{"gene":"CATSPERD","run_date":"2026-06-09T22:57:17","timeline":{"discoveries":[{"year":2011,"finding":"CATSPERD (encoded by Tmem146) is an essential auxiliary subunit of the CATSPER channel complex in spermatozoa. Mice lacking CATSPERδ are infertile, and their spermatozoa lack both Ca²⁺ current (CatSper current) and hyperactivated motility, establishing CATSPERδ as required for CATSPER channel assembly and/or transport to the sperm tail.","method":"Gene knockout mouse model with electrophysiology (Ca²⁺ current measurement), sperm motility analysis, and localization studies demonstrating sperm tail-specific expression","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 / Strong — clean KO mouse with defined cellular phenotypes (loss of Ca²⁺ current and hyperactivated motility), replicated across multiple functional readouts in a focused mechanistic study","pmids":["21224844"],"is_preprint":false},{"year":2025,"finding":"Hyperactivated motility dependent on CATSPERδ is required for sperm to locate and cross the fish micropyle during cross-species insemination. Sperm from CatSperd-null mice failed to interact with or cross the zebrafish micropyle, demonstrating that CATSPER-channel-dependent hyperactivation underlies this sperm motility function.","method":"Cross-species insemination assay using CatSperd knockout mouse sperm combined with confocal and electron microscopy","journal":"eLife","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — KO phenotype with clear functional readout in a defined assay, single lab, single study","pmids":["41100162"],"is_preprint":false}],"current_model":"CATSPERδ (CATSPERD/TMEM146) is a sperm tail-specific auxiliary subunit essential for assembly and/or membrane trafficking of the CATSPER Ca²⁺-selective channel complex; its absence abolishes the CatSper Ca²⁺ current and hyperactivated sperm motility, rendering males infertile."},"narrative":{"mechanistic_narrative":"CATSPERD (TMEM146/CATSPERδ) is a sperm tail-specific auxiliary subunit of the sperm CATSPER Ca²⁺-selective channel complex, required for the channel's assembly and/or trafficking to the flagellum [PMID:21224844]. Mice lacking CATSPERδ are infertile, and their spermatozoa lack the CatSper Ca²⁺ current and fail to undergo hyperactivated motility, establishing CATSPERδ as essential for functional channel formation [PMID:21224844]. This CATSPER-dependent hyperactivation drives flagellar motility behaviors needed for sperm to locate and penetrate the egg, including crossing the fish micropyle in a cross-species insemination assay [PMID:41100162]. Beyond its role in channel assembly and hyperactivated motility, no further molecular mechanism of CATSPERδ has been characterized in the available corpus.","teleology":[{"year":2011,"claim":"Established whether CATSPERδ is functionally required for the sperm Ca²⁺ channel, answering how loss of this subunit affects channel activity and fertility.","evidence":"Tmem146 knockout mouse with sperm electrophysiology, motility analysis, and localization studies","pmids":["21224844"],"confidence":"High","gaps":["Does not resolve whether CATSPERδ acts in channel assembly versus membrane trafficking","No structural model of how CATSPERδ integrates into the CATSPER complex","Direct binding partners within the complex not biochemically mapped"]},{"year":2025,"claim":"Defined a specific motility consequence of CATSPERδ-dependent hyperactivation, showing it is required for sperm to locate and cross a physical egg barrier.","evidence":"Cross-species insemination assay with CatSperd-null mouse sperm plus confocal and electron microscopy","pmids":["41100162"],"confidence":"Medium","gaps":["Single lab, single study with a heterologous (zebrafish micropyle) readout","Does not address physiological relevance in the native mammalian oviduct","Molecular link between Ca²⁺ current and the specific flagellar waveform not dissected"]},{"year":null,"claim":"The biochemical mechanism by which CATSPERδ promotes CATSPER channel assembly or trafficking, and its direct molecular partners, remain undefined.","evidence":"No further discoveries in the available corpus","pmids":[],"confidence":"Low","gaps":["No reconstitution or structural characterization of the CATSPERδ–channel interaction","No identified interacting subunits at residue resolution"]}],"mechanism_profile":{"molecular_activity":[],"localization":[],"pathway":[],"complexes":["CATSPER channel complex"],"partners":[],"other_free_text":[]}},"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":168,"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":19,"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":12,"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":6177,"output_tokens":588,"usd":0.013676,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":6959,"output_tokens":1086,"usd":0.030973,"stage2_stop_reason":"end_turn"},"total_usd":0.044649,"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\": 2011,\n      \"finding\": \"CATSPERD (encoded by Tmem146) is an essential auxiliary subunit of the CATSPER channel complex in spermatozoa. Mice lacking CATSPERδ are infertile, and their spermatozoa lack both Ca²⁺ current (CatSper current) and hyperactivated motility, establishing CATSPERδ as required for CATSPER channel assembly and/or transport to the sperm tail.\",\n      \"method\": \"Gene knockout mouse model with electrophysiology (Ca²⁺ current measurement), sperm motility analysis, and localization studies demonstrating sperm tail-specific expression\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — clean KO mouse with defined cellular phenotypes (loss of Ca²⁺ current and hyperactivated motility), replicated across multiple functional readouts in a focused mechanistic study\",\n      \"pmids\": [\"21224844\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Hyperactivated motility dependent on CATSPERδ is required for sperm to locate and cross the fish micropyle during cross-species insemination. Sperm from CatSperd-null mice failed to interact with or cross the zebrafish micropyle, demonstrating that CATSPER-channel-dependent hyperactivation underlies this sperm motility function.\",\n      \"method\": \"Cross-species insemination assay using CatSperd knockout mouse sperm combined with confocal and electron microscopy\",\n      \"journal\": \"eLife\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — KO phenotype with clear functional readout in a defined assay, single lab, single study\",\n      \"pmids\": [\"41100162\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"CATSPERδ (CATSPERD/TMEM146) is a sperm tail-specific auxiliary subunit essential for assembly and/or membrane trafficking of the CATSPER Ca²⁺-selective channel complex; its absence abolishes the CatSper Ca²⁺ current and hyperactivated sperm motility, rendering males infertile.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"CATSPERD (TMEM146/CATSPERδ) is a sperm tail-specific auxiliary subunit of the sperm CATSPER Ca²⁺-selective channel complex, required for the channel's assembly and/or trafficking to the flagellum [#0]. Mice lacking CATSPERδ are infertile, and their spermatozoa lack the CatSper Ca²⁺ current and fail to undergo hyperactivated motility, establishing CATSPERδ as essential for functional channel formation [#0]. This CATSPER-dependent hyperactivation drives flagellar motility behaviors needed for sperm to locate and penetrate the egg, including crossing the fish micropyle in a cross-species insemination assay [#1]. Beyond its role in channel assembly and hyperactivated motility, no further molecular mechanism of CATSPERδ has been characterized in the available corpus.\",\n  \"teleology\": [\n    {\n      \"year\": 2011,\n      \"claim\": \"Established whether CATSPERδ is functionally required for the sperm Ca²⁺ channel, answering how loss of this subunit affects channel activity and fertility.\",\n      \"evidence\": \"Tmem146 knockout mouse with sperm electrophysiology, motility analysis, and localization studies\",\n      \"pmids\": [\"21224844\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Does not resolve whether CATSPERδ acts in channel assembly versus membrane trafficking\",\n        \"No structural model of how CATSPERδ integrates into the CATSPER complex\",\n        \"Direct binding partners within the complex not biochemically mapped\"\n      ]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Defined a specific motility consequence of CATSPERδ-dependent hyperactivation, showing it is required for sperm to locate and cross a physical egg barrier.\",\n      \"evidence\": \"Cross-species insemination assay with CatSperd-null mouse sperm plus confocal and electron microscopy\",\n      \"pmids\": [\"41100162\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Single lab, single study with a heterologous (zebrafish micropyle) readout\",\n        \"Does not address physiological relevance in the native mammalian oviduct\",\n        \"Molecular link between Ca²⁺ current and the specific flagellar waveform not dissected\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The biochemical mechanism by which CATSPERδ promotes CATSPER channel assembly or trafficking, and its direct molecular partners, remain undefined.\",\n      \"evidence\": \"No further discoveries in the available corpus\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"No reconstitution or structural characterization of the CATSPERδ–channel interaction\",\n        \"No identified interacting subunits at residue resolution\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [],\n    \"localization\": [],\n    \"pathway\": [],\n    \"complexes\": [\"CATSPER channel complex\"],\n    \"partners\": [],\n    \"other_free_text\": []\n  }\n}\n```","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":3,"faith_total":3,"faith_pct":100.0}}