{"gene":"CATSPERT","run_date":"2026-06-09T22:57:17","timeline":{"discoveries":[{"year":2022,"finding":"CatSperτ (encoded by C2cd6/CATSPERT) is a membrane-associating C2 domain protein that independently migrates to sperm flagella and serves as a major targeting component of the multi-subunit CatSper Ca2+ channel complex, directing it into quadrilinear nanodomains in the flagellar membrane of developing spermatids; CatSperτ loss-of-function in mice abolishes sperm hyperactivated motility and male fertility, but CatSperτ is dispensable for functional channel assembly itself.","method":"Mouse knockout (loss-of-function), live-cell imaging of flagellar targeting, domain-function analysis (C2-dependent interaction with ciliary trafficking machinery), sperm motility and fertility assays","journal":"Cell reports","confidence":"High","confidence_rationale":"Tier 2 / Strong — clean KO with defined cellular phenotype, domain-level mechanistic dissection, and independent replication in a second concurrent study (PMID:34919125)","pmids":["34998468"],"is_preprint":false},{"year":2022,"finding":"C2CD6/CatSperτ is a subunit of the mouse CatSper complex that associates with the calcium-selective core-forming CatSper subunits; its deficiency depletes CatSper nanodomains from the flagellum, reduces CatSper currents, causes defective sperm hyperactivation, and results in complete male sterility in vivo and failure to fertilize oocytes in vitro. C2CD6 interacts with EFCAB9 (a pH-dependent calcium sensor within the CatSper complex), and restoration of fertilization capacity by Ca2+ ionophore or starvation treatment confirms a functional role in CatSper-dependent Ca2+ signaling.","method":"Mouse knockout, Co-immunoprecipitation (association with CatSper subunits and EFCAB9), patch-clamp electrophysiology (CatSper currents), in vitro and in vivo fertilization assays, immunofluorescence of flagellar nanodomains","journal":"Development (Cambridge, England)","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — KO phenotype, electrophysiology, Co-IP with multiple partners, in vitro/in vivo fertilization rescue, confirmed by independent concurrent study (PMID:34998468)","pmids":["34919125"],"is_preprint":false},{"year":2020,"finding":"A rare missense mutation in C2CD6 (ALS2CR11/CATSPERT) was identified in a patient with globozoospermia or acrosomal hypoplasia, suggesting a role for C2CD6 in acrosome biogenesis/sperm head formation in humans; however, functional validation was not performed in this study.","method":"Exome sequencing with Sanger confirmation in a human globozoospermia cohort","journal":"Human reproduction (Oxford, England)","confidence":"Low","confidence_rationale":"Tier 4 / Weak — human genetic association only, no functional follow-up performed in this paper","pmids":["31985809"],"is_preprint":false},{"year":2024,"finding":"PFOS exposure dysregulates phosphorylation of C2CD6 in bull spermatozoa, as detected by phosphoproteomic analysis, coinciding with impaired sperm capacitation-related functions; however, the specific kinase/phosphatase responsible and direct functional consequence for C2CD6 activity were not established.","method":"TMT-labeling and Nano LC-MS/MS phosphoproteomics of PFOS-treated bull sperm","journal":"Biology of reproduction","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single phosphoproteomic dataset, no mechanistic follow-up on C2CD6 specifically","pmids":["38847481"],"is_preprint":false}],"current_model":"CATSPERT (C2CD6/CatSperτ) encodes a C2 domain-containing membrane-associating protein that functions as an essential subunit of the sperm-specific, multi-subunit CatSper Ca2+ channel complex: it independently traffics to sperm flagella via C2 domain-dependent interactions with ciliary trafficking machinery, targets the entire CatSper complex into quadrilinear Ca2+ signaling nanodomains on the flagellar membrane, interacts with the CatSper core subunits and the pH-dependent calcium sensor EFCAB9, and is required for sperm hyperactivated motility and male fertility, though it is dispensable for functional channel assembly per se."},"narrative":{"mechanistic_narrative":"CATSPERT (C2CD6/CatSperτ) is a membrane-associating C2 domain protein that serves as an essential targeting subunit of the sperm-specific CatSper Ca2+ channel complex required for hyperactivated motility and male fertility [PMID:34998468, PMID:34919125]. It independently traffics to the sperm flagellum and, via its C2 domain-dependent interactions with ciliary trafficking machinery, directs the assembled multi-subunit CatSper complex into the quadrilinear Ca2+ signaling nanodomains of the flagellar membrane in developing spermatids [PMID:34998468]. Within the complex it associates with the calcium-selective core-forming CatSper subunits and with the pH-dependent calcium sensor EFCAB9 [PMID:34919125]. Loss of CatSperτ in mice depletes flagellar CatSper nanodomains, reduces CatSper currents, abolishes hyperactivation, and causes complete male sterility, yet it is dispensable for functional channel assembly per se — restoration of fertilization by Ca2+ ionophore confirms its role lies in proper localization rather than channel formation [PMID:34998468, PMID:34919125].","teleology":[{"year":2020,"claim":"Whether C2CD6 contributes to human male infertility was unknown; identifying a candidate mutation framed it as a sperm-relevant gene before its molecular function was defined.","evidence":"Exome sequencing with Sanger confirmation in a human globozoospermia cohort","pmids":["31985809"],"confidence":"Low","gaps":["No functional validation of the missense variant performed","Proposed link to acrosome biogenesis not mechanistically supported and not reconciled with later flagellar channel role"]},{"year":2022,"claim":"It was unknown how the CatSper complex is targeted to the flagellar membrane; CatSperτ was established as a C2 domain protein that independently traffics to the flagellum and directs the complex into its quadrilinear nanodomains, while being dispensable for channel assembly itself.","evidence":"Mouse knockout, live-cell imaging of flagellar targeting, C2 domain-function analysis, and sperm motility/fertility assays","pmids":["34998468"],"confidence":"High","gaps":["Identity of the ciliary trafficking machinery engaged by the C2 domain not molecularly defined","Structural basis of nanodomain organization unresolved"]},{"year":2022,"claim":"The biochemical placement of C2CD6 within the channel and the functional consequence of its loss were unresolved; it was shown to associate with core CatSper subunits and EFCAB9, with deficiency reducing CatSper currents and abolishing fertility, reversible by Ca2+ ionophore.","evidence":"Mouse knockout, Co-IP with CatSper subunits and EFCAB9, patch-clamp electrophysiology, in vitro/in vivo fertilization and rescue assays, immunofluorescence","pmids":["34919125"],"confidence":"High","gaps":["Direct vs. indirect nature of the EFCAB9 interaction not resolved by Co-IP alone","Stoichiometry within the complex not determined"]},{"year":2024,"claim":"Whether C2CD6 activity is post-translationally regulated during sperm function was unaddressed; phosphoproteomics showed its phosphorylation is dysregulated by PFOS exposure alongside impaired capacitation.","evidence":"TMT-labeling Nano LC-MS/MS phosphoproteomics of PFOS-treated bull sperm","pmids":["38847481"],"confidence":"Low","gaps":["Responsible kinase/phosphatase not identified","Functional consequence of phosphorylation for C2CD6 activity not established"]},{"year":null,"claim":"How the C2 domain selects flagellar trafficking machinery, how CatSperτ organizes the quadrilinear nanodomain architecture, and whether human variants cause infertility through this channel-targeting role remain open.","evidence":"","pmids":[],"confidence":"Low","gaps":["No structural model of CatSperτ within the CatSper complex","Human disease causality not functionally demonstrated","Regulatory inputs (e.g., phosphorylation) to targeting not mechanistically linked"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[0,1]},{"term_id":"GO:0008289","term_label":"lipid binding","supporting_discovery_ids":[0]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[0,1]},{"term_id":"GO:0005929","term_label":"cilium","supporting_discovery_ids":[0]}],"pathway":[{"term_id":"R-HSA-1474165","term_label":"Reproduction","supporting_discovery_ids":[0,1]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[1]}],"complexes":["CatSper Ca2+ channel complex"],"partners":["EFCAB9"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q53TS8","full_name":"Cation channel sperm-associated targeting subunit tau","aliases":["Amyotrophic lateral sclerosis 2 chromosomal region candidate gene 11 protein","C2 calcium-dependent domain-containing protein 6","Catsper channel auxiliary subunit tau"],"length_aa":1820,"mass_kda":209.1,"function":"Auxiliary component of the CatSper complex, a complex involved in sperm cell hyperactivation. Sperm cell hyperactivation is needed for sperm motility which is essential late in the preparation of sperm for fertilization. Required for CatSper complex targeting and trafficking into the quadrilinear nanodomains. Targets the preassembled CatSper complexes to elongating flagella, where it links the channel-carrying vesicles and motor proteins","subcellular_location":"Cell projection, cilium, flagellum membrane","url":"https://www.uniprot.org/uniprotkb/Q53TS8/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"C2CD6","url":"https://depmap.org/portal/gene/C2CD6","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/CATSPERT","total_profiled":1310},"omim":[],"hpa":{"profiled":true,"resolved_as":"C2CD6","reliability":"Approved","locations":[{"location":"Principal piece","reliability":"Approved"},{"location":"Acrosome","reliability":"Additional"},{"location":"Equatorial segment","reliability":"Additional"}],"tissue_specificity":"Tissue enriched","tissue_distribution":"Detected in some","driving_tissues":[{"tissue":"testis","ntpm":37.3}],"url":"https://www.proteinatlas.org/search/C2CD6"},"hgnc":{"alias_symbol":["FLJ25351"],"prev_symbol":["ALS2CR11","C2CD6"]},"alphafold":{"accession":"Q53TS8","domains":[{"cath_id":"2.60.40.150","chopping":"105-244","consensus_level":"high","plddt":85.7734,"start":105,"end":244}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q53TS8","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q53TS8-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q53TS8-F1-predicted_aligned_error_v6.png","plddt_mean":39.66},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=CATSPERT","jax_strain_url":"https://www.jax.org/strain/search?query=CATSPERT"},"sequence":{"accession":"Q53TS8","fasta_url":"https://rest.uniprot.org/uniprotkb/Q53TS8.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q53TS8/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q53TS8"}},"corpus_meta":[{"pmid":"31985809","id":"PMC_31985809","title":"Exome sequencing reveals novel causes as well as new candidate genes for human globozoospermia.","date":"2020","source":"Human reproduction (Oxford, England)","url":"https://pubmed.ncbi.nlm.nih.gov/31985809","citation_count":43,"is_preprint":false},{"pmid":"34998468","id":"PMC_34998468","title":"C2cd6-encoded CatSperτ targets sperm calcium channel to Ca2+ signaling domains in the flagellar membrane.","date":"2022","source":"Cell reports","url":"https://pubmed.ncbi.nlm.nih.gov/34998468","citation_count":38,"is_preprint":false},{"pmid":"25168388","id":"PMC_25168388","title":"Identification and characterization of novel associations in the CASP8/ALS2CR12 region on chromosome 2 with breast cancer risk.","date":"2014","source":"Human molecular genetics","url":"https://pubmed.ncbi.nlm.nih.gov/25168388","citation_count":38,"is_preprint":false},{"pmid":"33108537","id":"PMC_33108537","title":"Genetic analyses of a large cohort of infertile patients with globozoospermia, DPY19L2 still the main actor, GGN confirmed as a guest player.","date":"2020","source":"Human genetics","url":"https://pubmed.ncbi.nlm.nih.gov/33108537","citation_count":30,"is_preprint":false},{"pmid":"34919125","id":"PMC_34919125","title":"C2CD6 regulates targeting and organization of the CatSper calcium channel complex in sperm flagella.","date":"2022","source":"Development (Cambridge, England)","url":"https://pubmed.ncbi.nlm.nih.gov/34919125","citation_count":24,"is_preprint":false},{"pmid":"36047070","id":"PMC_36047070","title":"Globozoospermia: A Case Report and Systematic Review of Literature.","date":"2022","source":"The world journal of men's health","url":"https://pubmed.ncbi.nlm.nih.gov/36047070","citation_count":10,"is_preprint":false},{"pmid":"38847481","id":"PMC_38847481","title":"Male infertility and perfluoroalkyl and poly-fluoroalkyl substances: evidence for alterations in phosphorylation of proteins and fertility-related functional attributes in bull spermatozoa†.","date":"2024","source":"Biology of reproduction","url":"https://pubmed.ncbi.nlm.nih.gov/38847481","citation_count":8,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":6702,"output_tokens":1246,"usd":0.019398,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":7887,"output_tokens":1891,"usd":0.043355,"stage2_stop_reason":"end_turn"},"total_usd":0.062753,"stage1_batch_id":"msgbatch_01ACAxJQabDsht39JXeWG22d","stage2_batch_id":"msgbatch_01QEU22A9U5sbPTgsMzTmvSf","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2022,\n      \"finding\": \"CatSperτ (encoded by C2cd6/CATSPERT) is a membrane-associating C2 domain protein that independently migrates to sperm flagella and serves as a major targeting component of the multi-subunit CatSper Ca2+ channel complex, directing it into quadrilinear nanodomains in the flagellar membrane of developing spermatids; CatSperτ loss-of-function in mice abolishes sperm hyperactivated motility and male fertility, but CatSperτ is dispensable for functional channel assembly itself.\",\n      \"method\": \"Mouse knockout (loss-of-function), live-cell imaging of flagellar targeting, domain-function analysis (C2-dependent interaction with ciliary trafficking machinery), sperm motility and fertility assays\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — clean KO with defined cellular phenotype, domain-level mechanistic dissection, and independent replication in a second concurrent study (PMID:34919125)\",\n      \"pmids\": [\"34998468\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"C2CD6/CatSperτ is a subunit of the mouse CatSper complex that associates with the calcium-selective core-forming CatSper subunits; its deficiency depletes CatSper nanodomains from the flagellum, reduces CatSper currents, causes defective sperm hyperactivation, and results in complete male sterility in vivo and failure to fertilize oocytes in vitro. C2CD6 interacts with EFCAB9 (a pH-dependent calcium sensor within the CatSper complex), and restoration of fertilization capacity by Ca2+ ionophore or starvation treatment confirms a functional role in CatSper-dependent Ca2+ signaling.\",\n      \"method\": \"Mouse knockout, Co-immunoprecipitation (association with CatSper subunits and EFCAB9), patch-clamp electrophysiology (CatSper currents), in vitro and in vivo fertilization assays, immunofluorescence of flagellar nanodomains\",\n      \"journal\": \"Development (Cambridge, England)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — KO phenotype, electrophysiology, Co-IP with multiple partners, in vitro/in vivo fertilization rescue, confirmed by independent concurrent study (PMID:34998468)\",\n      \"pmids\": [\"34919125\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"A rare missense mutation in C2CD6 (ALS2CR11/CATSPERT) was identified in a patient with globozoospermia or acrosomal hypoplasia, suggesting a role for C2CD6 in acrosome biogenesis/sperm head formation in humans; however, functional validation was not performed in this study.\",\n      \"method\": \"Exome sequencing with Sanger confirmation in a human globozoospermia cohort\",\n      \"journal\": \"Human reproduction (Oxford, England)\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 4 / Weak — human genetic association only, no functional follow-up performed in this paper\",\n      \"pmids\": [\"31985809\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"PFOS exposure dysregulates phosphorylation of C2CD6 in bull spermatozoa, as detected by phosphoproteomic analysis, coinciding with impaired sperm capacitation-related functions; however, the specific kinase/phosphatase responsible and direct functional consequence for C2CD6 activity were not established.\",\n      \"method\": \"TMT-labeling and Nano LC-MS/MS phosphoproteomics of PFOS-treated bull sperm\",\n      \"journal\": \"Biology of reproduction\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single phosphoproteomic dataset, no mechanistic follow-up on C2CD6 specifically\",\n      \"pmids\": [\"38847481\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"CATSPERT (C2CD6/CatSperτ) encodes a C2 domain-containing membrane-associating protein that functions as an essential subunit of the sperm-specific, multi-subunit CatSper Ca2+ channel complex: it independently traffics to sperm flagella via C2 domain-dependent interactions with ciliary trafficking machinery, targets the entire CatSper complex into quadrilinear Ca2+ signaling nanodomains on the flagellar membrane, interacts with the CatSper core subunits and the pH-dependent calcium sensor EFCAB9, and is required for sperm hyperactivated motility and male fertility, though it is dispensable for functional channel assembly per se.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"CATSPERT (C2CD6/CatSperτ) is a membrane-associating C2 domain protein that serves as an essential targeting subunit of the sperm-specific CatSper Ca2+ channel complex required for hyperactivated motility and male fertility [#0, #1]. It independently traffics to the sperm flagellum and, via its C2 domain-dependent interactions with ciliary trafficking machinery, directs the assembled multi-subunit CatSper complex into the quadrilinear Ca2+ signaling nanodomains of the flagellar membrane in developing spermatids [#0]. Within the complex it associates with the calcium-selective core-forming CatSper subunits and with the pH-dependent calcium sensor EFCAB9 [#1]. Loss of CatSperτ in mice depletes flagellar CatSper nanodomains, reduces CatSper currents, abolishes hyperactivation, and causes complete male sterility, yet it is dispensable for functional channel assembly per se — restoration of fertilization by Ca2+ ionophore confirms its role lies in proper localization rather than channel formation [#0, #1].\",\n  \"teleology\": [\n    {\n      \"year\": 2020,\n      \"claim\": \"Whether C2CD6 contributes to human male infertility was unknown; identifying a candidate mutation framed it as a sperm-relevant gene before its molecular function was defined.\",\n      \"evidence\": \"Exome sequencing with Sanger confirmation in a human globozoospermia cohort\",\n      \"pmids\": [\"31985809\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No functional validation of the missense variant performed\", \"Proposed link to acrosome biogenesis not mechanistically supported and not reconciled with later flagellar channel role\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"It was unknown how the CatSper complex is targeted to the flagellar membrane; CatSperτ was established as a C2 domain protein that independently traffics to the flagellum and directs the complex into its quadrilinear nanodomains, while being dispensable for channel assembly itself.\",\n      \"evidence\": \"Mouse knockout, live-cell imaging of flagellar targeting, C2 domain-function analysis, and sperm motility/fertility assays\",\n      \"pmids\": [\"34998468\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Identity of the ciliary trafficking machinery engaged by the C2 domain not molecularly defined\", \"Structural basis of nanodomain organization unresolved\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"The biochemical placement of C2CD6 within the channel and the functional consequence of its loss were unresolved; it was shown to associate with core CatSper subunits and EFCAB9, with deficiency reducing CatSper currents and abolishing fertility, reversible by Ca2+ ionophore.\",\n      \"evidence\": \"Mouse knockout, Co-IP with CatSper subunits and EFCAB9, patch-clamp electrophysiology, in vitro/in vivo fertilization and rescue assays, immunofluorescence\",\n      \"pmids\": [\"34919125\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct vs. indirect nature of the EFCAB9 interaction not resolved by Co-IP alone\", \"Stoichiometry within the complex not determined\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Whether C2CD6 activity is post-translationally regulated during sperm function was unaddressed; phosphoproteomics showed its phosphorylation is dysregulated by PFOS exposure alongside impaired capacitation.\",\n      \"evidence\": \"TMT-labeling Nano LC-MS/MS phosphoproteomics of PFOS-treated bull sperm\",\n      \"pmids\": [\"38847481\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Responsible kinase/phosphatase not identified\", \"Functional consequence of phosphorylation for C2CD6 activity not established\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How the C2 domain selects flagellar trafficking machinery, how CatSperτ organizes the quadrilinear nanodomain architecture, and whether human variants cause infertility through this channel-targeting role remain open.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No structural model of CatSperτ within the CatSper complex\", \"Human disease causality not functionally demonstrated\", \"Regulatory inputs (e.g., phosphorylation) to targeting not mechanistically linked\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [0, 1]},\n      {\"term_id\": \"GO:0008289\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [0, 1]},\n      {\"term_id\": \"GO:0005929\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1474165\", \"supporting_discovery_ids\": [0, 1]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [1]}\n    ],\n    \"complexes\": [\"CatSper Ca2+ channel complex\"],\n    \"partners\": [\"EFCAB9\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":4,"faith_total":4,"faith_pct":100.0}}