{"gene":"SPATA46","run_date":"2026-04-28T20:42:08","timeline":{"discoveries":[{"year":2016,"finding":"SPATA46 is a nuclear membrane protein expressed predominantly in condensed spermatids, localized to the subacrosomal area via a transmembrane region in its N-terminus. Knockout mice exhibit discontinuous nuclear envelope, nuclear cavities, abnormal sperm head shape, and failure of sperm-egg fusion, establishing SPATA46 as essential for sperm head reshaping and sperm-egg fusion.","method":"Spata46 knockout mouse model, immunolocalization, subcellular fractionation, anti-SPATA46 antibody inhibition assay, in vitro fertilization","journal":"Biology of reproduction","confidence":"High","confidence_rationale":"Tier 2 — clean KO with defined cellular phenotypes (nuclear envelope defects, acrosome/head shape, sperm-egg fusion) plus antibody inhibition in natural sperm, multiple orthogonal methods in single study","pmids":["27488028"],"is_preprint":false},{"year":2022,"finding":"SPATA46, as a nuclear envelope protein, interacts with the inner acrosomal membrane protein SPACA1 and the perinuclear theca protein ACTRT1 to anchor the developing acrosome to the nucleus during spermiogenesis.","method":"Co-immunoprecipitation, Actrt1-knockout mouse model with phenotypic rescue/interaction analysis","journal":"Development (Cambridge, England)","confidence":"Medium","confidence_rationale":"Tier 3 — single Co-IP identifying SPATA46 as an ACTRT1-interacting nuclear envelope partner, supported by KO phenotypic context","pmids":["35616329"],"is_preprint":false}],"current_model":"SPATA46 is a transmembrane nuclear envelope protein expressed in condensed spermatids that localizes to the subacrosomal region, where it is required for maintaining nuclear envelope integrity and sperm head morphology during spermiogenesis, anchors the developing acrosome to the nucleus through interactions with ACTRT1 and SPACA1, and is necessary for sperm-egg fusion."},"narrative":{"teleology":[{"year":2016,"claim":"Whether the uncharacterized spermatid protein SPATA46 has a functional role in spermiogenesis was unknown; knockout and antibody-blocking experiments established it as a transmembrane nuclear envelope protein required for nuclear envelope integrity, sperm head shaping, and sperm-egg fusion.","evidence":"Spata46-knockout mouse model with immunolocalization, subcellular fractionation, antibody inhibition, and IVF assays","pmids":["27488028"],"confidence":"High","gaps":["Molecular partners mediating SPATA46 function at the nuclear envelope were not identified","Mechanism by which SPATA46 loss disrupts sperm-egg fusion is unclear","Whether SPATA46 deficiency causes male infertility in humans was not tested"]},{"year":2022,"claim":"How the acrosome is physically anchored to the spermatid nucleus was unresolved; co-immunoprecipitation in the context of Actrt1-knockout phenotyping revealed that SPATA46 interacts with ACTRT1 and SPACA1 to bridge the nuclear envelope to the inner acrosomal membrane.","evidence":"Co-immunoprecipitation and Actrt1-knockout mouse phenotypic analysis","pmids":["35616329"],"confidence":"Medium","gaps":["Interaction validated by a single Co-IP without reciprocal pull-down or direct binding assay","Stoichiometry and structural basis of the SPATA46–ACTRT1–SPACA1 complex are unknown","Whether additional partners participate in acrosome–nucleus anchoring remains untested"]},{"year":null,"claim":"The precise mechanism by which SPATA46 loss leads to failure of sperm-egg fusion — independent of its structural role in head shaping — has not been dissected, nor have causative mutations been identified in human male infertility.","evidence":"","pmids":[],"confidence":"Low","gaps":["No human genetic data linking SPATA46 mutations to infertility","No structure of SPATA46 or its complexes","Functional separation of SPATA46's role in nuclear envelope integrity versus sperm-egg fusion has not been achieved"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0005198","term_label":"structural molecule activity","supporting_discovery_ids":[0,1]}],"localization":[{"term_id":"GO:0005635","term_label":"nuclear envelope","supporting_discovery_ids":[0,1]}],"pathway":[{"term_id":"R-HSA-1474165","term_label":"Reproduction","supporting_discovery_ids":[0]}],"complexes":[],"partners":["ACTRT1","SPACA1"],"other_free_text":[]},"mechanistic_narrative":"SPATA46 is a transmembrane nuclear envelope protein expressed in condensed spermatids that localizes to the subacrosomal region, where it is essential for maintaining nuclear envelope integrity, sperm head morphology, and sperm-egg fusion during spermiogenesis; knockout mice display discontinuous nuclear envelope, nuclear cavities, abnormal head shape, and fertilization failure [PMID:27488028]. SPATA46 bridges the nuclear envelope to the developing acrosome by interacting with the inner acrosomal membrane protein SPACA1 and the perinuclear theca protein ACTRT1, thereby anchoring the acrosome to the nucleus [PMID:35616329]."},"prefetch_data":{"uniprot":{"accession":"Q5T0L3","full_name":"Spermatogenesis-associated protein 46","aliases":[],"length_aa":261,"mass_kda":29.1,"function":"Plays a role in spermiogenesis and fertilization","subcellular_location":"Nucleus membrane","url":"https://www.uniprot.org/uniprotkb/Q5T0L3/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/SPATA46","classification":"Not Classified","n_dependent_lines":2,"n_total_lines":1208,"dependency_fraction":0.0016556291390728477},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/SPATA46","total_profiled":1310},"omim":[{"mim_id":"617257","title":"SPERMATOGENESIS-ASSOCIATED PROTEIN 46; SPATA46","url":"https://www.omim.org/entry/617257"},{"mim_id":"300487","title":"ACTIN-RELATED PROTEIN T1; ACTRT1","url":"https://www.omim.org/entry/300487"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"","locations":[],"tissue_specificity":"Tissue enriched","tissue_distribution":"Detected in some","driving_tissues":[{"tissue":"testis","ntpm":29.7}],"url":"https://www.proteinatlas.org/search/SPATA46"},"hgnc":{"alias_symbol":["TEKT2BP2"],"prev_symbol":["C1orf111"]},"alphafold":{"accession":"Q5T0L3","domains":[{"cath_id":"1.10.287","chopping":"183-233","consensus_level":"medium","plddt":88.969,"start":183,"end":233}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q5T0L3","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q5T0L3-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q5T0L3-F1-predicted_aligned_error_v6.png","plddt_mean":55.03},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=SPATA46","jax_strain_url":"https://www.jax.org/strain/search?query=SPATA46"},"sequence":{"accession":"Q5T0L3","fasta_url":"https://rest.uniprot.org/uniprotkb/Q5T0L3.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q5T0L3/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q5T0L3"}},"corpus_meta":[{"pmid":"30701647","id":"PMC_30701647","title":"Nuclear envelope dynamics during mammalian spermatogenesis: new insights on male fertility.","date":"2019","source":"Biological reviews of the Cambridge Philosophical Society","url":"https://pubmed.ncbi.nlm.nih.gov/30701647","citation_count":39,"is_preprint":false},{"pmid":"35616329","id":"PMC_35616329","title":"Loss of perinuclear theca ACTRT1 causes acrosome detachment and severe male subfertility in mice.","date":"2022","source":"Development (Cambridge, England)","url":"https://pubmed.ncbi.nlm.nih.gov/35616329","citation_count":29,"is_preprint":false},{"pmid":"24394471","id":"PMC_24394471","title":"Molecular cloning and subcellular localization of Tektin2-binding protein 1 (Ccdc 172) in rat spermatozoa.","date":"2014","source":"The journal of histochemistry and cytochemistry : official journal of the Histochemistry Society","url":"https://pubmed.ncbi.nlm.nih.gov/24394471","citation_count":21,"is_preprint":false},{"pmid":"27488028","id":"PMC_27488028","title":"Deficiency of SPATA46, a Novel Nuclear Membrane Protein, Causes Subfertility in Male Mice.","date":"2016","source":"Biology of reproduction","url":"https://pubmed.ncbi.nlm.nih.gov/27488028","citation_count":18,"is_preprint":false},{"pmid":"37833923","id":"PMC_37833923","title":"Comprehensive Analysis of the Transcriptome-Wide m6A Methylome in Shaziling Pig Testicular Development.","date":"2023","source":"International journal of molecular sciences","url":"https://pubmed.ncbi.nlm.nih.gov/37833923","citation_count":10,"is_preprint":false},{"pmid":"33064378","id":"PMC_33064378","title":"USP26 deubiquitinates androgen receptor (AR) in the maintenance of sperm maturation and spermatogenesis through the androgen receptor signaling pathway.","date":"2020","source":"Advances in clinical and experimental medicine : official organ Wroclaw Medical University","url":"https://pubmed.ncbi.nlm.nih.gov/33064378","citation_count":10,"is_preprint":false},{"pmid":"32405957","id":"PMC_32405957","title":"Transcriptomic profiling of long non-coding RNAs in non-virus associated hepatocellular carcinoma.","date":"2020","source":"Cell biochemistry and biophysics","url":"https://pubmed.ncbi.nlm.nih.gov/32405957","citation_count":3,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":4806,"output_tokens":573,"usd":0.011506},"stage2":{"model":"claude-opus-4-6","input_tokens":3736,"output_tokens":953,"usd":0.063757},"total_usd":0.075263,"stage1_batch_id":"msgbatch_011rkcQdVV1RaFq9XhcG6df6","stage2_batch_id":"msgbatch_01RzgrJafdF4EWHhj5mNi6dh","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2016,\n      \"finding\": \"SPATA46 is a nuclear membrane protein expressed predominantly in condensed spermatids, localized to the subacrosomal area via a transmembrane region in its N-terminus. Knockout mice exhibit discontinuous nuclear envelope, nuclear cavities, abnormal sperm head shape, and failure of sperm-egg fusion, establishing SPATA46 as essential for sperm head reshaping and sperm-egg fusion.\",\n      \"method\": \"Spata46 knockout mouse model, immunolocalization, subcellular fractionation, anti-SPATA46 antibody inhibition assay, in vitro fertilization\",\n      \"journal\": \"Biology of reproduction\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — clean KO with defined cellular phenotypes (nuclear envelope defects, acrosome/head shape, sperm-egg fusion) plus antibody inhibition in natural sperm, multiple orthogonal methods in single study\",\n      \"pmids\": [\"27488028\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"SPATA46, as a nuclear envelope protein, interacts with the inner acrosomal membrane protein SPACA1 and the perinuclear theca protein ACTRT1 to anchor the developing acrosome to the nucleus during spermiogenesis.\",\n      \"method\": \"Co-immunoprecipitation, Actrt1-knockout mouse model with phenotypic rescue/interaction analysis\",\n      \"journal\": \"Development (Cambridge, England)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — single Co-IP identifying SPATA46 as an ACTRT1-interacting nuclear envelope partner, supported by KO phenotypic context\",\n      \"pmids\": [\"35616329\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"SPATA46 is a transmembrane nuclear envelope protein expressed in condensed spermatids that localizes to the subacrosomal region, where it is required for maintaining nuclear envelope integrity and sperm head morphology during spermiogenesis, anchors the developing acrosome to the nucleus through interactions with ACTRT1 and SPACA1, and is necessary for sperm-egg fusion.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"SPATA46 is a transmembrane nuclear envelope protein expressed in condensed spermatids that localizes to the subacrosomal region, where it is essential for maintaining nuclear envelope integrity, sperm head morphology, and sperm-egg fusion during spermiogenesis; knockout mice display discontinuous nuclear envelope, nuclear cavities, abnormal head shape, and fertilization failure [PMID:27488028]. SPATA46 bridges the nuclear envelope to the developing acrosome by interacting with the inner acrosomal membrane protein SPACA1 and the perinuclear theca protein ACTRT1, thereby anchoring the acrosome to the nucleus [PMID:35616329].\",\n  \"teleology\": [\n    {\n      \"year\": 2016,\n      \"claim\": \"Whether the uncharacterized spermatid protein SPATA46 has a functional role in spermiogenesis was unknown; knockout and antibody-blocking experiments established it as a transmembrane nuclear envelope protein required for nuclear envelope integrity, sperm head shaping, and sperm-egg fusion.\",\n      \"evidence\": \"Spata46-knockout mouse model with immunolocalization, subcellular fractionation, antibody inhibition, and IVF assays\",\n      \"pmids\": [\"27488028\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Molecular partners mediating SPATA46 function at the nuclear envelope were not identified\",\n        \"Mechanism by which SPATA46 loss disrupts sperm-egg fusion is unclear\",\n        \"Whether SPATA46 deficiency causes male infertility in humans was not tested\"\n      ]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"How the acrosome is physically anchored to the spermatid nucleus was unresolved; co-immunoprecipitation in the context of Actrt1-knockout phenotyping revealed that SPATA46 interacts with ACTRT1 and SPACA1 to bridge the nuclear envelope to the inner acrosomal membrane.\",\n      \"evidence\": \"Co-immunoprecipitation and Actrt1-knockout mouse phenotypic analysis\",\n      \"pmids\": [\"35616329\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Interaction validated by a single Co-IP without reciprocal pull-down or direct binding assay\",\n        \"Stoichiometry and structural basis of the SPATA46–ACTRT1–SPACA1 complex are unknown\",\n        \"Whether additional partners participate in acrosome–nucleus anchoring remains untested\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The precise mechanism by which SPATA46 loss leads to failure of sperm-egg fusion — independent of its structural role in head shaping — has not been dissected, nor have causative mutations been identified in human male infertility.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"No human genetic data linking SPATA46 mutations to infertility\",\n        \"No structure of SPATA46 or its complexes\",\n        \"Functional separation of SPATA46's role in nuclear envelope integrity versus sperm-egg fusion has not been achieved\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0005198\", \"supporting_discovery_ids\": [0, 1]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005635\", \"supporting_discovery_ids\": [0, 1]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1474165\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"ACTRT1\", \"SPACA1\"],\n    \"other_free_text\": []\n  }\n}\n```"}