Reciprocal Co-IP with mass spectrometry, Cabcoco1 knockout mouse with MMAF readout, and immunoelectron microscopy in mouse","pmids":["37601242"],"confidence":"High","gaps":["Mechanism by which CABCOCO1 contributes to radial spoke or IFT function not resolved","Whether the interaction with RSPH1 and IFT proteins is direct or bridged by CCDC189 not determined","Role of calcium binding in the CCDC189 interaction not addressed"]},{"year":2025,"claim":"Raised a possible role in left-right axis determination beyond the sperm flagellum, linking CABCOCO1 variants to laterality defects.","evidence":"Whole-exome sequencing of congenital heart disease patients with situs ambiguus","pmids":["40467998"],"confidence":"Low","gaps":["Variant association only; no functional experiment performed on CABCOCO1 in this context","Causality and ciliary mechanism in laterality not demonstrated","No link drawn to motile cilia of the embryonic node"]},{"year":null,"claim":"How CABCOCO1's calcium-binding activity is mechanistically coupled to radial-spoke/IFT function and flagellar assembly remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No structural model of CABCOCO1 or its complexes","Calcium-dependence of partner interactions untested","Role outside spermatogenesis (e.g., motile cilia in laterality) unconfirmed"]}],"mechanism_profile":{"molecular_activity":[],"localization":[{"term_id":"GO:0005929","term_label":"cilium","supporting_discovery_ids":[0,1]},{"term_id":"GO:0005815","term_label":"microtubule organizing center","supporting_discovery_ids":[0]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[0]}],"pathway":[],"complexes":[],"partners":["CCDC189","RSPH1"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q8IVU9","full_name":"Ciliary-associated calcium-binding coiled-coil protein 1","aliases":[],"length_aa":208,"mass_kda":23.9,"function":"Calcium-binding protein. May be involved in the control of sperm flagellar movement","subcellular_location":"Cytoplasm; Cytoplasm, cytoskeleton, microtubule organizing center, centrosome; Cell projection, cilium, flagellum","url":"https://www.uniprot.org/uniprotkb/Q8IVU9/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/CABCOCO1","classification":"Not Classified","n_dependent_lines":7,"n_total_lines":1208,"dependency_fraction":0.005794701986754967},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/CABCOCO1","total_profiled":1310},"omim":[],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Centrosome","reliability":"Approved"},{"location":"Basal body","reliability":"Approved"},{"location":"Nucleoplasm","reliability":"Additional"},{"location":"Cytosol","reliability":"Additional"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"brain","ntpm":13.6},{"tissue":"fallopian tube","ntpm":25.1},{"tissue":"testis","ntpm":14.4}],"url":"https://www.proteinatlas.org/search/CABCOCO1"},"hgnc":{"alias_symbol":["bA63A2.1","Em:AC022398.2","MGC44593","ARIEL"],"prev_symbol":["C10orf107"]},"alphafold":{"accession":"Q8IVU9","domains":[{"cath_id":"-","chopping":"6-86","consensus_level":"high","plddt":82.1806,"start":6,"end":86}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q8IVU9","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q8IVU9-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q8IVU9-F1-predicted_aligned_error_v6.png","plddt_mean":77.31},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=CABCOCO1","jax_strain_url":"https://www.jax.org/strain/search?query=CABCOCO1"},"sequence":{"accession":"Q8IVU9","fasta_url":"https://rest.uniprot.org/uniprotkb/Q8IVU9.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q8IVU9/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q8IVU9"}},"corpus_meta":[{"pmid":"9142125","id":"PMC_9142125","title":"Maternal 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Recombinant CABCOCO1 showed calcium-binding activity via Stains-all, ruthenium red staining, and direct terbium-binding measurement. Immunohistochemical analyses showed localization in spermatogenic cells, initially in the cytoplasm of spermatocytes, concentrated around centrioles of spermatids, co-localizing with the centrosomal protein pericentrin. During spermiogenesis, CABCOCO1 relocalized from the centrosome to the sperm flagellum. In porcine sperm (where the proximal centriole is retained), CABCOCO1 localized to both the basal body and flagellum.\",\n      \"method\": \"In vitro calcium-binding assay (Stains-all, ruthenium red, terbium binding of recombinant protein); immunohistochemistry; subcellular fractionation/localization\",\n      \"journal\": \"Molecular reproduction and development\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1–2 / Weak — in vitro calcium-binding assay with recombinant protein and multiple staining methods, plus direct immunolocalization, but single lab, single study\",\n      \"pmids\": [\"26990073\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"CABCOCO1 physically interacts with CCDC189, a radial-spoke-associated protein of the sperm axoneme. CCDC189 was localized to the radial spoke of the first peripheral microtubule doublet by immunoelectron microscopy. Co-immunoprecipitation and mass spectrometry identified CABCOCO1 as a CCDC189-interacting protein. Inactivation of Cabcoco1 caused malformation of sperm flagella (MMAF phenotype). Inactivation of CCDC189 caused downregulation of CABCOCO1 protein expression. Both CCDC189 and CABCOCO1 were found to interact with the radial-spoke-specific protein RSPH1 and intraflagellar transport proteins.\",\n      \"method\": \"Co-immunoprecipitation, mass spectrometry, Cabcoco1 knockout mouse (loss-of-function with MMAF phenotype readout), immunoelectron microscopy, immunoblotting\",\n      \"journal\": \"National science review\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP with MS identification, knockout phenotype with defined cellular readout, immunoelectron microscopy localization, multiple orthogonal methods in a single study\",\n      \"pmids\": [\"37601242\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"C10ORF107 (CABCOCO1) was identified as a candidate gene variant in patients with congenital heart disease presenting with laterality defects (situs ambiguus), suggesting a role in left-right axis determination, potentially through ciliary function.\",\n      \"method\": \"Whole-exome sequencing of CHD patients with laterality defects\",\n      \"journal\": \"Journal of human genetics\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 4 / Weak — genomic sequencing/variant association only, no functional mechanistic experiment performed on CABCOCO1 itself\",\n      \"pmids\": [\"40467998\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"CABCOCO1 (ciliary-associated calcium-binding coiled-coil protein 1) is a calcium-binding protein that localizes to the sperm flagellum and centrosome/basal body during spermiogenesis; it physically interacts with the radial-spoke-associated protein CCDC189 and with RSPH1 and intraflagellar transport proteins at the axoneme, and loss of CABCOCO1 causes multiple morphological abnormalities of the sperm flagella (MMAF), establishing its role in sperm flagellum formation.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"CABCOCO1 is a calcium-binding protein that functions in sperm flagellum formation during spermiogenesis [#0, #1]. It exhibits direct calcium-binding activity and undergoes a developmentally programmed relocalization, concentrating around centrioles and co-localizing with pericentrin in spermatids before redistributing to the sperm flagellum; in species retaining the proximal centriole it localizes to both the basal body and the flagellum [#0]. At the axoneme, CABCOCO1 physically interacts with the radial-spoke-associated protein CCDC189 and engages the radial-spoke-specific protein RSPH1 and intraflagellar transport proteins, with CCDC189 required to maintain CABCOCO1 protein levels [#1]. Loss of CABCOCO1 causes multiple morphological abnormalities of the sperm flagella (MMAF), establishing it as essential for normal flagellar architecture [#1]. Beyond its role in sperm flagellum assembly, no further mechanistic detail has been characterized in the available corpus.\",\n  \"teleology\": [\n    {\n      \"year\": 2016,\n      \"claim\": \"Established CABCOCO1 as a genuine calcium-binding protein with a spermatogenic localization pattern, raising the question of how a calcium sensor participates in centriole and flagellum biology.\",\n      \"evidence\": \"In vitro calcium-binding assays (Stains-all, ruthenium red, terbium binding) on recombinant protein plus immunohistochemical localization across spermatogenic stages\",\n      \"pmids\": [\"26990073\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Functional consequence of calcium binding not tested\",\n        \"Single lab, single study without loss-of-function validation\",\n        \"Molecular partners at the centriole or flagellum not identified\"\n      ]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Defined CABCOCO1's molecular context at the axoneme and its functional requirement, showing it acts within the radial-spoke/IFT machinery and is needed for sperm flagellum integrity.\",\n      \"evidence\": \"Reciprocal Co-IP with mass spectrometry, Cabcoco1 knockout mouse with MMAF readout, and immunoelectron microscopy in mouse\",\n      \"pmids\": [\"37601242\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Mechanism by which CABCOCO1 contributes to radial spoke or IFT function not resolved\",\n        \"Whether the interaction with RSPH1 and IFT proteins is direct or bridged by CCDC189 not determined\",\n        \"Role of calcium binding in the CCDC189 interaction not addressed\"\n      ]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Raised a possible role in left-right axis determination beyond the sperm flagellum, linking CABCOCO1 variants to laterality defects.\",\n      \"evidence\": \"Whole-exome sequencing of congenital heart disease patients with situs ambiguus\",\n      \"pmids\": [\"40467998\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"Variant association only; no functional experiment performed on CABCOCO1 in this context\",\n        \"Causality and ciliary mechanism in laterality not demonstrated\",\n        \"No link drawn to motile cilia of the embryonic node\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How CABCOCO1's calcium-binding activity is mechanistically coupled to radial-spoke/IFT function and flagellar assembly remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"No structural model of CABCOCO1 or its complexes\",\n        \"Calcium-dependence of partner interactions untested\",\n        \"Role outside spermatogenesis (e.g., motile cilia in laterality) unconfirmed\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [],\n    \"localization\": [\n      {\"term_id\": \"GO:0005929\", \"supporting_discovery_ids\": [0, 1]},\n      {\"term_id\": \"GO:0005815\", \"supporting_discovery_ids\": [0]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"pathway\": [],\n    \"complexes\": [],\n    \"partners\": [\"CCDC189\", \"RSPH1\"],\n    \"other_free_text\": []\n  }\n}\n```","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":4,"faith_total":4,"faith_pct":100.0}}