{"gene":"FNDC8","run_date":"2026-04-28T17:46:04","timeline":{"discoveries":[{"year":2025,"finding":"FNDC8 is a testis-enriched protein localized to the perinuclear theca (PT) during spermiogenesis. Genetic disruption of Fndc8 in mice causes male infertility characterized by acrosome detachment from the nuclear membrane and sperm head surface collapse. FNDC8 physically interacts with CCIN and ACTL7A, and its depletion destabilizes both binding partners, indicating FNDC8 is integral to PT structural integrity by mediating protein interactions critical for sperm head morphogenesis.","method":"Knockout mouse model (loss-of-function), co-immunoprecipitation (interaction with CCIN and ACTL7A), subcellular localization by immunofluorescence, fertility/morphology phenotypic readout","journal":"Zoological research","confidence":"Medium","confidence_rationale":"Tier 2 — clean KO with defined cellular phenotype plus reciprocal protein interactions; single lab, single study","pmids":["41169243"],"is_preprint":false}],"current_model":"FNDC8 is a perinuclear theca-localized protein in spermatids that physically interacts with CCIN and ACTL7A to stabilize the perinuclear theca and ensure proper sperm head shaping during spermiogenesis; its loss causes acrosome detachment and sperm head collapse leading to male infertility."},"narrative":{"teleology":[{"year":2025,"claim":"The first functional characterization of FNDC8 established it as a PT-localized scaffolding protein required for sperm head morphogenesis, resolving that its loss leads to acrosome detachment, sperm head collapse, and male infertility through destabilization of CCIN and ACTL7A.","evidence":"Fndc8 knockout mouse with fertility, morphology, immunofluorescence localization, and co-immunoprecipitation assays","pmids":["41169243"],"confidence":"Medium","gaps":["Single-lab, single-study finding awaiting independent replication","Molecular basis of FNDC8–CCIN and FNDC8–ACTL7A interactions (e.g., domain mapping, structural data) is unknown","Whether FNDC8 has additional roles outside spermiogenesis or interacts with other PT components has not been explored"]},{"year":null,"claim":"It remains unknown how FNDC8 is recruited to the perinuclear theca, whether its fibronectin type III domain directly mediates its protein–protein interactions, and whether FNDC8 dysfunction contributes to human male infertility.","evidence":"","pmids":[],"confidence":"Low","gaps":["No structural or domain-function analysis of the FNIII domain in FNDC8","No human genetic or clinical data linking FNDC8 variants to infertility","Temporal hierarchy of PT assembly relative to FNDC8, CCIN, and ACTL7A is unresolved"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0005198","term_label":"structural molecule activity","supporting_discovery_ids":[0]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[0]}],"pathway":[{"term_id":"R-HSA-1474165","term_label":"Reproduction","supporting_discovery_ids":[0]}],"complexes":[],"partners":["CCIN","ACTL7A"],"other_free_text":[]},"mechanistic_narrative":"FNDC8 is a testis-enriched protein that localizes to the perinuclear theca (PT) of spermatids, where it physically interacts with CCIN and ACTL7A to maintain PT structural integrity during spermiogenesis [PMID:41169243]. Genetic disruption of Fndc8 in mice causes male infertility characterized by acrosome detachment from the nuclear membrane and sperm head surface collapse, with concomitant destabilization of its binding partners CCIN and ACTL7A [PMID:41169243]."},"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 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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,"source_track":"pubmed_title"},{"pmid":"12477932","id":"PMC_12477932","title":"Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences.","date":"2002","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/12477932","citation_count":1479,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"32296183","id":"PMC_32296183","title":"A reference map of the human binary protein interactome.","date":"2020","source":"Nature","url":"https://pubmed.ncbi.nlm.nih.gov/32296183","citation_count":849,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"33961781","id":"PMC_33961781","title":"Dual proteome-scale networks reveal 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Review.","date":"2022","source":"Medicine","url":"https://pubmed.ncbi.nlm.nih.gov/36626432","citation_count":19,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"38334954","id":"PMC_38334954","title":"DSBSO-Based XL-MS Analysis of Breast Cancer PDX Tissues to Delineate Protein Interaction Network in Clinical Samples.","date":"2024","source":"Journal of proteome research","url":"https://pubmed.ncbi.nlm.nih.gov/38334954","citation_count":7,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"40437099","id":"PMC_40437099","title":"EndoMAP.v1 charts the structural landscape of human early endosome complexes.","date":"2025","source":"Nature","url":"https://pubmed.ncbi.nlm.nih.gov/40437099","citation_count":6,"is_preprint":false,"source_track":"gene2pubmed"}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":1899,"output_tokens":390,"usd":0.005773},"stage2":{"model":"claude-opus-4-6","input_tokens":3538,"output_tokens":731,"usd":0.053948},"total_usd":0.126559,"stage1_batch_id":"msgbatch_0118RScg3WGaGkaZRtWZbtce","stage2_batch_id":"msgbatch_01Cpfzvtbj42aqp5oYZ5Te2s","note":"batch pricing = 50% of standard","round2_stage1":{"model":"claude-sonnet-4-6","input_tokens":5319,"output_tokens":389,"usd":0.010896},"round2_rules_fired":"R3","round2_stage2":{"model":"claude-opus-4-6","input_tokens":3779,"output_tokens":736,"usd":0.055942}},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2025,\n      \"finding\": \"FNDC8 is a testis-enriched protein localized to the perinuclear theca (PT) of sperm, where it interacts with CCIN and ACTL7A; genetic disruption of Fndc8 causes male infertility with acrosome detachment and sperm head collapse, and depletion of FNDC8 destabilizes both CCIN and ACTL7A, indicating FNDC8 is required for structural integrity of the PT during spermiogenesis.\",\n      \"method\": \"Genetic knockout mouse model (loss-of-function with defined phenotypic readout), co-immunoprecipitation (protein–protein interaction), subcellular localization by direct experiment (immunofluorescence/fractionation)\",\n      \"journal\": \"Zoological research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — clean KO with defined cellular phenotype plus reciprocal interaction data, but single lab, single study\",\n      \"pmids\": [\"41169243\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"FNDC8 is a testis-enriched perinuclear theca component that physically interacts with CCIN and ACTL7A to stabilize these proteins and maintain structural integrity of the perinuclear theca, thereby ensuring proper sperm head morphogenesis during spermiogenesis; loss of FNDC8 causes acrosome detachment, sperm head collapse, and male infertility.\"\n}\n```\n\n--- ROUND 2 (R2/R3, augmented corpus) ---\n\n```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2025,\n      \"finding\": \"FNDC8 is a testis-enriched protein localized to the perinuclear theca (PT) during spermiogenesis. Genetic disruption of Fndc8 in mice causes male infertility characterized by acrosome detachment from the nuclear membrane and sperm head surface collapse. FNDC8 physically interacts with CCIN and ACTL7A, and its depletion destabilizes both binding partners, indicating FNDC8 is integral to PT structural integrity by mediating protein interactions critical for sperm head morphogenesis.\",\n      \"method\": \"Knockout mouse model (loss-of-function), co-immunoprecipitation (interaction with CCIN and ACTL7A), subcellular localization by immunofluorescence, fertility/morphology phenotypic readout\",\n      \"journal\": \"Zoological research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — clean KO with defined cellular phenotype plus reciprocal protein interactions; single lab, single study\",\n      \"pmids\": [\"41169243\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"FNDC8 is a perinuclear theca-localized protein in spermatids that physically interacts with CCIN and ACTL7A to stabilize the perinuclear theca and ensure proper sperm head shaping during spermiogenesis; its loss causes acrosome detachment and sperm head collapse leading to male infertility.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"FNDC8 is a testis-enriched protein that localizes to the perinuclear theca (PT) of spermatids, where it physically interacts with CCIN and ACTL7A to stabilize these structural proteins and maintain PT integrity during spermiogenesis [PMID:41169243]. Genetic disruption of Fndc8 in mice causes acrosome detachment, sperm head collapse, and male infertility, establishing FNDC8 as essential for proper sperm head morphogenesis [PMID:41169243].\",\n  \"teleology\": [\n    {\n      \"year\": 2025,\n      \"claim\": \"The first functional characterization of FNDC8 established that it is a structural component of the perinuclear theca required for sperm head integrity, resolving the gene's biological role from an uncharacterized fibronectin domain-containing protein to a key scaffold that stabilizes CCIN and ACTL7A during spermiogenesis.\",\n      \"evidence\": \"Fndc8 knockout mouse model with fertility and morphological phenotyping, co-immunoprecipitation for CCIN and ACTL7A interactions, immunofluorescence and fractionation for PT localization\",\n      \"pmids\": [\"41169243\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Single study from one laboratory; independent replication is needed\",\n        \"The fibronectin type III domain's specific contribution to protein–protein interactions or structural function has not been dissected\",\n        \"Whether FNDC8 has functions outside spermiogenesis or in other tissues is unknown\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The molecular mechanism by which FNDC8 stabilizes CCIN and ACTL7A — whether through direct scaffolding, preventing degradation, or facilitating assembly — remains unresolved, and no structural model of the FNDC8-containing complex exists.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"No biochemical reconstitution of the FNDC8–CCIN–ACTL7A complex\",\n        \"No structural data for FNDC8 or the ternary complex\",\n        \"Human genetic validation linking FNDC8 mutations to male infertility is absent\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0005198\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [0]}\n    ],\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}\n```\n\n--- ROUND 2 (R2/R3, augmented corpus) ---\n\n```json\n{\n  \"mechanistic_narrative\": \"FNDC8 is a testis-enriched protein that localizes to the perinuclear theca (PT) of spermatids, where it physically interacts with CCIN and ACTL7A to maintain PT structural integrity during spermiogenesis [PMID:41169243]. Genetic disruption of Fndc8 in mice causes male infertility characterized by acrosome detachment from the nuclear membrane and sperm head surface collapse, with concomitant destabilization of its binding partners CCIN and ACTL7A [PMID:41169243].\",\n  \"teleology\": [\n    {\n      \"year\": 2025,\n      \"claim\": \"The first functional characterization of FNDC8 established it as a PT-localized scaffolding protein required for sperm head morphogenesis, resolving that its loss leads to acrosome detachment, sperm head collapse, and male infertility through destabilization of CCIN and ACTL7A.\",\n      \"evidence\": \"Fndc8 knockout mouse with fertility, morphology, immunofluorescence localization, and co-immunoprecipitation assays\",\n      \"pmids\": [\"41169243\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Single-lab, single-study finding awaiting independent replication\",\n        \"Molecular basis of FNDC8–CCIN and FNDC8–ACTL7A interactions (e.g., domain mapping, structural data) is unknown\",\n        \"Whether FNDC8 has additional roles outside spermiogenesis or interacts with other PT components has not been explored\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"It remains unknown how FNDC8 is recruited to the perinuclear theca, whether its fibronectin type III domain directly mediates its protein–protein interactions, and whether FNDC8 dysfunction contributes to human male infertility.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"No structural or domain-function analysis of the FNIII domain in FNDC8\",\n        \"No human genetic or clinical data linking FNDC8 variants to infertility\",\n        \"Temporal hierarchy of PT assembly relative to FNDC8, CCIN, and ACTL7A is unresolved\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0005198\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [0]}\n    ],\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}\n```"}