{"gene":"CATSPERD","run_date":"2026-04-28T17:28:52","timeline":{"discoveries":[{"year":2011,"finding":"CATSPERD (encoded by Tmem146) is an essential auxiliary subunit of the CATSPER channel complex in sperm; mice lacking CATSPERδ are infertile, their spermatozoa lack Ca²⁺ current and hyperactivated motility, establishing CATSPERδ as required for proper CATSPER channel assembly and/or transport to the sperm tail.","method":"Gene knockout mouse model (loss-of-function), electrophysiology (Ca²⁺ current recording), motility assays, co-immunoprecipitation/complex analysis, sperm tail-specific expression characterization","journal":"Nature Communications","confidence":"High","confidence_rationale":"Tier 2 — clean KO with defined cellular phenotype (loss of Ca²⁺ current, loss of hyperactivation, infertility), replicated across multiple functional readouts in a highly cited study","pmids":["21224844"],"is_preprint":false},{"year":2025,"finding":"CATSPERδ-deficient mouse sperm, which fail to undergo hyperactivation, cannot interact with or cross the zebrafish micropyle, demonstrating that hyperactive motility dependent on the CATSPER channel (including CATSPERδ) is mechanistically required for sperm entry into the egg micropyle.","method":"Cross-species insemination assay using CatSperd knockout mouse sperm, confocal and electron microscopy","journal":"eLife","confidence":"Medium","confidence_rationale":"Tier 2 — clean KO with specific functional phenotype in a novel assay, single study","pmids":["41100162"],"is_preprint":false}],"current_model":"CATSPERδ (CATSPERD/TMEM146) is an essential auxiliary subunit of the tetrameric CATSPER Ca²⁺-selective channel in the sperm tail; it is required for proper CATSPER channel assembly and/or trafficking, and its absence abolishes sperm Ca²⁺ current and hyperactivated motility, thereby causing male infertility and preventing sperm from crossing the egg's micropyle."},"narrative":{"teleology":[{"year":2011,"claim":"Identification of CATSPERδ as an essential auxiliary subunit of the CATSPER channel resolved the question of whether additional non-pore-forming components are required for channel function, showing that its absence eliminates sperm Ca²⁺ current, hyperactivated motility, and fertility.","evidence":"Tmem146 knockout mouse with electrophysiology, motility assays, co-immunoprecipitation, and fertility assessment","pmids":["21224844"],"confidence":"High","gaps":["Structural basis of CATSPERδ interaction with the pore-forming CATSPER subunits is unknown","Whether CATSPERδ loss prevents channel assembly versus trafficking has not been resolved","Stoichiometry and topology of CATSPERδ within the channel complex remain undefined"]},{"year":2025,"claim":"Demonstrating that CATSPERδ-deficient sperm cannot interact with or cross the egg micropyle established a direct functional link between CATSPER-dependent hyperactivation and the mechanical process of egg penetration.","evidence":"Cross-species insemination of CatSperd knockout mouse sperm with zebrafish eggs, confocal and electron microscopy","pmids":["41100162"],"confidence":"Medium","gaps":["Single cross-species assay; replication in a conspecific system would strengthen the conclusion","Whether CATSPERδ has additional roles beyond enabling hyperactivation during micropyle penetration is untested","Molecular mechanism by which hyperactivation facilitates micropyle crossing is not defined"]},{"year":null,"claim":"Key unresolved questions include the structural architecture of CATSPERδ within the CATSPER complex, whether CATSPERδ contributes to channel gating or solely to assembly/trafficking, and whether CATSPERD mutations cause human male infertility.","evidence":"","pmids":[],"confidence":"Low","gaps":["No high-resolution structural data for CATSPERδ or its interface with pore subunits","No human genetic studies directly linking CATSPERD variants to infertility in the timeline","Mechanism distinguishing assembly failure from trafficking failure in CATSPERδ-null sperm is unresolved"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0005198","term_label":"structural molecule activity","supporting_discovery_ids":[0]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[0]}],"pathway":[{"term_id":"R-HSA-1474165","term_label":"Reproduction","supporting_discovery_ids":[0,1]}],"complexes":["CATSPER channel complex"],"partners":["CATSPER1","CATSPER2","CATSPER3","CATSPER4"],"other_free_text":[]},"mechanistic_narrative":"CATSPERδ (encoded by CATSPERD/TMEM146) is an essential auxiliary subunit of the sperm-specific CATSPER Ca²⁺-selective channel complex; loss of CATSPERδ in knockout mice abolishes the sperm Ca²⁺ current and prevents hyperactivated motility, resulting in male infertility [PMID:21224844]. CATSPERδ is required for proper CATSPER channel assembly and/or trafficking to the sperm flagellum, and CATSPERδ-dependent hyperactivation is mechanistically necessary for sperm to interact with and penetrate the egg micropyle [PMID:21224844, PMID:41100162]."},"prefetch_data":{"uniprot":{"accession":"Q86XM0","full_name":"Cation channel sperm-associated auxiliary subunit delta","aliases":["Transmembrane protein 146"],"length_aa":798,"mass_kda":90.5,"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 CATSPER1 stability before intraflagellar transport and/or incorporation of the CatSper complex channel into the flagellar membrane","subcellular_location":"Cell projection, cilium, flagellum membrane","url":"https://www.uniprot.org/uniprotkb/Q86XM0/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/CATSPERD","classification":"Not Classified","n_dependent_lines":18,"n_total_lines":1208,"dependency_fraction":0.014900662251655629},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/CATSPERD","total_profiled":1310},"omim":[{"mim_id":"617510","title":"CATION CHANNEL, SPERM-ASSOCIATED, AUXILIARY SUBUNIT EPSILON; CATSPERE","url":"https://www.omim.org/entry/617510"},{"mim_id":"617490","title":"CATION CHANNEL, SPERM-ASSOCIATED, AUXILIARY SUBUNIT DELTA; CATSPERD","url":"https://www.omim.org/entry/617490"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Mid piece","reliability":"Approved"}],"tissue_specificity":"Tissue enriched","tissue_distribution":"Detected in single","driving_tissues":[{"tissue":"testis","ntpm":8.1}],"url":"https://www.proteinatlas.org/search/CATSPERD"},"hgnc":{"alias_symbol":["MGC39581"],"prev_symbol":["TMEM146"]},"alphafold":{"accession":"Q86XM0","domains":[{"cath_id":"-","chopping":"106-235","consensus_level":"medium","plddt":91.0618,"start":106,"end":235},{"cath_id":"2.60.40.2020","chopping":"390-509","consensus_level":"high","plddt":88.3852,"start":390,"end":509},{"cath_id":"-","chopping":"515-713","consensus_level":"high","plddt":93.4707,"start":515,"end":713}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q86XM0","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q86XM0-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q86XM0-F1-predicted_aligned_error_v6.png","plddt_mean":86.19},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=CATSPERD","jax_strain_url":"https://www.jax.org/strain/search?query=CATSPERD"},"sequence":{"accession":"Q86XM0","fasta_url":"https://rest.uniprot.org/uniprotkb/Q86XM0.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q86XM0/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q86XM0"}},"corpus_meta":[{"pmid":"21224844","id":"PMC_21224844","title":"A novel gene required for male fertility and functional CATSPER channel formation in spermatozoa.","date":"2011","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/21224844","citation_count":166,"is_preprint":false},{"pmid":"33100131","id":"PMC_33100131","title":"Epigenome-wide association study identifies DNA methylation sites associated with target organ damage in older African Americans.","date":"2020","source":"Epigenetics","url":"https://pubmed.ncbi.nlm.nih.gov/33100131","citation_count":18,"is_preprint":false},{"pmid":"36048845","id":"PMC_36048845","title":"Exome sequencing and functional analyses revealed CETN1 variants leads to impaired cell division and male fertility.","date":"2023","source":"Human molecular genetics","url":"https://pubmed.ncbi.nlm.nih.gov/36048845","citation_count":11,"is_preprint":false},{"pmid":"36672807","id":"PMC_36672807","title":"Identification of Circular RNAs of Testis and Caput Epididymis and Prediction of Their Potential Functional Roles in Donkeys.","date":"2022","source":"Genes","url":"https://pubmed.ncbi.nlm.nih.gov/36672807","citation_count":8,"is_preprint":false},{"pmid":"25481096","id":"PMC_25481096","title":"Identification of a novel isoform of the leukemia-associated MLLT1 (ENL/LTG19) protein.","date":"2014","source":"Gene expression patterns : GEP","url":"https://pubmed.ncbi.nlm.nih.gov/25481096","citation_count":3,"is_preprint":false},{"pmid":"35330493","id":"PMC_35330493","title":"Neoexpression of JUNO in Oral Tumors Is Accompanied with the Complete Suppression of Four Other Genes and Suggests the Application of New Biomarker Tools.","date":"2022","source":"Journal of personalized medicine","url":"https://pubmed.ncbi.nlm.nih.gov/35330493","citation_count":2,"is_preprint":false},{"pmid":"41100162","id":"PMC_41100162","title":"Cross-species insemination reveals mouse sperm ability to enter and cross the fish micropyle.","date":"2025","source":"eLife","url":"https://pubmed.ncbi.nlm.nih.gov/41100162","citation_count":0,"is_preprint":false},{"pmid":"41300787","id":"PMC_41300787","title":"Genome-Wide Association Study of First-Parity Reproductive Traits in Suzi Pig.","date":"2025","source":"Genes","url":"https://pubmed.ncbi.nlm.nih.gov/41300787","citation_count":0,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":5414,"output_tokens":589,"usd":0.012538},"stage2":{"model":"claude-opus-4-6","input_tokens":3786,"output_tokens":1038,"usd":0.06732},"total_usd":0.079858,"stage1_batch_id":"msgbatch_011kfMfE81o6CTcyhVUqumuW","stage2_batch_id":"msgbatch_01DTputS6WNkH745x1nVSoBo","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2011,\n      \"finding\": \"CATSPERD (encoded by Tmem146) is an essential auxiliary subunit of the CATSPER channel complex in sperm; mice lacking CATSPERδ are infertile, their spermatozoa lack Ca²⁺ current and hyperactivated motility, establishing CATSPERδ as required for proper CATSPER channel assembly and/or transport to the sperm tail.\",\n      \"method\": \"Gene knockout mouse model (loss-of-function), electrophysiology (Ca²⁺ current recording), motility assays, co-immunoprecipitation/complex analysis, sperm tail-specific expression characterization\",\n      \"journal\": \"Nature Communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — clean KO with defined cellular phenotype (loss of Ca²⁺ current, loss of hyperactivation, infertility), replicated across multiple functional readouts in a highly cited study\",\n      \"pmids\": [\"21224844\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"CATSPERδ-deficient mouse sperm, which fail to undergo hyperactivation, cannot interact with or cross the zebrafish micropyle, demonstrating that hyperactive motility dependent on the CATSPER channel (including CATSPERδ) is mechanistically required for sperm entry into the egg micropyle.\",\n      \"method\": \"Cross-species insemination assay using CatSperd knockout mouse sperm, confocal and electron microscopy\",\n      \"journal\": \"eLife\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — clean KO with specific functional phenotype in a novel assay, single study\",\n      \"pmids\": [\"41100162\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"CATSPERδ (CATSPERD/TMEM146) is an essential auxiliary subunit of the tetrameric CATSPER Ca²⁺-selective channel in the sperm tail; it is required for proper CATSPER channel assembly and/or trafficking, and its absence abolishes sperm Ca²⁺ current and hyperactivated motility, thereby causing male infertility and preventing sperm from crossing the egg's micropyle.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"CATSPERδ (encoded by CATSPERD/TMEM146) is an essential auxiliary subunit of the sperm-specific CATSPER Ca²⁺-selective channel complex; loss of CATSPERδ in knockout mice abolishes the sperm Ca²⁺ current and prevents hyperactivated motility, resulting in male infertility [PMID:21224844]. CATSPERδ is required for proper CATSPER channel assembly and/or trafficking to the sperm flagellum, and CATSPERδ-dependent hyperactivation is mechanistically necessary for sperm to interact with and penetrate the egg micropyle [PMID:21224844, PMID:41100162].\",\n  \"teleology\": [\n    {\n      \"year\": 2011,\n      \"claim\": \"Identification of CATSPERδ as an essential auxiliary subunit of the CATSPER channel resolved the question of whether additional non-pore-forming components are required for channel function, showing that its absence eliminates sperm Ca²⁺ current, hyperactivated motility, and fertility.\",\n      \"evidence\": \"Tmem146 knockout mouse with electrophysiology, motility assays, co-immunoprecipitation, and fertility assessment\",\n      \"pmids\": [\"21224844\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Structural basis of CATSPERδ interaction with the pore-forming CATSPER subunits is unknown\",\n        \"Whether CATSPERδ loss prevents channel assembly versus trafficking has not been resolved\",\n        \"Stoichiometry and topology of CATSPERδ within the channel complex remain undefined\"\n      ]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Demonstrating that CATSPERδ-deficient sperm cannot interact with or cross the egg micropyle established a direct functional link between CATSPER-dependent hyperactivation and the mechanical process of egg penetration.\",\n      \"evidence\": \"Cross-species insemination of CatSperd knockout mouse sperm with zebrafish eggs, confocal and electron microscopy\",\n      \"pmids\": [\"41100162\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Single cross-species assay; replication in a conspecific system would strengthen the conclusion\",\n        \"Whether CATSPERδ has additional roles beyond enabling hyperactivation during micropyle penetration is untested\",\n        \"Molecular mechanism by which hyperactivation facilitates micropyle crossing is not defined\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"Key unresolved questions include the structural architecture of CATSPERδ within the CATSPER complex, whether CATSPERδ contributes to channel gating or solely to assembly/trafficking, and whether CATSPERD mutations cause human male infertility.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"No high-resolution structural data for CATSPERδ or its interface with pore subunits\",\n        \"No human genetic studies directly linking CATSPERD variants to infertility in the timeline\",\n        \"Mechanism distinguishing assembly failure from trafficking failure in CATSPERδ-null sperm is unresolved\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\n        \"term_id\": \"GO:0005198\",\n        \"supporting_discovery_ids\": [0]\n      }\n    ],\n    \"localization\": [\n      {\n        \"term_id\": \"GO:0005886\",\n        \"supporting_discovery_ids\": [0]\n      }\n    ],\n    \"pathway\": [\n      {\n        \"term_id\": \"R-HSA-1474165\",\n        \"supporting_discovery_ids\": [0, 1]\n      }\n    ],\n    \"complexes\": [\n      \"CATSPER channel complex\"\n    ],\n    \"partners\": [\n      \"CATSPER1\",\n      \"CATSPER2\",\n      \"CATSPER3\",\n      \"CATSPER4\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}