{"gene":"FNDC8","run_date":"2026-06-09T23:54:44","timeline":{"discoveries":[{"year":2025,"finding":"FNDC8 is a testis-enriched protein localized to the perinuclear theca (PT) during spermiogenesis, as determined by direct localization experiments; genetic disruption of Fndc8 in mice causes male infertility with acrosome detachment from the nuclear membrane and sperm head surface collapse, establishing a defined role for FNDC8 in PT structural integrity and sperm head morphogenesis.","method":"Genetic knockout (loss-of-function) with phenotypic readout (male infertility, acrosome detachment, sperm head collapse); subcellular localization experiments","journal":"Zoological research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — clean KO with defined cellular phenotype and direct localization, single lab, multiple orthogonal observations but no in vitro reconstitution or structural data","pmids":["41169243"],"is_preprint":false},{"year":2025,"finding":"FNDC8 physically interacts with CCIN and ACTL7A during spermiogenesis, and depletion of FNDC8 destabilizes both binding partners, indicating FNDC8 mediates protein interactions critical for PT integrity.","method":"Protein interaction assay (interaction identified experimentally); loss-of-function showing destabilization of CCIN and ACTL7A upon Fndc8 depletion","journal":"Zoological research","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — interaction and destabilization data from single lab, multiple partners tested, but abstract does not specify Co-IP or pulldown details explicitly","pmids":["41169243"],"is_preprint":false}],"current_model":"FNDC8 is a testis-enriched perinuclear theca (PT) protein that physically interacts with CCIN and ACTL7A to maintain PT structural integrity during spermiogenesis; its loss destabilizes both partners and causes acrosome detachment and sperm head collapse, leading to male infertility."},"narrative":{"mechanistic_narrative":"FNDC8 is a testis-enriched protein that localizes to the perinuclear theca (PT) during spermiogenesis and is required for sperm head morphogenesis [PMID:41169243]. It physically interacts with the PT components CCIN and ACTL7A, and its depletion destabilizes both partners, indicating that FNDC8 maintains PT structural integrity by scaffolding these interactions [PMID:41169243]. Genetic disruption of Fndc8 in mice causes acrosome detachment from the nuclear membrane and collapse of the sperm head surface, resulting in male infertility [PMID:41169243]. Beyond these localization, interaction, and loss-of-function findings [PMID:41169243], no further mechanistic detail — including biochemical activity, structural basis of binding, or interaction stoichiometry — has been characterized in the available corpus.","teleology":[{"year":2025,"claim":"Establishing where FNDC8 acts and what its loss does answered whether this testis-enriched protein has a defined cellular role in sperm formation.","evidence":"Subcellular localization experiments plus genetic knockout in mice with phenotypic readout (male infertility, acrosome detachment, sperm head collapse)","pmids":["41169243"],"confidence":"Medium","gaps":["No in vitro reconstitution or structural data defining how FNDC8 stabilizes PT architecture","Single-lab study without independent replication","Mechanism linking PT defect to acrosome detachment not resolved"]},{"year":2025,"claim":"Identifying CCIN and ACTL7A as FNDC8 partners answered how FNDC8 mediates PT integrity at the molecular level — by maintaining the stability of these binding partners.","evidence":"Protein interaction assay plus loss-of-function showing destabilization of CCIN and ACTL7A upon Fndc8 depletion","pmids":["41169243"],"confidence":"Medium","gaps":["Co-IP versus pulldown details and reciprocal validation not specified","Whether FNDC8 binds CCIN and ACTL7A directly or via a larger complex is unknown","Binding interfaces and stoichiometry uncharacterized"]},{"year":null,"claim":"The molecular activity of FNDC8 and the biochemical basis by which it stabilizes its PT partners remain unknown.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No enzymatic or structural activity assigned to FNDC8","No structural model of the FNDC8–CCIN–ACTL7A assembly","No human disease link established in the corpus"]}],"mechanism_profile":{"molecular_activity":[],"localization":[],"pathway":[{"term_id":"R-HSA-1474165","term_label":"Reproduction","supporting_discovery_ids":[0]}],"complexes":[],"partners":["CCIN","ACTL7A"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q8TC99","full_name":"Fibronectin type III domain-containing protein 8","aliases":[],"length_aa":324,"mass_kda":35.9,"function":"","subcellular_location":"","url":"https://www.uniprot.org/uniprotkb/Q8TC99/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/FNDC8","classification":"Not Classified","n_dependent_lines":1,"n_total_lines":1208,"dependency_fraction":0.0008278145695364238},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/FNDC8","total_profiled":1310},"omim":[{"mim_id":"621579","title":"FIBRONECTIN TYPE III DOMAIN-CONTAINING PROTEIN 8; FNDC8","url":"https://www.omim.org/entry/621579"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Cytosol","reliability":"Approved"}],"tissue_specificity":"Tissue enriched","tissue_distribution":"Detected in single","driving_tissues":[{"tissue":"testis","ntpm":86.3}],"url":"https://www.proteinatlas.org/search/FNDC8"},"hgnc":{"alias_symbol":["DKFZp434H2215"],"prev_symbol":[]},"alphafold":{"accession":"Q8TC99","domains":[{"cath_id":"2.60.40.10","chopping":"99-104_177-221_239-277","consensus_level":"medium","plddt":91.1504,"start":99,"end":277}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q8TC99","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q8TC99-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q8TC99-F1-predicted_aligned_error_v6.png","plddt_mean":59.97},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=FNDC8","jax_strain_url":"https://www.jax.org/strain/search?query=FNDC8"},"sequence":{"accession":"Q8TC99","fasta_url":"https://rest.uniprot.org/uniprotkb/Q8TC99.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q8TC99/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q8TC99"}},"corpus_meta":[{"pmid":"41169243","id":"PMC_41169243","title":"Perinuclear theca protein FNDC8 interacts with CCIN and ACTL7A to ensure proper sperm head shaping during spermiogenesis.","date":"2025","source":"Zoological research","url":"https://pubmed.ncbi.nlm.nih.gov/41169243","citation_count":0,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":2662,"output_tokens":567,"usd":0.008245,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":6889,"output_tokens":1112,"usd":0.031123,"stage2_stop_reason":"end_turn"},"total_usd":0.039368,"stage1_batch_id":"msgbatch_01AsR7g8dGTEiEw9U83bJeWn","stage2_batch_id":"msgbatch_01YV5ZyxtFNUZEjxRcpd9jzb","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2025,\n      \"finding\": \"FNDC8 is a testis-enriched protein localized to the perinuclear theca (PT) during spermiogenesis, as determined by direct localization experiments; genetic disruption of Fndc8 in mice causes male infertility with acrosome detachment from the nuclear membrane and sperm head surface collapse, establishing a defined role for FNDC8 in PT structural integrity and sperm head morphogenesis.\",\n      \"method\": \"Genetic knockout (loss-of-function) with phenotypic readout (male infertility, acrosome detachment, sperm head collapse); subcellular localization experiments\",\n      \"journal\": \"Zoological research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — clean KO with defined cellular phenotype and direct localization, single lab, multiple orthogonal observations but no in vitro reconstitution or structural data\",\n      \"pmids\": [\"41169243\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"FNDC8 physically interacts with CCIN and ACTL7A during spermiogenesis, and depletion of FNDC8 destabilizes both binding partners, indicating FNDC8 mediates protein interactions critical for PT integrity.\",\n      \"method\": \"Protein interaction assay (interaction identified experimentally); loss-of-function showing destabilization of CCIN and ACTL7A upon Fndc8 depletion\",\n      \"journal\": \"Zoological research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — interaction and destabilization data from single lab, multiple partners tested, but abstract does not specify Co-IP or pulldown details explicitly\",\n      \"pmids\": [\"41169243\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"FNDC8 is a testis-enriched perinuclear theca (PT) protein that physically interacts with CCIN and ACTL7A to maintain PT structural integrity during spermiogenesis; its loss destabilizes both partners and causes acrosome detachment and sperm head collapse, leading to male infertility.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"FNDC8 is a testis-enriched protein that localizes to the perinuclear theca (PT) during spermiogenesis and is required for sperm head morphogenesis [#0]. It physically interacts with the PT components CCIN and ACTL7A, and its depletion destabilizes both partners, indicating that FNDC8 maintains PT structural integrity by scaffolding these interactions [#1]. Genetic disruption of Fndc8 in mice causes acrosome detachment from the nuclear membrane and collapse of the sperm head surface, resulting in male infertility [#0]. Beyond these localization, interaction, and loss-of-function findings [#0, #1], no further mechanistic detail — including biochemical activity, structural basis of binding, or interaction stoichiometry — has been characterized in the available corpus.\",\n  \"teleology\": [\n    {\n      \"year\": 2025,\n      \"claim\": \"Establishing where FNDC8 acts and what its loss does answered whether this testis-enriched protein has a defined cellular role in sperm formation.\",\n      \"evidence\": \"Subcellular localization experiments plus genetic knockout in mice with phenotypic readout (male infertility, acrosome detachment, sperm head collapse)\",\n      \"pmids\": [\"41169243\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"No in vitro reconstitution or structural data defining how FNDC8 stabilizes PT architecture\",\n        \"Single-lab study without independent replication\",\n        \"Mechanism linking PT defect to acrosome detachment not resolved\"\n      ]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Identifying CCIN and ACTL7A as FNDC8 partners answered how FNDC8 mediates PT integrity at the molecular level — by maintaining the stability of these binding partners.\",\n      \"evidence\": \"Protein interaction assay plus loss-of-function showing destabilization of CCIN and ACTL7A upon Fndc8 depletion\",\n      \"pmids\": [\"41169243\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Co-IP versus pulldown details and reciprocal validation not specified\",\n        \"Whether FNDC8 binds CCIN and ACTL7A directly or via a larger complex is unknown\",\n        \"Binding interfaces and stoichiometry uncharacterized\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The molecular activity of FNDC8 and the biochemical basis by which it stabilizes its PT partners remain unknown.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"No enzymatic or structural activity assigned to FNDC8\",\n        \"No structural model of the FNDC8–CCIN–ACTL7A assembly\",\n        \"No human disease link established in the corpus\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [],\n    \"localization\": [],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1474165\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"CCIN\", \"ACTL7A\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"faith_supported":4,"faith_total":4,"faith_pct":100.0}}