{"gene":"ACTRT1","run_date":"2026-04-28T17:12:37","timeline":{"discoveries":[{"year":2017,"finding":"ACTRT1 (encoding ARP-T1) directly binds to the GLI1 promoter, thereby inhibiting GLI1 transcriptional expression and suppressing Hedgehog pathway activation; loss of ARP-T1 leads to aberrant Hedgehog signaling activation, and exogenous ACTRT1 expression reduces proliferation of cell lines with Hedgehog pathway activation in vitro and in vivo.","method":"Chromatin immunoprecipitation (ChIP) showing direct promoter binding; loss-of-function (mutations/enhancer RNA mutations) with GLI1 expression readout; in vitro and in vivo proliferation assays with ACTRT1 re-expression","journal":"Nature medicine","confidence":"High","confidence_rationale":"Tier 2 — direct promoter binding assay plus functional rescue experiments in multiple model systems, single rigorous study with multiple orthogonal methods","pmids":["28869610"],"is_preprint":false},{"year":2022,"finding":"ACTRT1 protein forms a multimeric complex with ACTRT2, ACTL7A, and ACTL9 in the subacrosomal region of spermatids, and localizes to the acroplaxome layer of the perinuclear theca; loss of ACTRT1 in Actrt1-knockout mice causes loosening of the acroplaxome, acrosome detachment from sperm nuclei, malformed sperm heads, reduced ACTL7A and PLCζ content, and severe subfertility.","method":"Co-immunoprecipitation to demonstrate multimeric complex; Actrt1-knockout mouse model with phenotypic analysis; immunofluorescence and western blotting for protein localization and content","journal":"Development (Cambridge, England)","confidence":"High","confidence_rationale":"Tier 2 — Co-IP for complex identification plus KO mouse with specific molecular and fertility phenotypes, multiple orthogonal methods in one study","pmids":["35616329"],"is_preprint":false},{"year":2022,"finding":"ACTRT1 anchors developing acrosomes to the nucleus by interacting with the inner acrosomal membrane protein SPACA1 and nuclear envelope proteins PARP11 and SPATA46; loss of ACTRT1 weakens the interaction between ACTL7A and SPACA1.","method":"Co-immunoprecipitation of ACTRT1 with SPACA1, PARP11, SPATA46; Actrt1-KO mice showing disrupted ACTL7A-SPACA1 interaction by co-IP","journal":"Development (Cambridge, England)","confidence":"Medium","confidence_rationale":"Tier 2/3 — Co-IP interactions with functional consequence in KO model, single lab study","pmids":["35616329"],"is_preprint":false},{"year":2021,"finding":"Pathogenic variants (whole-gene deletions) in ACTRT1 in human males cause acephalic spermatozoa syndrome, with acrosomal detachment and fertilization failure, consistent with Actrt1-KO mouse phenotype; ICSI combined with artificial oocyte activation rescued fertilization.","method":"Whole exome sequencing; Sanger confirmation; Actrt1-KO mouse phenotype comparison; western blot and immunostaining for ACTL7A and PLCζ","journal":"Frontiers in cell and developmental biology","confidence":"Medium","confidence_rationale":"Tier 2 — human loss-of-function variants with molecular validation and KO mouse corroboration, single lab","pmids":["34422805"],"is_preprint":false},{"year":2024,"finding":"ACTRT1 whole-gene deletion in human males leads to acrosomal ultrastructural defects (acrosome detachment), decreased ACTL7A and PLCζ expression in sperm, and fertilization failure; ICSI combined with artificial oocyte activation effectively overcame fertilization failure in one proband.","method":"Whole exome sequencing confirmed by whole genome sequencing and PCR; electron microscopy of sperm ultrastructure; western blot and immunostaining for ACTL7A and PLCζ","journal":"Human reproduction (Oxford, England)","confidence":"Medium","confidence_rationale":"Tier 2 — human deletion genetics with molecular and ultrastructural mechanistic readouts, independent replication of KO mouse findings in humans","pmids":["38414365"],"is_preprint":false},{"year":2021,"finding":"ARP-T1/ACTRT1 localizes to the midbody during cytokinesis and to the basal body of primary cilia during interphase; ARP-T1 interactome includes proteins involved in ciliogenesis, endosomal recycling, and septin ring formation; ACTRT1 knockdown reduces ciliary length, and tissue from BDCS patients with ARP-T1 mutations shows reduced ciliary length correlating with ARP-T1 levels.","method":"Immunofluorescence for subcellular localization; mass spectrometry-based interactome (PXD016557); siRNA knockdown with ciliary length measurement; patient tissue analysis","journal":"Communications biology","confidence":"Medium","confidence_rationale":"Tier 2/3 — direct localization experiments with functional consequence (cilia length) and interactome, single lab with multiple methods","pmids":["33972689"],"is_preprint":false},{"year":2002,"finding":"Arp-T1 (ACTRT1) and Arp-T2 are novel actin-related proteins specifically synthesized in the testis during late spermatid differentiation and localize to the calyx (cytoskeletal perinuclear theca) of mammalian sperm heads, identified as major acidic components of the calyx.","method":"Partial amino acid sequencing of calyx protein fractions; antibodies raised against human proteins; immunoblotting and immunofluorescence microscopy","journal":"Experimental cell research","confidence":"Medium","confidence_rationale":"Tier 2 — direct protein identification and subcellular localization by immunofluorescence and fractionation, foundational localization study","pmids":["12243744"],"is_preprint":false}],"current_model":"ACTRT1 encodes the actin-related protein ARP-T1, which forms a multimeric complex with ACTRT2, ACTL7A, and ACTL9 in the subacrosomal (acroplaxome) region of spermatids, anchoring developing acrosomes to the sperm nucleus via interactions with SPACA1, PARP11, and SPATA46; in somatic cells, ARP-T1 binds directly to the GLI1 promoter to repress Hedgehog pathway transcription, and localizes to the basal body of primary cilia to regulate ciliary length, such that loss of ACTRT1 causes both acrosome detachment/male infertility and aberrant Hedgehog/GLI1 activation underlying Bazex-Dupré-Christol syndrome and basal cell carcinoma."},"narrative":{"teleology":[{"year":2002,"claim":"The identity and sperm-specific localization of ARP-T1 were unknown; protein sequencing and immunostaining established ACTRT1 as a novel actin-related protein of the perinuclear theca (calyx) of mammalian spermatids, defining its structural context.","evidence":"Partial amino acid sequencing, immunoblotting, and immunofluorescence of calyx protein fractions from mammalian sperm","pmids":["12243744"],"confidence":"Medium","gaps":["No functional studies performed; role of ARP-T1 in sperm biology was unknown","Binding partners within the calyx were not identified","Expression and function in somatic cells were not explored"]},{"year":2017,"claim":"The somatic function of ACTRT1 was uncharacterized; ChIP and functional rescue experiments demonstrated that ARP-T1 directly binds the GLI1 promoter to repress Hedgehog pathway transcription, linking ACTRT1 loss-of-function to Bazex-Dupré-Christol syndrome and basal cell carcinoma.","evidence":"ChIP for direct GLI1 promoter binding; loss-of-function mutations with GLI1 expression readout; in vitro and in vivo proliferation assays with ACTRT1 re-expression","pmids":["28869610"],"confidence":"High","gaps":["Mechanism by which an actin-related protein binds DNA and represses transcription was not resolved","Structural basis for ARP-T1 interaction with the GLI1 promoter was not determined","Whether transcriptional repression extends to other Hedgehog target genes was not tested"]},{"year":2021,"claim":"The subcellular localization and function of ACTRT1 in non-germ somatic cells beyond transcriptional repression were unclear; localization studies revealed ARP-T1 at the basal body of primary cilia and midbody during cytokinesis, and knockdown demonstrated a role in regulating ciliary length.","evidence":"Immunofluorescence for localization; mass spectrometry interactome; siRNA knockdown with ciliary length measurement; analysis of patient tissue from BDCS individuals","pmids":["33972689"],"confidence":"Medium","gaps":["The interactome was identified by mass spectrometry without extensive reciprocal validation of individual interactions","Mechanism by which basal body-localized ARP-T1 controls ciliary length was not established","Relationship between ciliary length regulation and Hedgehog pathway repression was not resolved"]},{"year":2021,"claim":"Whether ACTRT1 loss causes human male infertility was unknown; whole-exome sequencing identified whole-gene ACTRT1 deletions in men with acephalic spermatozoa syndrome, with acrosomal detachment and fertilization failure mirroring the Actrt1-KO mouse.","evidence":"Whole exome sequencing with Sanger confirmation; western blot and immunostaining for ACTL7A and PLCζ; comparison with Actrt1-KO mouse phenotype","pmids":["34422805"],"confidence":"Medium","gaps":["Observed in a small number of probands from a single study","Whether partial loss-of-function mutations also cause infertility was not addressed","Molecular rescue in human sperm was not attempted"]},{"year":2022,"claim":"The molecular composition and structural role of the ACTRT1 complex in spermatids were undefined; co-IP and knockout studies established that ACTRT1 forms a multimeric complex with ACTRT2, ACTL7A, and ACTL9 and bridges the acrosome to the nucleus via interactions with SPACA1, PARP11, and SPATA46.","evidence":"Co-immunoprecipitation for complex identification; Actrt1-knockout mouse with phenotypic, immunofluorescence, and western blot analyses","pmids":["35616329"],"confidence":"High","gaps":["Stoichiometry and structure of the ACTRT1-containing complex are unknown","Whether ACTRT1 directly binds each partner or acts through ACTL7A was not fully distinguished","How the complex mechanically resists acrosomal detachment forces is not resolved"]},{"year":2024,"claim":"Independent replication in human patients confirmed that ACTRT1 whole-gene deletion causes acrosomal ultrastructural defects with decreased ACTL7A and PLCζ expression, and demonstrated that ICSI with artificial oocyte activation can rescue fertilization failure.","evidence":"WES confirmed by WGS and PCR; electron microscopy of sperm ultrastructure; western blot and immunostaining","pmids":["38414365"],"confidence":"Medium","gaps":["Number of reported families remains small","Genotype-phenotype correlation for hypomorphic alleles is not established","Whether PLCζ reduction is a direct or indirect consequence of ACTRT1 loss is unknown"]},{"year":null,"claim":"The structural basis for ARP-T1's dual roles — as a cytoskeletal scaffold in spermatid acroplaxomes and as a DNA-binding transcriptional repressor in somatic cells — remains unresolved, and no structure of the ACTRT1-containing complex or ARP-T1–DNA interface has been determined.","evidence":"","pmids":[],"confidence":"Low","gaps":["No crystal or cryo-EM structure of ACTRT1 or its complexes exists","The DNA-binding domain or motif in ARP-T1 is unidentified","How basal body localization, ciliary length regulation, and GLI1 promoter repression are mechanistically coordinated is unknown"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0003677","term_label":"DNA binding","supporting_discovery_ids":[0]},{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[0]},{"term_id":"GO:0005198","term_label":"structural molecule activity","supporting_discovery_ids":[1,2,6]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[0,1,2]},{"term_id":"GO:0005815","term_label":"microtubule organizing center","supporting_discovery_ids":[5]},{"term_id":"GO:0005929","term_label":"cilium","supporting_discovery_ids":[5]},{"term_id":"GO:0005856","term_label":"cytoskeleton","supporting_discovery_ids":[1,6]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[0,5]},{"term_id":"R-HSA-1474165","term_label":"Reproduction","supporting_discovery_ids":[1,2,3,4]}],"complexes":["ACTRT1-ACTRT2-ACTL7A-ACTL9 acroplaxome complex"],"partners":["ACTRT2","ACTL7A","ACTL9","SPACA1","PARP11","SPATA46"],"other_free_text":[]},"mechanistic_narrative":"ACTRT1 encodes actin-related protein ARP-T1, which functions as a structural scaffold in the sperm acroplaxome and as a transcriptional repressor of Hedgehog signaling in somatic cells. In spermatids, ACTRT1 forms a multimeric complex with ACTRT2, ACTL7A, and ACTL9 in the subacrosomal perinuclear theca and anchors the developing acrosome to the sperm nucleus through interactions with the inner acrosomal membrane protein SPACA1 and nuclear envelope proteins PARP11 and SPATA46; loss of ACTRT1 causes acrosome detachment, malformed sperm heads, and male infertility in mice and humans [PMID:35616329, PMID:34422805, PMID:38414365]. In somatic cells, ARP-T1 directly binds the GLI1 promoter to repress Hedgehog pathway transcription, and loss-of-function mutations lead to aberrant GLI1 activation underlying Bazex-Dupré-Christol syndrome and basal cell carcinoma susceptibility [PMID:28869610]. ACTRT1 also localizes to the basal body of primary cilia and regulates ciliary length, with knockdown or patient mutations resulting in shortened cilia [PMID:33972689]."},"prefetch_data":{"uniprot":{"accession":"Q8TDG2","full_name":"Actin-related protein T1","aliases":[],"length_aa":376,"mass_kda":41.7,"function":"Negatively regulates the Hedgehog (SHH) signaling. Binds to the promoter of the SHH signaling mediator, GLI1, and inhibits its expression","subcellular_location":"Cytoplasm, cytoskeleton; Cytoplasm; Nucleus; Cytoplasmic vesicle, secretory vesicle, acrosome","url":"https://www.uniprot.org/uniprotkb/Q8TDG2/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/ACTRT1","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/ACTRT1","total_profiled":1310},"omim":[{"mim_id":"301845","title":"BAZEX-DUPRE-CHRISTOL SYNDROME; BDCS","url":"https://www.omim.org/entry/301845"},{"mim_id":"300768","title":"CYLICIN 1; CYLC1","url":"https://www.omim.org/entry/300768"},{"mim_id":"300487","title":"ACTIN-RELATED PROTEIN T1; ACTRT1","url":"https://www.omim.org/entry/300487"},{"mim_id":"258150","title":"SPERMATOGENIC FAILURE 1; SPGF1","url":"https://www.omim.org/entry/258150"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"","locations":[],"tissue_specificity":"Tissue enriched","tissue_distribution":"Detected in single","driving_tissues":[{"tissue":"testis","ntpm":3.9}],"url":"https://www.proteinatlas.org/search/ACTRT1"},"hgnc":{"alias_symbol":["AIP1","KIAA0705","ARIP1","Arp-T1"],"prev_symbol":[]},"alphafold":{"accession":"Q8TDG2","domains":[{"cath_id":"3.30.420.40","chopping":"5-143_341-375","consensus_level":"medium","plddt":92.5844,"start":5,"end":375},{"cath_id":"3.30.420.40","chopping":"149-184_273-337","consensus_level":"medium","plddt":96.9569,"start":149,"end":337},{"cath_id":"3.90.640.10","chopping":"186-263","consensus_level":"high","plddt":90.7255,"start":186,"end":263}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q8TDG2","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q8TDG2-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q8TDG2-F1-predicted_aligned_error_v6.png","plddt_mean":93.06},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=ACTRT1","jax_strain_url":"https://www.jax.org/strain/search?query=ACTRT1"},"sequence":{"accession":"Q8TDG2","fasta_url":"https://rest.uniprot.org/uniprotkb/Q8TDG2.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q8TDG2/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q8TDG2"}},"corpus_meta":[{"pmid":"14505569","id":"PMC_14505569","title":"AIP1/ALIX 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loss of ARP-T1 leads to aberrant Hedgehog signaling activation, and exogenous ACTRT1 expression reduces proliferation of cell lines with Hedgehog pathway activation in vitro and in vivo.\",\n      \"method\": \"Chromatin immunoprecipitation (ChIP) showing direct promoter binding; loss-of-function (mutations/enhancer RNA mutations) with GLI1 expression readout; in vitro and in vivo proliferation assays with ACTRT1 re-expression\",\n      \"journal\": \"Nature medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — direct promoter binding assay plus functional rescue experiments in multiple model systems, single rigorous study with multiple orthogonal methods\",\n      \"pmids\": [\"28869610\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"ACTRT1 protein forms a multimeric complex with ACTRT2, ACTL7A, and ACTL9 in the subacrosomal region of spermatids, and localizes to the acroplaxome layer of the perinuclear theca; loss of ACTRT1 in Actrt1-knockout mice causes loosening of the acroplaxome, acrosome detachment from sperm nuclei, malformed sperm heads, reduced ACTL7A and PLCζ content, and severe subfertility.\",\n      \"method\": \"Co-immunoprecipitation to demonstrate multimeric complex; Actrt1-knockout mouse model with phenotypic analysis; immunofluorescence and western blotting for protein localization and content\",\n      \"journal\": \"Development (Cambridge, England)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — Co-IP for complex identification plus KO mouse with specific molecular and fertility phenotypes, multiple orthogonal methods in one study\",\n      \"pmids\": [\"35616329\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"ACTRT1 anchors developing acrosomes to the nucleus by interacting with the inner acrosomal membrane protein SPACA1 and nuclear envelope proteins PARP11 and SPATA46; loss of ACTRT1 weakens the interaction between ACTL7A and SPACA1.\",\n      \"method\": \"Co-immunoprecipitation of ACTRT1 with SPACA1, PARP11, SPATA46; Actrt1-KO mice showing disrupted ACTL7A-SPACA1 interaction by co-IP\",\n      \"journal\": \"Development (Cambridge, England)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2/3 — Co-IP interactions with functional consequence in KO model, single lab study\",\n      \"pmids\": [\"35616329\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Pathogenic variants (whole-gene deletions) in ACTRT1 in human males cause acephalic spermatozoa syndrome, with acrosomal detachment and fertilization failure, consistent with Actrt1-KO mouse phenotype; ICSI combined with artificial oocyte activation rescued fertilization.\",\n      \"method\": \"Whole exome sequencing; Sanger confirmation; Actrt1-KO mouse phenotype comparison; western blot and immunostaining for ACTL7A and PLCζ\",\n      \"journal\": \"Frontiers in cell and developmental biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — human loss-of-function variants with molecular validation and KO mouse corroboration, single lab\",\n      \"pmids\": [\"34422805\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"ACTRT1 whole-gene deletion in human males leads to acrosomal ultrastructural defects (acrosome detachment), decreased ACTL7A and PLCζ expression in sperm, and fertilization failure; ICSI combined with artificial oocyte activation effectively overcame fertilization failure in one proband.\",\n      \"method\": \"Whole exome sequencing confirmed by whole genome sequencing and PCR; electron microscopy of sperm ultrastructure; western blot and immunostaining for ACTL7A and PLCζ\",\n      \"journal\": \"Human reproduction (Oxford, England)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — human deletion genetics with molecular and ultrastructural mechanistic readouts, independent replication of KO mouse findings in humans\",\n      \"pmids\": [\"38414365\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"ARP-T1/ACTRT1 localizes to the midbody during cytokinesis and to the basal body of primary cilia during interphase; ARP-T1 interactome includes proteins involved in ciliogenesis, endosomal recycling, and septin ring formation; ACTRT1 knockdown reduces ciliary length, and tissue from BDCS patients with ARP-T1 mutations shows reduced ciliary length correlating with ARP-T1 levels.\",\n      \"method\": \"Immunofluorescence for subcellular localization; mass spectrometry-based interactome (PXD016557); siRNA knockdown with ciliary length measurement; patient tissue analysis\",\n      \"journal\": \"Communications biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2/3 — direct localization experiments with functional consequence (cilia length) and interactome, single lab with multiple methods\",\n      \"pmids\": [\"33972689\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"Arp-T1 (ACTRT1) and Arp-T2 are novel actin-related proteins specifically synthesized in the testis during late spermatid differentiation and localize to the calyx (cytoskeletal perinuclear theca) of mammalian sperm heads, identified as major acidic components of the calyx.\",\n      \"method\": \"Partial amino acid sequencing of calyx protein fractions; antibodies raised against human proteins; immunoblotting and immunofluorescence microscopy\",\n      \"journal\": \"Experimental cell research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — direct protein identification and subcellular localization by immunofluorescence and fractionation, foundational localization study\",\n      \"pmids\": [\"12243744\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"ACTRT1 encodes the actin-related protein ARP-T1, which forms a multimeric complex with ACTRT2, ACTL7A, and ACTL9 in the subacrosomal (acroplaxome) region of spermatids, anchoring developing acrosomes to the sperm nucleus via interactions with SPACA1, PARP11, and SPATA46; in somatic cells, ARP-T1 binds directly to the GLI1 promoter to repress Hedgehog pathway transcription, and localizes to the basal body of primary cilia to regulate ciliary length, such that loss of ACTRT1 causes both acrosome detachment/male infertility and aberrant Hedgehog/GLI1 activation underlying Bazex-Dupré-Christol syndrome and basal cell carcinoma.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"ACTRT1 encodes actin-related protein ARP-T1, which functions as a structural scaffold in the sperm acroplaxome and as a transcriptional repressor of Hedgehog signaling in somatic cells. In spermatids, ACTRT1 forms a multimeric complex with ACTRT2, ACTL7A, and ACTL9 in the subacrosomal perinuclear theca and anchors the developing acrosome to the sperm nucleus through interactions with the inner acrosomal membrane protein SPACA1 and nuclear envelope proteins PARP11 and SPATA46; loss of ACTRT1 causes acrosome detachment, malformed sperm heads, and male infertility in mice and humans [PMID:35616329, PMID:34422805, PMID:38414365]. In somatic cells, ARP-T1 directly binds the GLI1 promoter to repress Hedgehog pathway transcription, and loss-of-function mutations lead to aberrant GLI1 activation underlying Bazex-Dupré-Christol syndrome and basal cell carcinoma susceptibility [PMID:28869610]. ACTRT1 also localizes to the basal body of primary cilia and regulates ciliary length, with knockdown or patient mutations resulting in shortened cilia [PMID:33972689].\",\n  \"teleology\": [\n    {\n      \"year\": 2002,\n      \"claim\": \"The identity and sperm-specific localization of ARP-T1 were unknown; protein sequencing and immunostaining established ACTRT1 as a novel actin-related protein of the perinuclear theca (calyx) of mammalian spermatids, defining its structural context.\",\n      \"evidence\": \"Partial amino acid sequencing, immunoblotting, and immunofluorescence of calyx protein fractions from mammalian sperm\",\n      \"pmids\": [\"12243744\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"No functional studies performed; role of ARP-T1 in sperm biology was unknown\",\n        \"Binding partners within the calyx were not identified\",\n        \"Expression and function in somatic cells were not explored\"\n      ]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"The somatic function of ACTRT1 was uncharacterized; ChIP and functional rescue experiments demonstrated that ARP-T1 directly binds the GLI1 promoter to repress Hedgehog pathway transcription, linking ACTRT1 loss-of-function to Bazex-Dupré-Christol syndrome and basal cell carcinoma.\",\n      \"evidence\": \"ChIP for direct GLI1 promoter binding; loss-of-function mutations with GLI1 expression readout; in vitro and in vivo proliferation assays with ACTRT1 re-expression\",\n      \"pmids\": [\"28869610\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Mechanism by which an actin-related protein binds DNA and represses transcription was not resolved\",\n        \"Structural basis for ARP-T1 interaction with the GLI1 promoter was not determined\",\n        \"Whether transcriptional repression extends to other Hedgehog target genes was not tested\"\n      ]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"The subcellular localization and function of ACTRT1 in non-germ somatic cells beyond transcriptional repression were unclear; localization studies revealed ARP-T1 at the basal body of primary cilia and midbody during cytokinesis, and knockdown demonstrated a role in regulating ciliary length.\",\n      \"evidence\": \"Immunofluorescence for localization; mass spectrometry interactome; siRNA knockdown with ciliary length measurement; analysis of patient tissue from BDCS individuals\",\n      \"pmids\": [\"33972689\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"The interactome was identified by mass spectrometry without extensive reciprocal validation of individual interactions\",\n        \"Mechanism by which basal body-localized ARP-T1 controls ciliary length was not established\",\n        \"Relationship between ciliary length regulation and Hedgehog pathway repression was not resolved\"\n      ]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Whether ACTRT1 loss causes human male infertility was unknown; whole-exome sequencing identified whole-gene ACTRT1 deletions in men with acephalic spermatozoa syndrome, with acrosomal detachment and fertilization failure mirroring the Actrt1-KO mouse.\",\n      \"evidence\": \"Whole exome sequencing with Sanger confirmation; western blot and immunostaining for ACTL7A and PLCζ; comparison with Actrt1-KO mouse phenotype\",\n      \"pmids\": [\"34422805\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Observed in a small number of probands from a single study\",\n        \"Whether partial loss-of-function mutations also cause infertility was not addressed\",\n        \"Molecular rescue in human sperm was not attempted\"\n      ]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"The molecular composition and structural role of the ACTRT1 complex in spermatids were undefined; co-IP and knockout studies established that ACTRT1 forms a multimeric complex with ACTRT2, ACTL7A, and ACTL9 and bridges the acrosome to the nucleus via interactions with SPACA1, PARP11, and SPATA46.\",\n      \"evidence\": \"Co-immunoprecipitation for complex identification; Actrt1-knockout mouse with phenotypic, immunofluorescence, and western blot analyses\",\n      \"pmids\": [\"35616329\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Stoichiometry and structure of the ACTRT1-containing complex are unknown\",\n        \"Whether ACTRT1 directly binds each partner or acts through ACTL7A was not fully distinguished\",\n        \"How the complex mechanically resists acrosomal detachment forces is not resolved\"\n      ]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Independent replication in human patients confirmed that ACTRT1 whole-gene deletion causes acrosomal ultrastructural defects with decreased ACTL7A and PLCζ expression, and demonstrated that ICSI with artificial oocyte activation can rescue fertilization failure.\",\n      \"evidence\": \"WES confirmed by WGS and PCR; electron microscopy of sperm ultrastructure; western blot and immunostaining\",\n      \"pmids\": [\"38414365\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Number of reported families remains small\",\n        \"Genotype-phenotype correlation for hypomorphic alleles is not established\",\n        \"Whether PLCζ reduction is a direct or indirect consequence of ACTRT1 loss is unknown\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The structural basis for ARP-T1's dual roles — as a cytoskeletal scaffold in spermatid acroplaxomes and as a DNA-binding transcriptional repressor in somatic cells — remains unresolved, and no structure of the ACTRT1-containing complex or ARP-T1–DNA interface has been determined.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"No crystal or cryo-EM structure of ACTRT1 or its complexes exists\",\n        \"The DNA-binding domain or motif in ARP-T1 is unidentified\",\n        \"How basal body localization, ciliary length regulation, and GLI1 promoter repression are mechanistically coordinated is unknown\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0003677\", \"supporting_discovery_ids\": [0]},\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [0]},\n      {\"term_id\": \"GO:0005198\", \"supporting_discovery_ids\": [1, 2, 6]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [0, 1, 2]},\n      {\"term_id\": \"GO:0005815\", \"supporting_discovery_ids\": [5]},\n      {\"term_id\": \"GO:0005929\", \"supporting_discovery_ids\": [5]},\n      {\"term_id\": \"GO:0005856\", \"supporting_discovery_ids\": [1, 6]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [0, 5]},\n      {\"term_id\": \"R-HSA-1474165\", \"supporting_discovery_ids\": [1, 2, 3, 4]}\n    ],\n    \"complexes\": [\n      \"ACTRT1-ACTRT2-ACTL7A-ACTL9 acroplaxome complex\"\n    ],\n    \"partners\": [\n      \"ACTRT2\",\n      \"ACTL7A\",\n      \"ACTL9\",\n      \"SPACA1\",\n      \"PARP11\",\n      \"SPATA46\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}