{"gene":"CATSPER4","run_date":"2026-04-28T17:28:52","timeline":{"discoveries":[{"year":2007,"finding":"Targeted disruption of murine CatSper4 abrogated the sperm-specific calcium current ICatSper, sperm hyperactivated motility, and male fertility without affecting spermatogenesis or initial motility, establishing CatSper4 as an essential pore-forming subunit of the flagellar CatSper channel complex.","method":"Gene knockout (targeted disruption), electrophysiology (ICatSper recording), sperm motility analysis, co-immunoprecipitation of CatSper proteins","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 1-2 — knockout phenotype with electrophysiological readout plus direct protein interaction data, replicated across multiple CatSper subunits in same study","pmids":["17227845"],"is_preprint":false},{"year":2007,"finding":"CatSper4 knockout male mice are completely infertile due to rapid loss of motility and absence of hyperactivated motility under capacitating conditions, confirming CatSper4 is required for sperm capacitation-associated hyperactivation.","method":"Gene knockout, computer-assisted sperm analysis (CASA), capacitation assay","journal":"Biology of reproduction","confidence":"High","confidence_rationale":"Tier 2 — independent replication of CatSper4 KO infertility phenotype with defined cellular readout","pmids":["17344468"],"is_preprint":false},{"year":2003,"finding":"CatSper4 contains a single channel-forming domain with the consensus pore-loop sequence TxDxW and a C-terminal coiled-coil domain predicted to mediate protein-protein interactions, supporting a heterotetrameric channel model with CatSper1-4.","method":"In silico gene identification, sequence/domain analysis, testis expression analysis","journal":"Reproductive biology and endocrinology : RB&E","confidence":"Medium","confidence_rationale":"Tier 3 — bioinformatic domain prediction with expression validation but no direct functional reconstitution","pmids":["12932298"],"is_preprint":false},{"year":2023,"finding":"CATSPERθ (Tmem249-encoded) serves as a scaffold for the pore-forming subunit CATSPER4 during CatSper channel assembly in sperm tail formation; CATSPERθ localizes at the interface of CatSper dimers and can self-interact, and its loss abolishes the entire CatSper channel from sperm flagella.","method":"Knockout mouse model, immunofluorescence localization, co-immunoprecipitation, Western blot, sperm motility and fertility assays","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 — KO mouse with defined channel assembly phenotype, direct protein interaction demonstrated, localization established with functional consequence","pmids":["37725640"],"is_preprint":false},{"year":2023,"finding":"Genetic abrogation of any CatSper transmembrane subunit (including CatSper4) results in loss of CATSPERθ protein in spermatid cells, indicating that intact CatSper subunits (including CATSPER4) are required for CATSPERθ stability during spermatogenesis and that CATSPERθ acts as a checkpoint for properly assembled CatSper channel trafficking to flagella.","method":"Knockout mouse model, Western blot in spermatids, immunofluorescence","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 — genetic epistasis with defined molecular readout (protein stability) in multiple KO lines","pmids":["37725640"],"is_preprint":false},{"year":2026,"finding":"The murine Catsper4 promoter contains a functional cAMP-responsive element (CRE) at +91 relative to the TSS, and CREMτ binds this element both in vitro and in vivo to regulate Catsper4 transcription; a core promoter spanning -99 to +63 bp was identified, and a 65 bp deletion at the 3'-end of the predicted promoter significantly enhanced transcription.","method":"Promoter-reporter assays, deletion analysis, electrophoretic mobility shift assay (EMSA), chromatin immunoprecipitation (ChIP), ChIP-seq data analysis (H3K4me3, H3K4me1, H3K27ac marks)","journal":"Reproductive sciences (Thousand Oaks, Calif.)","confidence":"Medium","confidence_rationale":"Tier 2 — EMSA and ChIP confirm CREMτ binding in vitro and in vivo, with functional promoter deletion analysis; single lab study","pmids":["41680579"],"is_preprint":false}],"current_model":"CATSPER4 is a sperm-specific, single-domain voltage-sensitive calcium channel subunit that assembles with CATSPER1-3 into a heterotetrameric channel complex in the sperm flagellum principal piece, where it is required for the alkalinization-activated calcium current (ICatSper), sperm hyperactivated motility, and male fertility; its assembly is scaffolded by CATSPERθ (Tmem249), and its transcription in spermatids is regulated by CREMτ binding to a CRE in its core promoter."},"narrative":{"teleology":[{"year":2003,"claim":"Identification of CATSPER4 as a fourth CatSper family member with a single channel-forming domain and predicted coiled-coil interaction motif established the molecular basis for a heterotetrameric channel model.","evidence":"In silico gene identification, domain/sequence analysis, testis expression profiling","pmids":["12932298"],"confidence":"Medium","gaps":["No functional reconstitution of the predicted channel","Stoichiometry and subunit arrangement within the tetramer not determined","No protein-level validation of domain assignments"]},{"year":2007,"claim":"Gene knockout demonstrated that CATSPER4 is essential for the sperm ICatSper calcium current, hyperactivated motility, and male fertility, resolving whether all four CatSper subunits are individually required for channel function.","evidence":"Targeted gene disruption in mice, patch-clamp electrophysiology of sperm ICatSper, co-immunoprecipitation, computer-assisted sperm motility analysis, fertility assays","pmids":["17227845","17344468"],"confidence":"High","gaps":["Channel gating mechanism and individual subunit contribution to pore conductance unknown","No structural data for the assembled CatSper complex","Human genetic confirmation of CATSPER4 loss-of-function causing infertility not yet reported"]},{"year":2023,"claim":"Discovery that CATSPERθ scaffolds CATSPER4 during channel assembly and that reciprocal dependence exists between pore subunits and CATSPERθ revealed a quality-control checkpoint for CatSper trafficking to flagella.","evidence":"CATSPERθ knockout mice, co-immunoprecipitation, immunofluorescence localization, Western blot in spermatids from multiple CatSper-subunit KO lines","pmids":["37725640"],"confidence":"High","gaps":["Direct binding interface between CATSPERθ and CATSPER4 not structurally resolved","Trafficking route from spermatid ER to flagellar membrane not mapped","Whether auxiliary subunits (β, γ, δ) also depend on CATSPERθ for assembly is unclear"]},{"year":2026,"claim":"Identification of a functional CRE in the CatSper4 promoter bound by CREMτ in spermatids established a transcriptional mechanism controlling CatSper4 expression during spermiogenesis.","evidence":"Promoter-reporter deletion analysis, EMSA, ChIP in mouse testis","pmids":["41680579"],"confidence":"Medium","gaps":["Single-lab study; independent replication pending","Whether CREMτ-dependent regulation extends to other CatSper subunit genes not tested","In vivo consequences of CRE mutation on CatSper4 protein levels and fertility not assessed"]},{"year":null,"claim":"The atomic structure of the CatSper heterotetrameric pore, the specific contribution of CATSPER4 to ion selectivity and gating, and the relevance of CATSPER4 mutations to human infertility remain unresolved.","evidence":"","pmids":[],"confidence":"High","gaps":["No high-resolution structure of the assembled CatSper channel","No human genetic studies directly linking CATSPER4 variants to male infertility","Mechanism by which alkalinization gates ICatSper through CATSPER4 is unknown"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0005215","term_label":"transporter activity","supporting_discovery_ids":[0,2]}],"localization":[{"term_id":"GO:0005929","term_label":"cilium","supporting_discovery_ids":[0,3]}],"pathway":[{"term_id":"R-HSA-1474165","term_label":"Reproduction","supporting_discovery_ids":[0,1]}],"complexes":["CatSper channel complex"],"partners":["CATSPER1","CATSPER2","CATSPER3","TMEM249"],"other_free_text":[]},"mechanistic_narrative":"CATSPER4 is an essential pore-forming subunit of the sperm-specific CatSper calcium channel, required for flagellar calcium influx, hyperactivated motility, and male fertility. It contains a single voltage-sensor-like channel domain with a conserved TxDxW pore-loop sequence and a C-terminal coiled-coil domain that mediates assembly into a heterotetrameric complex with CATSPER1–3 [PMID:12932298, PMID:17227845]. Targeted disruption of CatSper4 in mice abolishes the alkalinization-activated ICatSper current and causes complete male infertility without affecting spermatogenesis, demonstrating that CATSPER4 is indispensable for channel function [PMID:17227845, PMID:17344468]. Channel assembly in the sperm flagellum depends on the scaffold protein CATSPERθ (Tmem249), which directly interfaces with CATSPER4 at CatSper dimer junctions, while reciprocally, intact CATSPER4 is required for CATSPERθ protein stability [PMID:37725640]."},"prefetch_data":{"uniprot":{"accession":"Q7RTX7","full_name":"Cation channel sperm-associated protein 4","aliases":[],"length_aa":472,"mass_kda":54.1,"function":"Pore-forming subunit of the CatSper complex, a sperm-specific voltage-gated calcium channel that plays a central role in calcium-dependent physiological responses essential for successful fertilization, such as sperm hyperactivation, acrosome reaction and chemotaxis towards the oocyte","subcellular_location":"Cell projection, cilium, flagellum membrane","url":"https://www.uniprot.org/uniprotkb/Q7RTX7/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/CATSPER4","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/CATSPER4","total_profiled":1310},"omim":[{"mim_id":"613452","title":"CATION CHANNEL, SPERM-ASSOCIATED, AUXILIARY SUBUNIT GAMMA; CATSPERG","url":"https://www.omim.org/entry/613452"},{"mim_id":"611169","title":"CATION CHANNEL, SPERM-ASSOCIATED, AUXILIARY SUBUNIT BETA; CATSPERB","url":"https://www.omim.org/entry/611169"},{"mim_id":"609121","title":"CATION CHANNEL, SPERM-ASSOCIATED, 4; CATSPER4","url":"https://www.omim.org/entry/609121"},{"mim_id":"609120","title":"CATION CHANNEL, SPERM-ASSOCIATED, 3; CATSPER3","url":"https://www.omim.org/entry/609120"},{"mim_id":"607249","title":"CATION CHANNEL, SPERM-ASSOCIATED, 2; CATSPER2","url":"https://www.omim.org/entry/607249"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"","locations":[],"tissue_specificity":"Tissue enriched","tissue_distribution":"Detected in single","driving_tissues":[{"tissue":"testis","ntpm":11.0}],"url":"https://www.proteinatlas.org/search/CATSPER4"},"hgnc":{"alias_symbol":[],"prev_symbol":[]},"alphafold":{"accession":"Q7RTX7","domains":[{"cath_id":"1.20.120.350","chopping":"72-197","consensus_level":"high","plddt":77.7197,"start":72,"end":197},{"cath_id":"1.10.287.70","chopping":"208-319","consensus_level":"high","plddt":88.6695,"start":208,"end":319}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q7RTX7","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q7RTX7-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q7RTX7-F1-predicted_aligned_error_v6.png","plddt_mean":68.0},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=CATSPER4","jax_strain_url":"https://www.jax.org/strain/search?query=CATSPER4"},"sequence":{"accession":"Q7RTX7","fasta_url":"https://rest.uniprot.org/uniprotkb/Q7RTX7.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q7RTX7/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q7RTX7"}},"corpus_meta":[{"pmid":"17227845","id":"PMC_17227845","title":"All four CatSper ion channel proteins are required for male fertility and sperm cell hyperactivated motility.","date":"2007","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/17227845","citation_count":410,"is_preprint":false},{"pmid":"17344468","id":"PMC_17344468","title":"Catsper3 and Catsper4 are essential for sperm hyperactivated motility and male fertility in the mouse.","date":"2007","source":"Biology of reproduction","url":"https://pubmed.ncbi.nlm.nih.gov/17344468","citation_count":145,"is_preprint":false},{"pmid":"18340633","id":"PMC_18340633","title":"The mouse sperm proteome characterized via IPG strip prefractionation and LC-MS/MS identification.","date":"2008","source":"Proteomics","url":"https://pubmed.ncbi.nlm.nih.gov/18340633","citation_count":126,"is_preprint":false},{"pmid":"12932298","id":"PMC_12932298","title":"Identification of human and mouse CatSper3 and CatSper4 genes: characterisation of a common interaction domain and evidence for expression in testis.","date":"2003","source":"Reproductive biology and endocrinology : RB&E","url":"https://pubmed.ncbi.nlm.nih.gov/12932298","citation_count":119,"is_preprint":false},{"pmid":"21255775","id":"PMC_21255775","title":"A comprehensive gene mutation screen in men with asthenozoospermia.","date":"2011","source":"Fertility and sterility","url":"https://pubmed.ncbi.nlm.nih.gov/21255775","citation_count":31,"is_preprint":false},{"pmid":"37725640","id":"PMC_37725640","title":"A CUG-initiated CATSPERθ functions in the CatSper channel assembly and serves as a checkpoint for flagellar trafficking.","date":"2023","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/37725640","citation_count":19,"is_preprint":false},{"pmid":"34585662","id":"PMC_34585662","title":"Effect of freeze-thawing process on lipid peroxidation, miRNAs, ion channels, apoptosis and global DNA methylation in ram spermatozoa.","date":"2021","source":"Reproduction, fertility, and development","url":"https://pubmed.ncbi.nlm.nih.gov/34585662","citation_count":18,"is_preprint":false},{"pmid":"28948304","id":"PMC_28948304","title":"Histological analysis and identification of spermatogenesis-related genes in 2-, 6-, and 12-month-old sheep testes.","date":"2017","source":"Die Naturwissenschaften","url":"https://pubmed.ncbi.nlm.nih.gov/28948304","citation_count":18,"is_preprint":false},{"pmid":"33536540","id":"PMC_33536540","title":"Detection of selection signatures for response to Aleutian mink disease virus infection in American mink.","date":"2021","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/33536540","citation_count":18,"is_preprint":false},{"pmid":"21970684","id":"PMC_21970684","title":"Molecular cloning, spatial and temporal expression analysis of CatSper genes in the Chinese Meishan pigs.","date":"2011","source":"Reproductive biology and endocrinology : RB&E","url":"https://pubmed.ncbi.nlm.nih.gov/21970684","citation_count":10,"is_preprint":false},{"pmid":"37815627","id":"PMC_37815627","title":"Transcriptome Analysis Reveals Spermatogenesis-Related CircRNAs and LncRNAs in Goat Spermatozoa.","date":"2023","source":"Biochemical genetics","url":"https://pubmed.ncbi.nlm.nih.gov/37815627","citation_count":8,"is_preprint":false},{"pmid":"38038214","id":"PMC_38038214","title":"Reduction of cryopreservation-induced structural, functional and molecular damages in ram sperm by hydrated C60 fullerene.","date":"2023","source":"Reproduction in domestic animals = Zuchthygiene","url":"https://pubmed.ncbi.nlm.nih.gov/38038214","citation_count":4,"is_preprint":false},{"pmid":"36993167","id":"PMC_36993167","title":"A CUG-initiated CATSPERθ functions in the CatSper channel assembly and serves as a checkpoint for flagellar trafficking.","date":"2023","source":"bioRxiv : the preprint server for biology","url":"https://pubmed.ncbi.nlm.nih.gov/36993167","citation_count":3,"is_preprint":false},{"pmid":"39506588","id":"PMC_39506588","title":"Identification of Potential Biomarkers Associated with Spermatogenesis in Azoospermia.","date":"2024","source":"Clinical laboratory","url":"https://pubmed.ncbi.nlm.nih.gov/39506588","citation_count":2,"is_preprint":false},{"pmid":"36472830","id":"PMC_36472830","title":"In Silico Analysis of CatSper Family Genes and APOB Gene Regulation in Male Infertility.","date":"2022","source":"Advances in experimental medicine and biology","url":"https://pubmed.ncbi.nlm.nih.gov/36472830","citation_count":1,"is_preprint":false},{"pmid":"41680579","id":"PMC_41680579","title":"Molecular Characterization of the Murine Catsper4 Promoter and its Regulation by CREMτ.","date":"2026","source":"Reproductive sciences (Thousand Oaks, Calif.)","url":"https://pubmed.ncbi.nlm.nih.gov/41680579","citation_count":0,"is_preprint":false},{"pmid":"41043282","id":"PMC_41043282","title":"Integrated application of transcriptomics and metabolomics provides insights into sexual dimorphism in Apostichopus japonicus.","date":"2025","source":"Comparative biochemistry and physiology. Part D, Genomics & proteomics","url":"https://pubmed.ncbi.nlm.nih.gov/41043282","citation_count":0,"is_preprint":false},{"pmid":"41543154","id":"PMC_41543154","title":"<p>Echinacoside alleviates asthenozoospermia by upregulating Sox5‑mediated transcriptional activation of the CatSper gene</p>.","date":"2026","source":"Molecular medicine reports","url":"https://pubmed.ncbi.nlm.nih.gov/41543154","citation_count":0,"is_preprint":false},{"pmid":"41762345","id":"PMC_41762345","title":"Intraepididymal platelet-rich plasma improves semen cryoresistance via antioxidant, lipid and molecular modulation during the non-breeding season in rams.","date":"2026","source":"Veterinary research communications","url":"https://pubmed.ncbi.nlm.nih.gov/41762345","citation_count":0,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":12070,"output_tokens":1525,"usd":0.029542},"stage2":{"model":"claude-opus-4-6","input_tokens":4791,"output_tokens":1487,"usd":0.091695},"total_usd":0.121237,"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\": 2007,\n      \"finding\": \"Targeted disruption of murine CatSper4 abrogated the sperm-specific calcium current ICatSper, sperm hyperactivated motility, and male fertility without affecting spermatogenesis or initial motility, establishing CatSper4 as an essential pore-forming subunit of the flagellar CatSper channel complex.\",\n      \"method\": \"Gene knockout (targeted disruption), electrophysiology (ICatSper recording), sperm motility analysis, co-immunoprecipitation of CatSper proteins\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — knockout phenotype with electrophysiological readout plus direct protein interaction data, replicated across multiple CatSper subunits in same study\",\n      \"pmids\": [\"17227845\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"CatSper4 knockout male mice are completely infertile due to rapid loss of motility and absence of hyperactivated motility under capacitating conditions, confirming CatSper4 is required for sperm capacitation-associated hyperactivation.\",\n      \"method\": \"Gene knockout, computer-assisted sperm analysis (CASA), capacitation assay\",\n      \"journal\": \"Biology of reproduction\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — independent replication of CatSper4 KO infertility phenotype with defined cellular readout\",\n      \"pmids\": [\"17344468\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"CatSper4 contains a single channel-forming domain with the consensus pore-loop sequence TxDxW and a C-terminal coiled-coil domain predicted to mediate protein-protein interactions, supporting a heterotetrameric channel model with CatSper1-4.\",\n      \"method\": \"In silico gene identification, sequence/domain analysis, testis expression analysis\",\n      \"journal\": \"Reproductive biology and endocrinology : RB&E\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — bioinformatic domain prediction with expression validation but no direct functional reconstitution\",\n      \"pmids\": [\"12932298\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"CATSPERθ (Tmem249-encoded) serves as a scaffold for the pore-forming subunit CATSPER4 during CatSper channel assembly in sperm tail formation; CATSPERθ localizes at the interface of CatSper dimers and can self-interact, and its loss abolishes the entire CatSper channel from sperm flagella.\",\n      \"method\": \"Knockout mouse model, immunofluorescence localization, co-immunoprecipitation, Western blot, sperm motility and fertility assays\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — KO mouse with defined channel assembly phenotype, direct protein interaction demonstrated, localization established with functional consequence\",\n      \"pmids\": [\"37725640\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Genetic abrogation of any CatSper transmembrane subunit (including CatSper4) results in loss of CATSPERθ protein in spermatid cells, indicating that intact CatSper subunits (including CATSPER4) are required for CATSPERθ stability during spermatogenesis and that CATSPERθ acts as a checkpoint for properly assembled CatSper channel trafficking to flagella.\",\n      \"method\": \"Knockout mouse model, Western blot in spermatids, immunofluorescence\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — genetic epistasis with defined molecular readout (protein stability) in multiple KO lines\",\n      \"pmids\": [\"37725640\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"The murine Catsper4 promoter contains a functional cAMP-responsive element (CRE) at +91 relative to the TSS, and CREMτ binds this element both in vitro and in vivo to regulate Catsper4 transcription; a core promoter spanning -99 to +63 bp was identified, and a 65 bp deletion at the 3'-end of the predicted promoter significantly enhanced transcription.\",\n      \"method\": \"Promoter-reporter assays, deletion analysis, electrophoretic mobility shift assay (EMSA), chromatin immunoprecipitation (ChIP), ChIP-seq data analysis (H3K4me3, H3K4me1, H3K27ac marks)\",\n      \"journal\": \"Reproductive sciences (Thousand Oaks, Calif.)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — EMSA and ChIP confirm CREMτ binding in vitro and in vivo, with functional promoter deletion analysis; single lab study\",\n      \"pmids\": [\"41680579\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"CATSPER4 is a sperm-specific, single-domain voltage-sensitive calcium channel subunit that assembles with CATSPER1-3 into a heterotetrameric channel complex in the sperm flagellum principal piece, where it is required for the alkalinization-activated calcium current (ICatSper), sperm hyperactivated motility, and male fertility; its assembly is scaffolded by CATSPERθ (Tmem249), and its transcription in spermatids is regulated by CREMτ binding to a CRE in its core promoter.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"CATSPER4 is an essential pore-forming subunit of the sperm-specific CatSper calcium channel, required for flagellar calcium influx, hyperactivated motility, and male fertility. It contains a single voltage-sensor-like channel domain with a conserved TxDxW pore-loop sequence and a C-terminal coiled-coil domain that mediates assembly into a heterotetrameric complex with CATSPER1–3 [PMID:12932298, PMID:17227845]. Targeted disruption of CatSper4 in mice abolishes the alkalinization-activated ICatSper current and causes complete male infertility without affecting spermatogenesis, demonstrating that CATSPER4 is indispensable for channel function [PMID:17227845, PMID:17344468]. Channel assembly in the sperm flagellum depends on the scaffold protein CATSPERθ (Tmem249), which directly interfaces with CATSPER4 at CatSper dimer junctions, while reciprocally, intact CATSPER4 is required for CATSPERθ protein stability [PMID:37725640].\",\n  \"teleology\": [\n    {\n      \"year\": 2003,\n      \"claim\": \"Identification of CATSPER4 as a fourth CatSper family member with a single channel-forming domain and predicted coiled-coil interaction motif established the molecular basis for a heterotetrameric channel model.\",\n      \"evidence\": \"In silico gene identification, domain/sequence analysis, testis expression profiling\",\n      \"pmids\": [\"12932298\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"No functional reconstitution of the predicted channel\",\n        \"Stoichiometry and subunit arrangement within the tetramer not determined\",\n        \"No protein-level validation of domain assignments\"\n      ]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Gene knockout demonstrated that CATSPER4 is essential for the sperm ICatSper calcium current, hyperactivated motility, and male fertility, resolving whether all four CatSper subunits are individually required for channel function.\",\n      \"evidence\": \"Targeted gene disruption in mice, patch-clamp electrophysiology of sperm ICatSper, co-immunoprecipitation, computer-assisted sperm motility analysis, fertility assays\",\n      \"pmids\": [\"17227845\", \"17344468\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Channel gating mechanism and individual subunit contribution to pore conductance unknown\",\n        \"No structural data for the assembled CatSper complex\",\n        \"Human genetic confirmation of CATSPER4 loss-of-function causing infertility not yet reported\"\n      ]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Discovery that CATSPERθ scaffolds CATSPER4 during channel assembly and that reciprocal dependence exists between pore subunits and CATSPERθ revealed a quality-control checkpoint for CatSper trafficking to flagella.\",\n      \"evidence\": \"CATSPERθ knockout mice, co-immunoprecipitation, immunofluorescence localization, Western blot in spermatids from multiple CatSper-subunit KO lines\",\n      \"pmids\": [\"37725640\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Direct binding interface between CATSPERθ and CATSPER4 not structurally resolved\",\n        \"Trafficking route from spermatid ER to flagellar membrane not mapped\",\n        \"Whether auxiliary subunits (β, γ, δ) also depend on CATSPERθ for assembly is unclear\"\n      ]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Identification of a functional CRE in the CatSper4 promoter bound by CREMτ in spermatids established a transcriptional mechanism controlling CatSper4 expression during spermiogenesis.\",\n      \"evidence\": \"Promoter-reporter deletion analysis, EMSA, ChIP in mouse testis\",\n      \"pmids\": [\"41680579\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Single-lab study; independent replication pending\",\n        \"Whether CREMτ-dependent regulation extends to other CatSper subunit genes not tested\",\n        \"In vivo consequences of CRE mutation on CatSper4 protein levels and fertility not assessed\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The atomic structure of the CatSper heterotetrameric pore, the specific contribution of CATSPER4 to ion selectivity and gating, and the relevance of CATSPER4 mutations to human infertility remain unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"No high-resolution structure of the assembled CatSper channel\",\n        \"No human genetic studies directly linking CATSPER4 variants to male infertility\",\n        \"Mechanism by which alkalinization gates ICatSper through CATSPER4 is unknown\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0005215\", \"supporting_discovery_ids\": [0, 2]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005929\", \"supporting_discovery_ids\": [0, 3]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1474165\", \"supporting_discovery_ids\": [0, 1]}\n    ],\n    \"complexes\": [\n      \"CatSper channel complex\"\n    ],\n    \"partners\": [\n      \"CATSPER1\",\n      \"CATSPER2\",\n      \"CATSPER3\",\n      \"TMEM249\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}