{"gene":"CFAP58","run_date":"2026-04-28T17:28:52","timeline":{"discoveries":[{"year":2020,"finding":"CFAP58 localizes along the entire flagella of sperm and is concentrated in the mid-piece; loss-of-function variants cause axonemal and mitochondrial sheath malformations, and reduction in axoneme markers SPAG6 and SPEF2 and mitochondrial sheath protein HSP60, establishing CFAP58 as required for sperm flagellogenesis.","method":"Immunofluorescence, immunoblotting, transmission electron microscopy, CRISPR/Cas9 knockout mice, whole-exome sequencing","journal":"American journal of human genetics","confidence":"High","confidence_rationale":"Tier 2 — multiple orthogonal methods (IF, IB, TEM, KO mice) in humans and mouse model, replicated across cohorts","pmids":["32791035"],"is_preprint":false},{"year":2020,"finding":"Cfap58 was identified as a testis-enriched protein via mass spectrometry interactome analysis of Odf2/Cenexin; Cfap58 co-localizes with Odf2/Cenexin proteins, and knockdown impairs primary cilium elongation and sperm midpiece formation via modulation of the Notch signaling pathway.","method":"Mass spectrometry interactome, immunofluorescence, siRNA knockdown, drug administration studies","journal":"Bioscience reports","confidence":"Medium","confidence_rationale":"Tier 3 — single lab, mass spectrometry pulldown and knockdown with pathway inhibitor data, but no rescue or structural validation","pmids":["31904090"],"is_preprint":false},{"year":2020,"finding":"Biallelic mutations in CFAP58 cause absence of CFAP58 protein in sperm and result in MMAF phenotype, confirming CFAP58 as a structural component required for flagellar assembly.","method":"Whole-exome sequencing, immunofluorescence, protein absence confirmation","journal":"Clinical genetics","confidence":"Medium","confidence_rationale":"Tier 3 — single lab, replication of He et al. findings in independent patient cohort with protein-level confirmation","pmids":["33314088"],"is_preprint":false},{"year":2024,"finding":"FAP58/CCDC147 (the Chlamydomonas ortholog of CFAP58) forms a heterodimer with MBO2/CCDC146 that assembles into an L-shaped structure interconnecting inner dynein arm b with multiple regulatory complexes along the axoneme, stabilizing inner arm dynein b assembly; this structure varies between doublet microtubules and is required for proper ciliary waveform.","method":"Cryo-electron tomography, comparative proteomics, epitope tagging, genetic mutant analysis (Chlamydomonas mbo mutants)","journal":"Molecular biology of the cell","confidence":"High","confidence_rationale":"Tier 1 — cryo-ET structural data combined with proteomics and genetic mutant validation in a well-established model organism ortholog","pmids":["38568782"],"is_preprint":false},{"year":2024,"finding":"CFAP58 interacts with IFT88 and CCDC42, and may function as a cargo protein stabilizing CCDC42 in the intra-manchette transport/intra-flagellar transport pathway; Cfap58 knockout mice show defects in manchette structure leading to abnormal sperm head shaping in addition to sperm tail defects.","method":"Co-immunoprecipitation, gene knockout mice, immunofluorescence, manchette structural analysis","journal":"Development (Cambridge, England)","confidence":"Medium","confidence_rationale":"Tier 2/3 — co-IP identifies interaction partners, KO mice establish dual role in head shaping and flagellogenesis, but mechanistic pathway placement is partially inferred","pmids":["38602507"],"is_preprint":false},{"year":2025,"finding":"A homozygous truncating mutation in CFAP58 (p.R188*) disrupts central pair (CP) microtubule assembly in the sperm flagellar axoneme, leading to disorganization of axonemal proteins, as shown in both human patients and a knock-in mouse model.","method":"Transmission electron microscopy, Cfap58 mutant mouse model, immunofluorescence, whole-exome sequencing","journal":"Human molecular genetics","confidence":"Medium","confidence_rationale":"Tier 2 — mutant mouse model recapitulating patient phenotype with TEM showing CP assembly defect, single lab","pmids":["40675161"],"is_preprint":false}],"current_model":"CFAP58 is a cilia- and flagella-associated protein that localizes to the sperm flagellum and mid-piece, where it is required for axonemal central pair microtubule assembly, inner dynein arm stabilization (via a heterodimeric L-shaped complex with CCDC146/MBO2), mitochondrial sheath formation, and intra-flagellar/intra-manchette transport of cargo proteins such as CCDC42; loss of CFAP58 causes multiple morphological abnormalities of the sperm flagella (MMAF) and male infertility in both humans and mice."},"narrative":{"teleology":[{"year":2020,"claim":"Establishing that CFAP58 is a flagellar structural protein required for sperm flagellogenesis resolved its basic biological role: loss of CFAP58 causes axonemal and mitochondrial sheath malformations and reduces key axonemal (SPAG6, SPEF2) and mitochondrial sheath (HSP60) markers, while biallelic mutations cause MMAF in humans.","evidence":"Immunofluorescence, TEM, CRISPR/Cas9 knockout mice, and whole-exome sequencing in human MMAF patients and independent replication cohorts","pmids":["32791035","33314088"],"confidence":"High","gaps":["Precise molecular mechanism by which CFAP58 organizes axonemal and mitochondrial sheath components was unknown","Direct binding partners within the axoneme were not identified","Whether CFAP58 functions beyond the flagellum (e.g. in motile or primary cilia) was unresolved"]},{"year":2020,"claim":"Identification of CFAP58 as a testis-enriched interactor of ODF2/Cenexin linked it to midpiece organization and implicated Notch signaling modulation in its ciliary elongation function.","evidence":"Mass spectrometry interactome of Odf2/Cenexin, siRNA knockdown, and pathway inhibitor studies in cell lines","pmids":["31904090"],"confidence":"Medium","gaps":["Notch pathway connection was based on knockdown plus inhibitor without rescue or genetic confirmation","ODF2 interaction not validated by reciprocal Co-IP or in vivo crosslinking","Mechanism linking CFAP58–ODF2 interaction to midpiece assembly was not defined"]},{"year":2024,"claim":"Cryo-ET structural analysis of the Chlamydomonas ortholog revealed that CFAP58 forms an L-shaped heterodimer with CCDC146/MBO2 that physically bridges inner dynein arm b to axonemal regulatory complexes, establishing the first structural model for CFAP58 function in dynein stabilization and ciliary motility.","evidence":"Cryo-electron tomography, comparative proteomics, epitope tagging, and genetic mutant analysis in Chlamydomonas","pmids":["38568782"],"confidence":"High","gaps":["Whether the L-shaped heterodimer architecture is conserved in mammalian sperm axonemes is untested","How loss of this complex leads to the full MMAF phenotype including mitochondrial sheath defects is unclear","Structural basis for doublet-specific variation of the complex was not fully resolved"]},{"year":2024,"claim":"Discovery that CFAP58 interacts with IFT88 and CCDC42 and is required for normal manchette structure expanded its functional scope beyond flagellar axoneme to include intra-manchette transport and sperm head shaping.","evidence":"Co-immunoprecipitation, Cfap58 knockout mice with manchette and sperm head morphology analysis","pmids":["38602507"],"confidence":"Medium","gaps":["Whether CFAP58 is a direct cargo adapter in IFT or acts indirectly on transport is unresolved","Reciprocal validation of IFT88 and CCDC42 interactions by independent methods is lacking","Relative contribution of manchette versus flagellar defects to the infertility phenotype is not delineated"]},{"year":2025,"claim":"A patient-derived truncating mutation modeled in knock-in mice pinpointed CFAP58's role specifically in central pair microtubule assembly, distinguishing this function from its broader axonemal and mitochondrial sheath roles.","evidence":"Cfap58-R188* knock-in mouse model, TEM of central pair defects, immunofluorescence of axonemal protein disorganization","pmids":["40675161"],"confidence":"Medium","gaps":["Which domain or region of CFAP58 mediates central pair versus outer doublet functions is undefined","Whether partial truncation alleles retain some L-shaped heterodimer function with CCDC146 is untested","Single lab finding awaiting independent replication"]},{"year":null,"claim":"A unified structural and mechanistic model explaining how CFAP58 coordinates its multiple functions — central pair assembly, inner dynein arm stabilization via the CCDC146 heterodimer, mitochondrial sheath formation, and intra-manchette transport — in mammalian spermatogenesis remains to be established.","evidence":"","pmids":[],"confidence":"Low","gaps":["No high-resolution structure of mammalian CFAP58 or its complexes exists","Domain-function mapping has not been performed for the distinct flagellar and manchette roles","Whether CFAP58 has roles in motile cilia outside the male germline is unexplored"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0005198","term_label":"structural molecule activity","supporting_discovery_ids":[0,3]},{"term_id":"GO:0008092","term_label":"cytoskeletal protein binding","supporting_discovery_ids":[3,4]}],"localization":[{"term_id":"GO:0005929","term_label":"cilium","supporting_discovery_ids":[0,3,5]},{"term_id":"GO:0008092","term_label":"cytoskeletal protein binding","supporting_discovery_ids":[0,3]}],"pathway":[{"term_id":"R-HSA-1852241","term_label":"Organelle biogenesis and maintenance","supporting_discovery_ids":[0,3,5]}],"complexes":["FAP58–MBO2/CCDC146 L-shaped heterodimer"],"partners":["CCDC146","IFT88","CCDC42","ODF2","SPAG6","SPEF2"],"other_free_text":[]},"mechanistic_narrative":"CFAP58 is a cilia- and flagella-associated protein essential for sperm flagellum assembly, axonemal integrity, and sperm head shaping. It localizes along the entire sperm flagellum with enrichment at the mid-piece, where it is required for central pair microtubule assembly, mitochondrial sheath formation, and stabilization of axonemal markers such as SPAG6 and SPEF2 [PMID:32791035, PMID:40675161]. Its Chlamydomonas ortholog (FAP58/CCDC147) forms a heterodimeric L-shaped complex with MBO2/CCDC146 that interconnects inner dynein arm b with axonemal regulatory complexes, stabilizing inner arm dynein assembly and controlling ciliary waveform [PMID:38568782]. CFAP58 also participates in intra-manchette and intra-flagellar transport by interacting with IFT88 and stabilizing CCDC42, and biallelic loss-of-function mutations in CFAP58 cause multiple morphological abnormalities of the sperm flagella (MMAF) and male infertility in humans [PMID:38602507, PMID:32791035]."},"prefetch_data":{"uniprot":{"accession":"Q5T655","full_name":"Cilia- and flagella-associated protein 58","aliases":["Coiled-coil domain-containing protein 147"],"length_aa":872,"mass_kda":103.4,"function":"Has an essential role in the assembly and organization of the sperm flagellar axoneme (PubMed:32791035). Required for the elongation of the primary cilium and sperm flagellar midpiece via modulation of the Notch signaling pathway (By similarity)","subcellular_location":"Cell projection, cilium; Cell projection, cilium, flagellum; Cytoplasm, cytoskeleton, microtubule organizing center, centrosome","url":"https://www.uniprot.org/uniprotkb/Q5T655/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/CFAP58","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/CFAP58","total_profiled":1310},"omim":[{"mim_id":"619144","title":"SPERMATOGENIC FAILURE 49; SPGF49","url":"https://www.omim.org/entry/619144"},{"mim_id":"619129","title":"CILIA- AND FLAGELLA-ASSOCIATED PROTEIN 58; CFAP58","url":"https://www.omim.org/entry/619129"},{"mim_id":"258150","title":"SPERMATOGENIC FAILURE 1; SPGF1","url":"https://www.omim.org/entry/258150"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Principal piece","reliability":"Supported"},{"location":"Calyx","reliability":"Additional"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in some","driving_tissues":[{"tissue":"fallopian tube","ntpm":7.9},{"tissue":"testis","ntpm":12.8}],"url":"https://www.proteinatlas.org/search/CFAP58"},"hgnc":{"alias_symbol":["FLJ35908","bA554P13.1"],"prev_symbol":["C10orf80","CCDC147"]},"alphafold":{"accession":"Q5T655","domains":[],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q5T655","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q5T655-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q5T655-F1-predicted_aligned_error_v6.png","plddt_mean":79.56},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=CFAP58","jax_strain_url":"https://www.jax.org/strain/search?query=CFAP58"},"sequence":{"accession":"Q5T655","fasta_url":"https://rest.uniprot.org/uniprotkb/Q5T655.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q5T655/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q5T655"}},"corpus_meta":[{"pmid":"32791035","id":"PMC_32791035","title":"Bi-allelic Loss-of-function Variants in CFAP58 Cause Flagellar Axoneme and Mitochondrial Sheath Defects and Asthenoteratozoospermia in Humans and Mice.","date":"2020","source":"American journal of human genetics","url":"https://pubmed.ncbi.nlm.nih.gov/32791035","citation_count":89,"is_preprint":false},{"pmid":"34089056","id":"PMC_34089056","title":"Exome sequencing reveals variants in known and novel candidate genes for severe sperm motility disorders.","date":"2021","source":"Human reproduction (Oxford, England)","url":"https://pubmed.ncbi.nlm.nih.gov/34089056","citation_count":50,"is_preprint":false},{"pmid":"34173924","id":"PMC_34173924","title":"Immunogenomic profiling and pathological response results from a clinical trial of docetaxel and carboplatin in triple-negative breast cancer.","date":"2021","source":"Breast cancer research and treatment","url":"https://pubmed.ncbi.nlm.nih.gov/34173924","citation_count":32,"is_preprint":false},{"pmid":"26762739","id":"PMC_26762739","title":"Focused Analysis of Exome Sequencing Data for Rare Germline Mutations in Familial and Sporadic Lung Cancer.","date":"2016","source":"Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer","url":"https://pubmed.ncbi.nlm.nih.gov/26762739","citation_count":27,"is_preprint":false},{"pmid":"33314088","id":"PMC_33314088","title":"Biallelic mutations of CFAP58 are associated with multiple morphological abnormalities of the sperm flagella.","date":"2020","source":"Clinical genetics","url":"https://pubmed.ncbi.nlm.nih.gov/33314088","citation_count":21,"is_preprint":false},{"pmid":"33955803","id":"PMC_33955803","title":"Prediction of bladder cancer outcome by identifying and validating a mutation-derived genomic instability-associated long noncoding RNA (lncRNA) signature.","date":"2021","source":"Bioengineered","url":"https://pubmed.ncbi.nlm.nih.gov/33955803","citation_count":20,"is_preprint":false},{"pmid":"31904090","id":"PMC_31904090","title":"The novel testicular enrichment protein Cfap58 is required for Notch-associated ciliogenesis.","date":"2020","source":"Bioscience reports","url":"https://pubmed.ncbi.nlm.nih.gov/31904090","citation_count":12,"is_preprint":false},{"pmid":"38568782","id":"PMC_38568782","title":"The MBO2/FAP58 heterodimer stabilizes assembly of inner arm dynein b and reveals axoneme asymmetries involved in ciliary waveform.","date":"2024","source":"Molecular biology of the cell","url":"https://pubmed.ncbi.nlm.nih.gov/38568782","citation_count":6,"is_preprint":false},{"pmid":"38602507","id":"PMC_38602507","title":"CFAP58 is involved in the sperm head shaping and flagellogenesis of cattle and mice.","date":"2024","source":"Development (Cambridge, England)","url":"https://pubmed.ncbi.nlm.nih.gov/38602507","citation_count":5,"is_preprint":false},{"pmid":"40675161","id":"PMC_40675161","title":"A novel mutation in CFAP58 leads to MMAF in humans and mice by disrupting CP assembly.","date":"2025","source":"Human molecular genetics","url":"https://pubmed.ncbi.nlm.nih.gov/40675161","citation_count":1,"is_preprint":false},{"pmid":"40317966","id":"PMC_40317966","title":"Clinicopathological and molecular characterization of KRAS wild-type pancreatic ductal adenocarcinomas reveals precursor lesions with oncogenic mutations and fusions in RAS pathway genes.","date":"2025","source":"The Journal of pathology","url":"https://pubmed.ncbi.nlm.nih.gov/40317966","citation_count":0,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":7865,"output_tokens":1455,"usd":0.02271},"stage2":{"model":"claude-opus-4-6","input_tokens":4690,"output_tokens":1947,"usd":0.108188},"total_usd":0.130898,"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\": 2020,\n      \"finding\": \"CFAP58 localizes along the entire flagella of sperm and is concentrated in the mid-piece; loss-of-function variants cause axonemal and mitochondrial sheath malformations, and reduction in axoneme markers SPAG6 and SPEF2 and mitochondrial sheath protein HSP60, establishing CFAP58 as required for sperm flagellogenesis.\",\n      \"method\": \"Immunofluorescence, immunoblotting, transmission electron microscopy, CRISPR/Cas9 knockout mice, whole-exome sequencing\",\n      \"journal\": \"American journal of human genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods (IF, IB, TEM, KO mice) in humans and mouse model, replicated across cohorts\",\n      \"pmids\": [\"32791035\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Cfap58 was identified as a testis-enriched protein via mass spectrometry interactome analysis of Odf2/Cenexin; Cfap58 co-localizes with Odf2/Cenexin proteins, and knockdown impairs primary cilium elongation and sperm midpiece formation via modulation of the Notch signaling pathway.\",\n      \"method\": \"Mass spectrometry interactome, immunofluorescence, siRNA knockdown, drug administration studies\",\n      \"journal\": \"Bioscience reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — single lab, mass spectrometry pulldown and knockdown with pathway inhibitor data, but no rescue or structural validation\",\n      \"pmids\": [\"31904090\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Biallelic mutations in CFAP58 cause absence of CFAP58 protein in sperm and result in MMAF phenotype, confirming CFAP58 as a structural component required for flagellar assembly.\",\n      \"method\": \"Whole-exome sequencing, immunofluorescence, protein absence confirmation\",\n      \"journal\": \"Clinical genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — single lab, replication of He et al. findings in independent patient cohort with protein-level confirmation\",\n      \"pmids\": [\"33314088\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"FAP58/CCDC147 (the Chlamydomonas ortholog of CFAP58) forms a heterodimer with MBO2/CCDC146 that assembles into an L-shaped structure interconnecting inner dynein arm b with multiple regulatory complexes along the axoneme, stabilizing inner arm dynein b assembly; this structure varies between doublet microtubules and is required for proper ciliary waveform.\",\n      \"method\": \"Cryo-electron tomography, comparative proteomics, epitope tagging, genetic mutant analysis (Chlamydomonas mbo mutants)\",\n      \"journal\": \"Molecular biology of the cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — cryo-ET structural data combined with proteomics and genetic mutant validation in a well-established model organism ortholog\",\n      \"pmids\": [\"38568782\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"CFAP58 interacts with IFT88 and CCDC42, and may function as a cargo protein stabilizing CCDC42 in the intra-manchette transport/intra-flagellar transport pathway; Cfap58 knockout mice show defects in manchette structure leading to abnormal sperm head shaping in addition to sperm tail defects.\",\n      \"method\": \"Co-immunoprecipitation, gene knockout mice, immunofluorescence, manchette structural analysis\",\n      \"journal\": \"Development (Cambridge, England)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2/3 — co-IP identifies interaction partners, KO mice establish dual role in head shaping and flagellogenesis, but mechanistic pathway placement is partially inferred\",\n      \"pmids\": [\"38602507\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"A homozygous truncating mutation in CFAP58 (p.R188*) disrupts central pair (CP) microtubule assembly in the sperm flagellar axoneme, leading to disorganization of axonemal proteins, as shown in both human patients and a knock-in mouse model.\",\n      \"method\": \"Transmission electron microscopy, Cfap58 mutant mouse model, immunofluorescence, whole-exome sequencing\",\n      \"journal\": \"Human molecular genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — mutant mouse model recapitulating patient phenotype with TEM showing CP assembly defect, single lab\",\n      \"pmids\": [\"40675161\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"CFAP58 is a cilia- and flagella-associated protein that localizes to the sperm flagellum and mid-piece, where it is required for axonemal central pair microtubule assembly, inner dynein arm stabilization (via a heterodimeric L-shaped complex with CCDC146/MBO2), mitochondrial sheath formation, and intra-flagellar/intra-manchette transport of cargo proteins such as CCDC42; loss of CFAP58 causes multiple morphological abnormalities of the sperm flagella (MMAF) and male infertility in both humans and mice.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"CFAP58 is a cilia- and flagella-associated protein essential for sperm flagellum assembly, axonemal integrity, and sperm head shaping. It localizes along the entire sperm flagellum with enrichment at the mid-piece, where it is required for central pair microtubule assembly, mitochondrial sheath formation, and stabilization of axonemal markers such as SPAG6 and SPEF2 [PMID:32791035, PMID:40675161]. Its Chlamydomonas ortholog (FAP58/CCDC147) forms a heterodimeric L-shaped complex with MBO2/CCDC146 that interconnects inner dynein arm b with axonemal regulatory complexes, stabilizing inner arm dynein assembly and controlling ciliary waveform [PMID:38568782]. CFAP58 also participates in intra-manchette and intra-flagellar transport by interacting with IFT88 and stabilizing CCDC42, and biallelic loss-of-function mutations in CFAP58 cause multiple morphological abnormalities of the sperm flagella (MMAF) and male infertility in humans [PMID:38602507, PMID:32791035].\",\n  \"teleology\": [\n    {\n      \"year\": 2020,\n      \"claim\": \"Establishing that CFAP58 is a flagellar structural protein required for sperm flagellogenesis resolved its basic biological role: loss of CFAP58 causes axonemal and mitochondrial sheath malformations and reduces key axonemal (SPAG6, SPEF2) and mitochondrial sheath (HSP60) markers, while biallelic mutations cause MMAF in humans.\",\n      \"evidence\": \"Immunofluorescence, TEM, CRISPR/Cas9 knockout mice, and whole-exome sequencing in human MMAF patients and independent replication cohorts\",\n      \"pmids\": [\"32791035\", \"33314088\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Precise molecular mechanism by which CFAP58 organizes axonemal and mitochondrial sheath components was unknown\",\n        \"Direct binding partners within the axoneme were not identified\",\n        \"Whether CFAP58 functions beyond the flagellum (e.g. in motile or primary cilia) was unresolved\"\n      ]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Identification of CFAP58 as a testis-enriched interactor of ODF2/Cenexin linked it to midpiece organization and implicated Notch signaling modulation in its ciliary elongation function.\",\n      \"evidence\": \"Mass spectrometry interactome of Odf2/Cenexin, siRNA knockdown, and pathway inhibitor studies in cell lines\",\n      \"pmids\": [\"31904090\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Notch pathway connection was based on knockdown plus inhibitor without rescue or genetic confirmation\",\n        \"ODF2 interaction not validated by reciprocal Co-IP or in vivo crosslinking\",\n        \"Mechanism linking CFAP58–ODF2 interaction to midpiece assembly was not defined\"\n      ]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Cryo-ET structural analysis of the Chlamydomonas ortholog revealed that CFAP58 forms an L-shaped heterodimer with CCDC146/MBO2 that physically bridges inner dynein arm b to axonemal regulatory complexes, establishing the first structural model for CFAP58 function in dynein stabilization and ciliary motility.\",\n      \"evidence\": \"Cryo-electron tomography, comparative proteomics, epitope tagging, and genetic mutant analysis in Chlamydomonas\",\n      \"pmids\": [\"38568782\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Whether the L-shaped heterodimer architecture is conserved in mammalian sperm axonemes is untested\",\n        \"How loss of this complex leads to the full MMAF phenotype including mitochondrial sheath defects is unclear\",\n        \"Structural basis for doublet-specific variation of the complex was not fully resolved\"\n      ]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Discovery that CFAP58 interacts with IFT88 and CCDC42 and is required for normal manchette structure expanded its functional scope beyond flagellar axoneme to include intra-manchette transport and sperm head shaping.\",\n      \"evidence\": \"Co-immunoprecipitation, Cfap58 knockout mice with manchette and sperm head morphology analysis\",\n      \"pmids\": [\"38602507\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Whether CFAP58 is a direct cargo adapter in IFT or acts indirectly on transport is unresolved\",\n        \"Reciprocal validation of IFT88 and CCDC42 interactions by independent methods is lacking\",\n        \"Relative contribution of manchette versus flagellar defects to the infertility phenotype is not delineated\"\n      ]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"A patient-derived truncating mutation modeled in knock-in mice pinpointed CFAP58's role specifically in central pair microtubule assembly, distinguishing this function from its broader axonemal and mitochondrial sheath roles.\",\n      \"evidence\": \"Cfap58-R188* knock-in mouse model, TEM of central pair defects, immunofluorescence of axonemal protein disorganization\",\n      \"pmids\": [\"40675161\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Which domain or region of CFAP58 mediates central pair versus outer doublet functions is undefined\",\n        \"Whether partial truncation alleles retain some L-shaped heterodimer function with CCDC146 is untested\",\n        \"Single lab finding awaiting independent replication\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"A unified structural and mechanistic model explaining how CFAP58 coordinates its multiple functions — central pair assembly, inner dynein arm stabilization via the CCDC146 heterodimer, mitochondrial sheath formation, and intra-manchette transport — in mammalian spermatogenesis remains to be established.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"No high-resolution structure of mammalian CFAP58 or its complexes exists\",\n        \"Domain-function mapping has not been performed for the distinct flagellar and manchette roles\",\n        \"Whether CFAP58 has roles in motile cilia outside the male germline is unexplored\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0005198\", \"supporting_discovery_ids\": [0, 3]},\n      {\"term_id\": \"GO:0008092\", \"supporting_discovery_ids\": [3, 4]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005929\", \"supporting_discovery_ids\": [0, 3, 5]},\n      {\"term_id\": \"GO:0008092\", \"supporting_discovery_ids\": [0, 3]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1852241\", \"supporting_discovery_ids\": [0, 3, 5]}\n    ],\n    \"complexes\": [\n      \"FAP58–MBO2/CCDC146 L-shaped heterodimer\"\n    ],\n    \"partners\": [\n      \"CCDC146\",\n      \"IFT88\",\n      \"CCDC42\",\n      \"ODF2\",\n      \"SPAG6\",\n      \"SPEF2\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}