{"gene":"CFAP206","run_date":"2026-04-28T17:28:52","timeline":{"discoveries":[{"year":2020,"finding":"CFAP206 protein localizes to the basal body and to the axoneme of motile cilia, and is required for normal radial spoke formation; in Xenopus crispant larvae lacking Cfap206, ciliary beat frequency of skin multiciliated cells was enhanced and bead transport across the epidermal mucociliary epithelium was reduced; Cfap206 knockout mice display male infertility, hydrocephalus, and impaired mucociliary clearance without laterality defects; electron tomography of immotile knockout mouse sperm flagella indicated a role in radial spoke formation; Cfap206 expression is co-regulated with and dependent on the transcription factor FOXJ1.","method":"Xenopus CRISPR crispants (loss-of-function), mouse knockout, electron tomography, immunolocalization, ciliary beat frequency measurement, bead transport assay","journal":"Development (Cambridge, England)","confidence":"High","confidence_rationale":"Tier 2 — multiple orthogonal methods (KO mouse, Xenopus crispant, electron tomography, subcellular localization) with defined functional phenotypes across two model organisms","pmids":["32376681"],"is_preprint":false},{"year":2021,"finding":"Bi-allelic truncating variants in CFAP206 cause male infertility in humans; CFAP206 is a microtubule-docking adapter for radial spokes and inner dynein arms; loss of CFAP206 in patient sperm abolishes WDR66 and RSPH1 protein localization, indicating severe radial spoke and calmodulin/spoke-associated complex defects; Cfap206 knockout mice generated by CRISPR-Cas9 display male infertility with functional, structural, and ultrastructural sperm flagellum defects and very low embryo development rates by ICSI.","method":"Human exome sequencing (homozygous frameshift variant identification), immunostaining of patient sperm (WDR66, RSPH1 absence), CRISPR-Cas9 Cfap206 knockout mouse generation, sperm ultrastructure analysis, ICSI embryo development assay","journal":"Human genetics","confidence":"High","confidence_rationale":"Tier 2 — human genetic evidence combined with orthogonal mouse KO and patient immunostaining with defined molecular and cellular phenotypes","pmids":["34255152"],"is_preprint":false},{"year":2022,"finding":"In Tetrahymena, CFAP206 (FAP206 ortholog) is an RS2-associated protein whose stable docking depends on CFAP91; in CFAP91-KO Tetrahymena cells, the level of RS2-associated CFAP206 is significantly diminished, linking CFAP206 to the base of radial spoke RS2 and its stable assembly.","method":"Tetrahymena CFAP91 knockout, proteomic and localization analysis of radial spoke components, fluorescence microscopy","journal":"Cells","confidence":"Medium","confidence_rationale":"Tier 2 — genetic KO with proteomic readout in a ciliate model organism; single lab but orthogonal methods","pmids":["36552811"],"is_preprint":false}],"current_model":"CFAP206 is a microtubule-docking adapter protein that localizes to the basal body and axoneme of motile cilia and sperm flagella, where it is required for the stable assembly and positioning of radial spokes (particularly RS2) and associated inner dynein arms; loss of CFAP206 in humans and mice causes male infertility via multiple morphological flagellum abnormalities (MMAF) with disruption of radial spoke proteins WDR66 and RSPH1, and in broader ciliary contexts leads to impaired mucociliary clearance and hydrocephalus, while its expression is transcriptionally regulated by FOXJ1."},"narrative":{"teleology":[{"year":2020,"claim":"Establishing that CFAP206 is a ciliary structural component required for radial spoke formation and motile cilia function resolved its cellular role: it localizes to basal bodies and axonemes, and its loss produces hydrocephalus, male infertility, and impaired mucociliary clearance without laterality defects, placing it specifically in the motile (not nodal) cilia pathway.","evidence":"Xenopus CRISPR crispants, mouse knockout, electron tomography, immunolocalization, ciliary beat frequency and bead transport assays","pmids":["32376681"],"confidence":"High","gaps":["Precise position within the radial spoke repeat was not determined","Direct binding partners on the axonemal microtubule were not identified","Mechanism by which ciliary beat frequency increases despite impaired transport was unexplained"]},{"year":2021,"claim":"Linking CFAP206 to human disease and defining it as a microtubule-docking adapter for radial spokes and inner dynein arms established the molecular consequence of its loss: absence of WDR66 and RSPH1 from patient sperm axonemes, proving CFAP206 is required upstream for radial spoke complex recruitment.","evidence":"Human exome sequencing identifying bi-allelic truncating variants, immunostaining of patient sperm, CRISPR-Cas9 mouse knockout, sperm ultrastructure analysis, ICSI embryo development assay","pmids":["34255152"],"confidence":"High","gaps":["Whether CFAP206 directly contacts WDR66/RSPH1 or acts indirectly was not resolved","Mechanism of poor ICSI outcomes beyond flagellar defects was not explored","No rescue experiment was performed in human or mouse systems"]},{"year":2022,"claim":"Positioning CFAP206 specifically at the RS2 base and showing its stable docking depends on CFAP91 refined the assembly hierarchy, establishing that CFAP91 acts upstream of CFAP206 in RS2 biogenesis.","evidence":"Tetrahymena CFAP91 knockout with proteomic and fluorescence analysis of radial spoke components","pmids":["36552811"],"confidence":"Medium","gaps":["Whether CFAP91–CFAP206 interaction is direct or mediated by other RS2 components was not tested","This dependency was shown only in Tetrahymena; conservation in vertebrates was not confirmed","Structural basis for CFAP206 docking at the RS2 base is unknown"]},{"year":null,"claim":"The direct protein–protein interaction network of CFAP206 on the axonemal microtubule, its structural basis of docking at RS2, and whether it plays additional roles in inner dynein arm positioning independent of radial spokes remain unresolved.","evidence":"","pmids":[],"confidence":"Low","gaps":["No atomic or cryo-EM structure of CFAP206 or its complex exists","No biochemical reconstitution of CFAP206–radial spoke interactions has been performed","Whether CFAP206 loss contributes to primary ciliary dyskinesia beyond male infertility is undetermined"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[1,2]},{"term_id":"GO:0008092","term_label":"cytoskeletal protein binding","supporting_discovery_ids":[0,1]}],"localization":[{"term_id":"GO:0005929","term_label":"cilium","supporting_discovery_ids":[0,1,2]},{"term_id":"GO:0005815","term_label":"microtubule organizing center","supporting_discovery_ids":[0]}],"pathway":[{"term_id":"R-HSA-1852241","term_label":"Organelle biogenesis and maintenance","supporting_discovery_ids":[0,1,2]},{"term_id":"R-HSA-1474165","term_label":"Reproduction","supporting_discovery_ids":[0,1]}],"complexes":["Radial spoke 2 (RS2) complex"],"partners":["CFAP91","WDR66","RSPH1","FOXJ1"],"other_free_text":[]},"mechanistic_narrative":"CFAP206 is a microtubule-docking adapter protein that localizes to the basal body and axoneme of motile cilia and sperm flagella, where it associates with the base of radial spoke 2 (RS2) in a CFAP91-dependent manner and is essential for stable assembly and positioning of radial spokes and inner dynein arms [PMID:32376681, PMID:36552811]. Loss of CFAP206 abolishes axonemal localization of radial spoke proteins WDR66 and RSPH1 and causes flagellar ultrastructural defects, impaired mucociliary clearance, and hydrocephalus in mouse and Xenopus models, with its expression transcriptionally regulated by FOXJ1 [PMID:32376681]. Bi-allelic truncating variants in human CFAP206 cause male infertility through multiple morphological abnormalities of the sperm flagellum (MMAF), with severely reduced embryo development even after ICSI [PMID:34255152]."},"prefetch_data":{"uniprot":{"accession":"Q8IYR0","full_name":"Cilia- and flagella-associated protein 206","aliases":[],"length_aa":622,"mass_kda":71.2,"function":"Essential for sperm motility and is involved in the regulation of the beating frequency of motile cilia on the epithelial cells of the respiratory tract (By similarity). Required for the establishment of radial spokes in sperm flagella (By similarity)","subcellular_location":"Cytoplasm, cytoskeleton, cilium axoneme; Cytoplasm, cytoskeleton, cilium basal body","url":"https://www.uniprot.org/uniprotkb/Q8IYR0/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/CFAP206","classification":"Not Classified","n_dependent_lines":3,"n_total_lines":1208,"dependency_fraction":0.0024834437086092716},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/CFAP206","total_profiled":1310},"omim":[{"mim_id":"621387","title":"SPERMATOGENIC FAILURE 102; SPGF102","url":"https://www.omim.org/entry/621387"},{"mim_id":"621378","title":"CILIA- AND FLAGELLA-ASSOCIATED PROTEIN 161; CFAP161","url":"https://www.omim.org/entry/621378"},{"mim_id":"621376","title":"CILIA- AND FLAGELLA-ASSOCIATED PROTEIN 206; CFAP206","url":"https://www.omim.org/entry/621376"},{"mim_id":"258150","title":"SPERMATOGENIC FAILURE 1; SPGF1","url":"https://www.omim.org/entry/258150"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"","locations":[],"tissue_specificity":"Group enriched","tissue_distribution":"Detected in some","driving_tissues":[{"tissue":"fallopian tube","ntpm":21.0},{"tissue":"testis","ntpm":55.2}],"url":"https://www.proteinatlas.org/search/CFAP206"},"hgnc":{"alias_symbol":["FLJ25974","dJ382I10.1"],"prev_symbol":["C6orf165"]},"alphafold":{"accession":"Q8IYR0","domains":[{"cath_id":"-","chopping":"6-72","consensus_level":"high","plddt":85.75,"start":6,"end":72},{"cath_id":"-","chopping":"120-202","consensus_level":"high","plddt":93.9454,"start":120,"end":202},{"cath_id":"-","chopping":"385-490","consensus_level":"high","plddt":90.2089,"start":385,"end":490},{"cath_id":"1.20.140","chopping":"212-371","consensus_level":"high","plddt":92.5347,"start":212,"end":371}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q8IYR0","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q8IYR0-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q8IYR0-F1-predicted_aligned_error_v6.png","plddt_mean":85.38},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=CFAP206","jax_strain_url":"https://www.jax.org/strain/search?query=CFAP206"},"sequence":{"accession":"Q8IYR0","fasta_url":"https://rest.uniprot.org/uniprotkb/Q8IYR0.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q8IYR0/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q8IYR0"}},"corpus_meta":[{"pmid":"35207567","id":"PMC_35207567","title":"Omics and Male Infertility: Highlighting the Application of Transcriptomic Data.","date":"2022","source":"Life (Basel, Switzerland)","url":"https://pubmed.ncbi.nlm.nih.gov/35207567","citation_count":29,"is_preprint":false},{"pmid":"34255152","id":"PMC_34255152","title":"Bi-allelic truncating variants in CFAP206 cause male infertility in human and mouse.","date":"2021","source":"Human genetics","url":"https://pubmed.ncbi.nlm.nih.gov/34255152","citation_count":26,"is_preprint":false},{"pmid":"32376681","id":"PMC_32376681","title":"The FOXJ1 target Cfap206 is required for sperm motility, mucociliary clearance of the airways and brain development.","date":"2020","source":"Development (Cambridge, England)","url":"https://pubmed.ncbi.nlm.nih.gov/32376681","citation_count":22,"is_preprint":false},{"pmid":"36552811","id":"PMC_36552811","title":"Cfap91-Dependent Stability of the RS2 and RS3 Base Proteins and Adjacent Inner Dynein Arms in Tetrahymena Cilia.","date":"2022","source":"Cells","url":"https://pubmed.ncbi.nlm.nih.gov/36552811","citation_count":13,"is_preprint":false},{"pmid":"36714547","id":"PMC_36714547","title":"High-throughput proteomic characterization of seminal plasma from bulls with contrasting semen quality.","date":"2023","source":"3 Biotech","url":"https://pubmed.ncbi.nlm.nih.gov/36714547","citation_count":8,"is_preprint":false},{"pmid":"39104315","id":"PMC_39104315","title":"Obesity impairs ciliary function and mucociliary clearance in the murine airway epithelium.","date":"2024","source":"American journal of physiology. Lung cellular and molecular physiology","url":"https://pubmed.ncbi.nlm.nih.gov/39104315","citation_count":7,"is_preprint":false},{"pmid":"38033870","id":"PMC_38033870","title":"Cascading effects of hypobaric hypoxia on the testis: insights from a single-cell RNA sequencing analysis.","date":"2023","source":"Frontiers in cell and developmental biology","url":"https://pubmed.ncbi.nlm.nih.gov/38033870","citation_count":3,"is_preprint":false},{"pmid":"38051303","id":"PMC_38051303","title":"Genetic Factors and Long-term Treatment-Related Neurocognitive Deficits, Anxiety, and Depression in Childhood Leukemia Survivors: An Exome-Wide Association Study.","date":"2024","source":"Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology","url":"https://pubmed.ncbi.nlm.nih.gov/38051303","citation_count":2,"is_preprint":false},{"pmid":"38200094","id":"PMC_38200094","title":"Strong selection signatures for Aleutian disease tolerance acting on novel candidate genes linked to immune and cellular responses in American mink (Neogale vison).","date":"2024","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/38200094","citation_count":0,"is_preprint":false},{"pmid":"41583004","id":"PMC_41583004","title":"Exploring rare coding variants in UK biobank: preliminary associations with motor neuron disease.","date":"2026","source":"Frontiers in aging neuroscience","url":"https://pubmed.ncbi.nlm.nih.gov/41583004","citation_count":0,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":7424,"output_tokens":1042,"usd":0.018951},"stage2":{"model":"claude-opus-4-6","input_tokens":4223,"output_tokens":1439,"usd":0.085635},"total_usd":0.104586,"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\": \"CFAP206 protein localizes to the basal body and to the axoneme of motile cilia, and is required for normal radial spoke formation; in Xenopus crispant larvae lacking Cfap206, ciliary beat frequency of skin multiciliated cells was enhanced and bead transport across the epidermal mucociliary epithelium was reduced; Cfap206 knockout mice display male infertility, hydrocephalus, and impaired mucociliary clearance without laterality defects; electron tomography of immotile knockout mouse sperm flagella indicated a role in radial spoke formation; Cfap206 expression is co-regulated with and dependent on the transcription factor FOXJ1.\",\n      \"method\": \"Xenopus CRISPR crispants (loss-of-function), mouse knockout, electron tomography, immunolocalization, ciliary beat frequency measurement, bead transport assay\",\n      \"journal\": \"Development (Cambridge, England)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods (KO mouse, Xenopus crispant, electron tomography, subcellular localization) with defined functional phenotypes across two model organisms\",\n      \"pmids\": [\"32376681\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Bi-allelic truncating variants in CFAP206 cause male infertility in humans; CFAP206 is a microtubule-docking adapter for radial spokes and inner dynein arms; loss of CFAP206 in patient sperm abolishes WDR66 and RSPH1 protein localization, indicating severe radial spoke and calmodulin/spoke-associated complex defects; Cfap206 knockout mice generated by CRISPR-Cas9 display male infertility with functional, structural, and ultrastructural sperm flagellum defects and very low embryo development rates by ICSI.\",\n      \"method\": \"Human exome sequencing (homozygous frameshift variant identification), immunostaining of patient sperm (WDR66, RSPH1 absence), CRISPR-Cas9 Cfap206 knockout mouse generation, sperm ultrastructure analysis, ICSI embryo development assay\",\n      \"journal\": \"Human genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — human genetic evidence combined with orthogonal mouse KO and patient immunostaining with defined molecular and cellular phenotypes\",\n      \"pmids\": [\"34255152\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"In Tetrahymena, CFAP206 (FAP206 ortholog) is an RS2-associated protein whose stable docking depends on CFAP91; in CFAP91-KO Tetrahymena cells, the level of RS2-associated CFAP206 is significantly diminished, linking CFAP206 to the base of radial spoke RS2 and its stable assembly.\",\n      \"method\": \"Tetrahymena CFAP91 knockout, proteomic and localization analysis of radial spoke components, fluorescence microscopy\",\n      \"journal\": \"Cells\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — genetic KO with proteomic readout in a ciliate model organism; single lab but orthogonal methods\",\n      \"pmids\": [\"36552811\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"CFAP206 is a microtubule-docking adapter protein that localizes to the basal body and axoneme of motile cilia and sperm flagella, where it is required for the stable assembly and positioning of radial spokes (particularly RS2) and associated inner dynein arms; loss of CFAP206 in humans and mice causes male infertility via multiple morphological flagellum abnormalities (MMAF) with disruption of radial spoke proteins WDR66 and RSPH1, and in broader ciliary contexts leads to impaired mucociliary clearance and hydrocephalus, while its expression is transcriptionally regulated by FOXJ1.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"CFAP206 is a microtubule-docking adapter protein that localizes to the basal body and axoneme of motile cilia and sperm flagella, where it associates with the base of radial spoke 2 (RS2) in a CFAP91-dependent manner and is essential for stable assembly and positioning of radial spokes and inner dynein arms [PMID:32376681, PMID:36552811]. Loss of CFAP206 abolishes axonemal localization of radial spoke proteins WDR66 and RSPH1 and causes flagellar ultrastructural defects, impaired mucociliary clearance, and hydrocephalus in mouse and Xenopus models, with its expression transcriptionally regulated by FOXJ1 [PMID:32376681]. Bi-allelic truncating variants in human CFAP206 cause male infertility through multiple morphological abnormalities of the sperm flagellum (MMAF), with severely reduced embryo development even after ICSI [PMID:34255152].\",\n  \"teleology\": [\n    {\n      \"year\": 2020,\n      \"claim\": \"Establishing that CFAP206 is a ciliary structural component required for radial spoke formation and motile cilia function resolved its cellular role: it localizes to basal bodies and axonemes, and its loss produces hydrocephalus, male infertility, and impaired mucociliary clearance without laterality defects, placing it specifically in the motile (not nodal) cilia pathway.\",\n      \"evidence\": \"Xenopus CRISPR crispants, mouse knockout, electron tomography, immunolocalization, ciliary beat frequency and bead transport assays\",\n      \"pmids\": [\"32376681\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Precise position within the radial spoke repeat was not determined\",\n        \"Direct binding partners on the axonemal microtubule were not identified\",\n        \"Mechanism by which ciliary beat frequency increases despite impaired transport was unexplained\"\n      ]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Linking CFAP206 to human disease and defining it as a microtubule-docking adapter for radial spokes and inner dynein arms established the molecular consequence of its loss: absence of WDR66 and RSPH1 from patient sperm axonemes, proving CFAP206 is required upstream for radial spoke complex recruitment.\",\n      \"evidence\": \"Human exome sequencing identifying bi-allelic truncating variants, immunostaining of patient sperm, CRISPR-Cas9 mouse knockout, sperm ultrastructure analysis, ICSI embryo development assay\",\n      \"pmids\": [\"34255152\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Whether CFAP206 directly contacts WDR66/RSPH1 or acts indirectly was not resolved\",\n        \"Mechanism of poor ICSI outcomes beyond flagellar defects was not explored\",\n        \"No rescue experiment was performed in human or mouse systems\"\n      ]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Positioning CFAP206 specifically at the RS2 base and showing its stable docking depends on CFAP91 refined the assembly hierarchy, establishing that CFAP91 acts upstream of CFAP206 in RS2 biogenesis.\",\n      \"evidence\": \"Tetrahymena CFAP91 knockout with proteomic and fluorescence analysis of radial spoke components\",\n      \"pmids\": [\"36552811\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Whether CFAP91–CFAP206 interaction is direct or mediated by other RS2 components was not tested\",\n        \"This dependency was shown only in Tetrahymena; conservation in vertebrates was not confirmed\",\n        \"Structural basis for CFAP206 docking at the RS2 base is unknown\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The direct protein–protein interaction network of CFAP206 on the axonemal microtubule, its structural basis of docking at RS2, and whether it plays additional roles in inner dynein arm positioning independent of radial spokes remain unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"No atomic or cryo-EM structure of CFAP206 or its complex exists\",\n        \"No biochemical reconstitution of CFAP206–radial spoke interactions has been performed\",\n        \"Whether CFAP206 loss contributes to primary ciliary dyskinesia beyond male infertility is undetermined\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [1, 2]},\n      {\"term_id\": \"GO:0008092\", \"supporting_discovery_ids\": [0, 1]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005929\", \"supporting_discovery_ids\": [0, 1, 2]},\n      {\"term_id\": \"GO:0005815\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1852241\", \"supporting_discovery_ids\": [0, 1, 2]},\n      {\"term_id\": \"R-HSA-1474165\", \"supporting_discovery_ids\": [0, 1]}\n    ],\n    \"complexes\": [\n      \"Radial spoke 2 (RS2) complex\"\n    ],\n    \"partners\": [\n      \"CFAP91\",\n      \"WDR66\",\n      \"RSPH1\",\n      \"FOXJ1\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}