{"gene":"LRRCC1","run_date":"2026-04-28T18:30:27","timeline":{"discoveries":[{"year":2001,"finding":"VFL1 (Chlamydomonas ortholog of LRRCC1) encodes a 128 kD protein with five leucine-rich repeat sequences near the N-terminus and a large alpha-helical coiled-coil domain at the C-terminus. Epitope-tagged Vfl1p copurified with basal body flagellar apparatuses and localized by immunogold labeling inside the lumen of the basal body at the distal end, with rotationally asymmetric distribution near doublet microtubules facing the opposite basal body, establishing its role in correct rotational orientation of basal bodies.","method":"Epitope-tagged gene rescue, co-purification with basal body flagellar apparatus, immunofluorescence, immunogold electron microscopy","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 1-2 — multiple orthogonal methods (rescue, co-purification, immunogold EM) in a single study with functional validation","pmids":["11285274"],"is_preprint":false},{"year":2008,"finding":"CLERC (human ortholog of Chlamydomonas Vfl1, i.e., LRRCC1) is a centrosomal protein of 1032 amino acids (120 kDa) with leucine-rich repeat and coiled-coil domains. Endogenous CLERC associates with centrosomes throughout the cell cycle and accumulates during mitosis. RNAi-mediated depletion caused multipolar spindles and centrosome splitting into fractions containing single centrioles, demonstrating CLERC maintains centrosome structural integrity and spindle bipolarity.","method":"RNAi depletion, immunofluorescence localization throughout cell cycle, spindle pole phenotype analysis","journal":"Cell cycle (Georgetown, Tex.)","confidence":"High","confidence_rationale":"Tier 2 — clean KO/KD with defined cellular phenotype plus direct localization; multiple readouts (spindle multipolarity, centriole splitting)","pmids":["18728398"],"is_preprint":false},{"year":2022,"finding":"LRRCC1, the human ortholog of Chlamydomonas Vfl1, localizes preferentially to two consecutive triplets in the distal lumen of human centrioles as shown by ultrastructure expansion microscopy. LRRCC1 partially co-localizes with and affects recruitment of C2CD3 (also asymmetrically localized), together delineating a structure analogous to the flagellate 'acorn.' Depletion of LRRCC1 caused defects in centriole structure, ciliary assembly, and ciliary signaling.","method":"Ultrastructure expansion microscopy (U-ExM), RNAi depletion, co-localization and co-recruitment assays, ciliary signaling assays","journal":"eLife","confidence":"High","confidence_rationale":"Tier 1-2 — super-resolution structural localization combined with loss-of-function showing centriole, ciliogenesis, and signaling defects; multiple orthogonal methods","pmids":["35319462"],"is_preprint":false},{"year":2022,"finding":"Lrrcc1 in Xenopus multiciliated cells localizes as a basal body component at the proximal junction with striated rootlets. Knockdown of Lrrcc1 caused defects in basal body docking, spacing, and polarization, impaired the apical cytoskeleton, and altered ciliary beating, leading to greatly reduced cilia-powered fluid flow.","method":"Morpholino knockdown in Xenopus embryonic ciliated epidermis, immunofluorescence localization, cilia beat analysis, fluid flow assay","journal":"Journal of cell science","confidence":"High","confidence_rationale":"Tier 2 — vertebrate model with clean loss-of-function, defined subcellular localization, and multiple functional readouts (BB docking, polarization, beating, fluid flow)","pmids":["35067717"],"is_preprint":false},{"year":2019,"finding":"SMED-VFL1 (planarian ortholog of LRRCC1) is required for proper assembly of centriole appendages that tether cytoskeletal connectors, and its depletion disrupts centriole rotational asymmetry and bilaterally symmetric patterning of centrioles across the ventral epidermis.","method":"RNAi knockdown in planarian, immunofluorescence, centriole positioning analysis","journal":"Developmental cell","confidence":"Medium","confidence_rationale":"Tier 2 — clean RNAi with defined cellular phenotype in a model organism, but single study","pmids":["31743665"],"is_preprint":false},{"year":2025,"finding":"LRRCC1 is part of a C2CD3-SSNA1-LRRCC1 hierarchical targeting axis in the distal centriolar lumen. SSNA1 interactor screening and KO analysis placed LRRCC1 downstream of C2CD3 and SSNA1 in a targeting network required for distal lumen organization and ciliogenesis.","method":"KO-validated antibody, interactor screening, expansion microscopy, epistatic KO analysis","journal":"bioRxiv","confidence":"Medium","confidence_rationale":"Tier 2 — preprint with multiple orthogonal methods, but not yet peer-reviewed","pmids":["bio_10.1101_2025.04.28.648957"],"is_preprint":true},{"year":2016,"finding":"Mutations in LRRCC1 were identified in a ciliopathy patient cohort as a candidate causal gene for ciliopathy phenotypes, consistent with an established link to ciliogenesis.","method":"Genomic sequencing of ciliopathy patient cohort; bioinformatic functional linkage to ciliogenesis","journal":"Genome biology","confidence":"Low","confidence_rationale":"Tier 4 — genetic association without direct mechanistic experiment on LRRCC1 function","pmids":["27894351"],"is_preprint":false}],"current_model":"LRRCC1 (human ortholog of Chlamydomonas Vfl1/CLERC) is a leucine-rich repeat and coiled-coil domain protein that localizes asymmetrically to two consecutive triplets in the distal lumen of centrioles throughout the cell cycle, where it cooperates with C2CD3 (and is downstream of C2CD3 and SSNA1 in a targeting hierarchy) to maintain centriole structural integrity, establish rotational asymmetry, and promote primary ciliogenesis and ciliary signaling; its depletion causes multipolar spindles, basal body docking/polarization defects, impaired ciliary beating, and defective ciliary signaling."},"narrative":{"teleology":[{"year":2001,"claim":"Identification of the Chlamydomonas VFL1 gene product established that a leucine-rich repeat/coiled-coil protein resides asymmetrically in the distal basal body lumen and is required for correct rotational orientation of basal bodies, providing the first molecular handle on centriolar rotational asymmetry.","evidence":"Epitope-tagged rescue, immunogold EM, and co-purification with basal body apparatuses in Chlamydomonas","pmids":["11285274"],"confidence":"High","gaps":["Whether the mammalian ortholog shares the same localization and function was unknown","Direct interacting partners within the basal body lumen were not identified","How Vfl1 asymmetric positioning is established remained unresolved"]},{"year":2008,"claim":"Characterization of the human ortholog CLERC/LRRCC1 demonstrated that the protein associates with centrosomes throughout the cell cycle and is required to prevent centrosome splitting and multipolar spindle formation, extending the centriolar integrity function to mammalian cells.","evidence":"RNAi depletion in human cells with immunofluorescence and spindle pole analysis","pmids":["18728398"],"confidence":"High","gaps":["Sub-centriolar localization at nanometer resolution was not determined","Whether LRRCC1 is required for ciliogenesis in mammalian cells was untested","Mechanism by which LRRCC1 loss causes centrosome splitting was unknown"]},{"year":2019,"claim":"Work in planaria showed that the LRRCC1 ortholog SMED-VFL1 is required for centriole appendage assembly and bilaterally symmetric patterning of centrioles across tissues, generalizing the rotational asymmetry function to a metazoan context.","evidence":"RNAi knockdown in planarian ventral epidermis with centriole positioning analysis","pmids":["31743665"],"confidence":"Medium","gaps":["Single study in a non-standard model organism; independent confirmation in other metazoans needed","The molecular targets or appendage components regulated by SMED-VFL1 were not identified","Relationship to ciliary function in planaria was not directly assessed"]},{"year":2022,"claim":"Super-resolution expansion microscopy revealed that LRRCC1 occupies two consecutive triplets of the human distal centriolar lumen and cooperates with C2CD3 in an acorn-like structure required for centriole integrity, ciliogenesis, and ciliary signaling, resolving the nanoscale architecture and linking LRRCC1 to the ciliary signaling pathway.","evidence":"U-ExM, RNAi depletion, co-localization/co-recruitment assays, and Hedgehog signaling readouts in human cells","pmids":["35319462"],"confidence":"High","gaps":["Whether LRRCC1 directly binds C2CD3 or is co-recruited independently was unresolved","The full molecular composition of the human acorn structure was not determined","Structural basis for LRRCC1 asymmetric positioning on specific triplets was unknown"]},{"year":2022,"claim":"Functional studies in Xenopus multiciliated cells established that Lrrcc1 at the basal body proximal junction is essential for basal body docking, spacing, rotational polarization, and cilia-driven fluid flow, demonstrating its requirement in motile cilia function.","evidence":"Morpholino knockdown in Xenopus embryonic ciliated epidermis with beat frequency and flow assays","pmids":["35067717"],"confidence":"High","gaps":["Whether basal body docking defects are secondary to loss of rotational asymmetry or a separable function was not distinguished","Interaction partners at the proximal junction/rootlet interface were not identified"]},{"year":2025,"claim":"Epistatic KO analysis placed LRRCC1 downstream of C2CD3 and SSNA1 in a hierarchical targeting axis for distal lumen organization, defining the recruitment logic for the human acorn complex.","evidence":"(preprint) KO-validated antibodies, interactor screening, expansion microscopy, and epistatic KO analysis in human cells","pmids":["bio_10.1101_2025.04.28.648957"],"confidence":"Medium","gaps":["Preprint not yet peer-reviewed","Whether SSNA1 directly recruits LRRCC1 or acts indirectly through C2CD3 was not resolved","Structural basis for the hierarchical targeting was not determined"]},{"year":null,"claim":"The direct binding interfaces among LRRCC1, C2CD3, and SSNA1, the structural basis for LRRCC1's asymmetric positioning on specific centriolar triplets, and whether LRRCC1 mutations are causative for human ciliopathies remain to be established.","evidence":"","pmids":[],"confidence":"Low","gaps":["No crystal or cryo-EM structure of LRRCC1 or the acorn complex exists","No confirmed causative LRRCC1 mutations in human disease families","Mechanism by which LRRCC1 loss leads to multipolar spindles is unknown"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0005198","term_label":"structural molecule activity","supporting_discovery_ids":[0,1,2]}],"localization":[{"term_id":"GO:0005815","term_label":"microtubule organizing center","supporting_discovery_ids":[0,1,2,3]},{"term_id":"GO:0005929","term_label":"cilium","supporting_discovery_ids":[2,3]}],"pathway":[{"term_id":"R-HSA-1852241","term_label":"Organelle biogenesis and maintenance","supporting_discovery_ids":[0,1,2,3]},{"term_id":"R-HSA-1640170","term_label":"Cell Cycle","supporting_discovery_ids":[1]}],"complexes":[],"partners":["C2CD3","SSNA1"],"other_free_text":[]},"mechanistic_narrative":"LRRCC1 is a leucine-rich repeat and coiled-coil domain protein that localizes asymmetrically within the distal lumen of centrioles and basal bodies, where it establishes rotational asymmetry and maintains centriole structural integrity [PMID:11285274, PMID:35319462]. In human cells, LRRCC1 occupies two consecutive triplets of the distal centriolar lumen, partially co-localizes with C2CD3 in an acorn-like structure, and is required for proper ciliogenesis and ciliary signaling; its depletion causes multipolar spindles, centrosome splitting, and defective ciliary assembly [PMID:18728398, PMID:35319462]. In multiciliated epithelia, LRRCC1 is essential for basal body docking, spacing, rotational polarization, and cilia-driven fluid flow [PMID:35067717]. Across species from Chlamydomonas to planarians and vertebrates, LRRCC1/Vfl1 orthologs are required for centriole appendage assembly and the bilaterally symmetric orientation of basal bodies [PMID:11285274, PMID:31743665]."},"prefetch_data":{"uniprot":{"accession":"Q9C099","full_name":"Leucine-rich repeat and coiled-coil domain-containing protein 1","aliases":["Centrosomal leucine-rich repeat and coiled-coil domain-containing protein"],"length_aa":1032,"mass_kda":119.6,"function":"Required for the organization of the mitotic spindle. Maintains the structural integrity of centrosomes during mitosis","subcellular_location":"Cytoplasm, cytoskeleton, microtubule organizing center, centrosome, centriole","url":"https://www.uniprot.org/uniprotkb/Q9C099/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/LRRCC1","classification":"Not Classified","n_dependent_lines":2,"n_total_lines":1208,"dependency_fraction":0.0016556291390728477},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/LRRCC1","total_profiled":1310},"omim":[{"mim_id":"620676","title":"COILED-COIL DOMAIN-CONTAINING PROTEIN 61; CCDC61","url":"https://www.omim.org/entry/620676"},{"mim_id":"617791","title":"LEUCINE-RICH REPEAT- AND COILED-COIL DOMAIN-CONTAINING CENTROSOMAL PROTEIN 1; LRRCC1","url":"https://www.omim.org/entry/617791"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Centrosome","reliability":"Supported"},{"location":"Basal body","reliability":"Supported"},{"location":"Vesicles","reliability":"Additional"},{"location":"Primary cilium","reliability":"Additional"},{"location":"Primary cilium tip","reliability":"Additional"},{"location":"Cytosol","reliability":"Additional"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"testis","ntpm":31.3}],"url":"https://www.proteinatlas.org/search/LRRCC1"},"hgnc":{"alias_symbol":["KIAA1764","CLERC","VFL1"],"prev_symbol":[]},"alphafold":{"accession":"Q9C099","domains":[{"cath_id":"3.80.10.10","chopping":"26-214","consensus_level":"medium","plddt":88.6515,"start":26,"end":214}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9C099","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q9C099-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q9C099-F1-predicted_aligned_error_v6.png","plddt_mean":73.94},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=LRRCC1","jax_strain_url":"https://www.jax.org/strain/search?query=LRRCC1"},"sequence":{"accession":"Q9C099","fasta_url":"https://rest.uniprot.org/uniprotkb/Q9C099.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q9C099/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9C099"}},"corpus_meta":[{"pmid":"8244002","id":"PMC_8244002","title":"Cloning of flagellar genes in Chlamydomonas reinhardtii by DNA insertional mutagenesis.","date":"1993","source":"Genetics","url":"https://pubmed.ncbi.nlm.nih.gov/8244002","citation_count":191,"is_preprint":false},{"pmid":"27894351","id":"PMC_27894351","title":"Characterizing the morbid genome of ciliopathies.","date":"2016","source":"Genome biology","url":"https://pubmed.ncbi.nlm.nih.gov/27894351","citation_count":141,"is_preprint":false},{"pmid":"27713108","id":"PMC_27713108","title":"Chronic Exposure to Low Doses of Dioxin Promotes Liver Fibrosis Development in the C57BL/6J Diet-Induced Obesity Mouse Model.","date":"2016","source":"Environmental health perspectives","url":"https://pubmed.ncbi.nlm.nih.gov/27713108","citation_count":94,"is_preprint":false},{"pmid":"11285274","id":"PMC_11285274","title":"The Vfl1 Protein in Chlamydomonas localizes in a rotationally asymmetric pattern at the distal ends of the basal bodies.","date":"2001","source":"The Journal of cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/11285274","citation_count":79,"is_preprint":false},{"pmid":"9006937","id":"PMC_9006937","title":"Identification of two amino acids of the human cholecystokinin-A receptor that interact with the N-terminal moiety of cholecystokinin.","date":"1997","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/9006937","citation_count":67,"is_preprint":false},{"pmid":"2696598","id":"PMC_2696598","title":"Nucleus-basal body connector in Chlamydomonas: evidence for a role in basal body segregation and against essential roles in mitosis or in determining cell polarity.","date":"1989","source":"Cell motility and the cytoskeleton","url":"https://pubmed.ncbi.nlm.nih.gov/2696598","citation_count":59,"is_preprint":false},{"pmid":"1313017","id":"PMC_1313017","title":"Activated cGMP phosphodiesterase of retinal rods. A complex with transducin alpha subunit.","date":"1992","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/1313017","citation_count":58,"is_preprint":false},{"pmid":"8394130","id":"PMC_8394130","title":"G-protein-effector coupling: a real-time light-scattering assay for transducin-phosphodiesterase interaction.","date":"1993","source":"Biochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/8394130","citation_count":56,"is_preprint":false},{"pmid":"35544698","id":"PMC_35544698","title":"The glycosaminoglycan interactome 2.0.","date":"2022","source":"American journal of physiology. Cell physiology","url":"https://pubmed.ncbi.nlm.nih.gov/35544698","citation_count":53,"is_preprint":false},{"pmid":"15598228","id":"PMC_15598228","title":"A comparative expression analysis of gene transcripts in post-fertilization developmental stages of bovine embryos produced in vitro or in vivo.","date":"2004","source":"Reproduction in domestic animals = Zuchthygiene","url":"https://pubmed.ncbi.nlm.nih.gov/15598228","citation_count":50,"is_preprint":false},{"pmid":"3972905","id":"PMC_3972905","title":"Defective temporal and spatial control of flagellar assembly in a mutant of Chlamydomonas reinhardtii with variable flagellar number.","date":"1985","source":"The Journal of cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/3972905","citation_count":40,"is_preprint":false},{"pmid":"1331045","id":"PMC_1331045","title":"Enhanced GTPase activity of transducin when bound to cGMP phosphodiesterase in bovine retinal rods.","date":"1992","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/1331045","citation_count":30,"is_preprint":false},{"pmid":"12454973","id":"PMC_12454973","title":"Stage-specific expressed sequence tags obtained during preimplantation bovine development by differential display RT-PCR and suppression subtractive hybridization.","date":"2002","source":"Prenatal diagnosis","url":"https://pubmed.ncbi.nlm.nih.gov/12454973","citation_count":26,"is_preprint":false},{"pmid":"31743665","id":"PMC_31743665","title":"Emergence of a Bilaterally Symmetric Pattern from Chiral Components in the Planarian Epidermis.","date":"2019","source":"Developmental cell","url":"https://pubmed.ncbi.nlm.nih.gov/31743665","citation_count":19,"is_preprint":false},{"pmid":"35319462","id":"PMC_35319462","title":"Evolutionary conservation of centriole rotational asymmetry in the human centrosome.","date":"2022","source":"eLife","url":"https://pubmed.ncbi.nlm.nih.gov/35319462","citation_count":17,"is_preprint":false},{"pmid":"23320108","id":"PMC_23320108","title":"Katanin localization requires triplet microtubules in Chlamydomonas reinhardtii.","date":"2013","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/23320108","citation_count":15,"is_preprint":false},{"pmid":"18728398","id":"PMC_18728398","title":"An evolutionarily conserved leucine-rich repeat protein CLERC is a centrosomal protein required for spindle pole integrity.","date":"2008","source":"Cell cycle (Georgetown, Tex.)","url":"https://pubmed.ncbi.nlm.nih.gov/18728398","citation_count":11,"is_preprint":false},{"pmid":"35067717","id":"PMC_35067717","title":"Lrrcc1 and Ccdc61 are conserved effectors of multiciliated cell function.","date":"2022","source":"Journal of cell science","url":"https://pubmed.ncbi.nlm.nih.gov/35067717","citation_count":9,"is_preprint":false},{"pmid":"11185510","id":"PMC_11185510","title":"Genetics. Reprogramming X inactivation.","date":"2000","source":"Science (New York, N.Y.)","url":"https://pubmed.ncbi.nlm.nih.gov/11185510","citation_count":8,"is_preprint":false},{"pmid":"1310620","id":"PMC_1310620","title":"cGMP phosphodiesterase dependent light-induced scattering changes in suspensions of retinal disc membranes.","date":"1992","source":"Biochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/1310620","citation_count":5,"is_preprint":false},{"pmid":"36340761","id":"PMC_36340761","title":"A two-stage hybrid gene selection algorithm combined with machine learning models to predict the rupture status in intracranial aneurysms.","date":"2022","source":"Frontiers in neuroscience","url":"https://pubmed.ncbi.nlm.nih.gov/36340761","citation_count":4,"is_preprint":false},{"pmid":"29019298","id":"PMC_29019298","title":"A learned artisan debates the system of the world: Le Clerc versus Mallemant de Messange.","date":"2017","source":"British journal for the history of science","url":"https://pubmed.ncbi.nlm.nih.gov/29019298","citation_count":0,"is_preprint":false},{"pmid":null,"id":"bio_10.1101_2025.04.28.648957","title":"SSNA1 organizes the distal luminal centriolar network and promotes ciliogenesis without microtubule association","date":"2025-04-28","source":"bioRxiv","url":"https://doi.org/10.1101/2025.04.28.648957","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":12267,"output_tokens":1866,"usd":0.032396},"stage2":{"model":"claude-opus-4-6","input_tokens":5120,"output_tokens":2008,"usd":0.1137},"total_usd":0.146096,"stage1_batch_id":"msgbatch_01Mgbec4vM6c9vXht7JVJzss","stage2_batch_id":"msgbatch_01JkuuH5RB2BdJNsgnhjbC6s","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2001,\n      \"finding\": \"VFL1 (Chlamydomonas ortholog of LRRCC1) encodes a 128 kD protein with five leucine-rich repeat sequences near the N-terminus and a large alpha-helical coiled-coil domain at the C-terminus. Epitope-tagged Vfl1p copurified with basal body flagellar apparatuses and localized by immunogold labeling inside the lumen of the basal body at the distal end, with rotationally asymmetric distribution near doublet microtubules facing the opposite basal body, establishing its role in correct rotational orientation of basal bodies.\",\n      \"method\": \"Epitope-tagged gene rescue, co-purification with basal body flagellar apparatus, immunofluorescence, immunogold electron microscopy\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — multiple orthogonal methods (rescue, co-purification, immunogold EM) in a single study with functional validation\",\n      \"pmids\": [\"11285274\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"CLERC (human ortholog of Chlamydomonas Vfl1, i.e., LRRCC1) is a centrosomal protein of 1032 amino acids (120 kDa) with leucine-rich repeat and coiled-coil domains. Endogenous CLERC associates with centrosomes throughout the cell cycle and accumulates during mitosis. RNAi-mediated depletion caused multipolar spindles and centrosome splitting into fractions containing single centrioles, demonstrating CLERC maintains centrosome structural integrity and spindle bipolarity.\",\n      \"method\": \"RNAi depletion, immunofluorescence localization throughout cell cycle, spindle pole phenotype analysis\",\n      \"journal\": \"Cell cycle (Georgetown, Tex.)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — clean KO/KD with defined cellular phenotype plus direct localization; multiple readouts (spindle multipolarity, centriole splitting)\",\n      \"pmids\": [\"18728398\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"LRRCC1, the human ortholog of Chlamydomonas Vfl1, localizes preferentially to two consecutive triplets in the distal lumen of human centrioles as shown by ultrastructure expansion microscopy. LRRCC1 partially co-localizes with and affects recruitment of C2CD3 (also asymmetrically localized), together delineating a structure analogous to the flagellate 'acorn.' Depletion of LRRCC1 caused defects in centriole structure, ciliary assembly, and ciliary signaling.\",\n      \"method\": \"Ultrastructure expansion microscopy (U-ExM), RNAi depletion, co-localization and co-recruitment assays, ciliary signaling assays\",\n      \"journal\": \"eLife\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — super-resolution structural localization combined with loss-of-function showing centriole, ciliogenesis, and signaling defects; multiple orthogonal methods\",\n      \"pmids\": [\"35319462\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Lrrcc1 in Xenopus multiciliated cells localizes as a basal body component at the proximal junction with striated rootlets. Knockdown of Lrrcc1 caused defects in basal body docking, spacing, and polarization, impaired the apical cytoskeleton, and altered ciliary beating, leading to greatly reduced cilia-powered fluid flow.\",\n      \"method\": \"Morpholino knockdown in Xenopus embryonic ciliated epidermis, immunofluorescence localization, cilia beat analysis, fluid flow assay\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — vertebrate model with clean loss-of-function, defined subcellular localization, and multiple functional readouts (BB docking, polarization, beating, fluid flow)\",\n      \"pmids\": [\"35067717\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"SMED-VFL1 (planarian ortholog of LRRCC1) is required for proper assembly of centriole appendages that tether cytoskeletal connectors, and its depletion disrupts centriole rotational asymmetry and bilaterally symmetric patterning of centrioles across the ventral epidermis.\",\n      \"method\": \"RNAi knockdown in planarian, immunofluorescence, centriole positioning analysis\",\n      \"journal\": \"Developmental cell\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — clean RNAi with defined cellular phenotype in a model organism, but single study\",\n      \"pmids\": [\"31743665\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"LRRCC1 is part of a C2CD3-SSNA1-LRRCC1 hierarchical targeting axis in the distal centriolar lumen. SSNA1 interactor screening and KO analysis placed LRRCC1 downstream of C2CD3 and SSNA1 in a targeting network required for distal lumen organization and ciliogenesis.\",\n      \"method\": \"KO-validated antibody, interactor screening, expansion microscopy, epistatic KO analysis\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — preprint with multiple orthogonal methods, but not yet peer-reviewed\",\n      \"pmids\": [\"bio_10.1101_2025.04.28.648957\"],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Mutations in LRRCC1 were identified in a ciliopathy patient cohort as a candidate causal gene for ciliopathy phenotypes, consistent with an established link to ciliogenesis.\",\n      \"method\": \"Genomic sequencing of ciliopathy patient cohort; bioinformatic functional linkage to ciliogenesis\",\n      \"journal\": \"Genome biology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 4 — genetic association without direct mechanistic experiment on LRRCC1 function\",\n      \"pmids\": [\"27894351\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"LRRCC1 (human ortholog of Chlamydomonas Vfl1/CLERC) is a leucine-rich repeat and coiled-coil domain protein that localizes asymmetrically to two consecutive triplets in the distal lumen of centrioles throughout the cell cycle, where it cooperates with C2CD3 (and is downstream of C2CD3 and SSNA1 in a targeting hierarchy) to maintain centriole structural integrity, establish rotational asymmetry, and promote primary ciliogenesis and ciliary signaling; its depletion causes multipolar spindles, basal body docking/polarization defects, impaired ciliary beating, and defective ciliary signaling.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"LRRCC1 is a leucine-rich repeat and coiled-coil domain protein that localizes asymmetrically within the distal lumen of centrioles and basal bodies, where it establishes rotational asymmetry and maintains centriole structural integrity [PMID:11285274, PMID:35319462]. In human cells, LRRCC1 occupies two consecutive triplets of the distal centriolar lumen, partially co-localizes with C2CD3 in an acorn-like structure, and is required for proper ciliogenesis and ciliary signaling; its depletion causes multipolar spindles, centrosome splitting, and defective ciliary assembly [PMID:18728398, PMID:35319462]. In multiciliated epithelia, LRRCC1 is essential for basal body docking, spacing, rotational polarization, and cilia-driven fluid flow [PMID:35067717]. Across species from Chlamydomonas to planarians and vertebrates, LRRCC1/Vfl1 orthologs are required for centriole appendage assembly and the bilaterally symmetric orientation of basal bodies [PMID:11285274, PMID:31743665].\",\n  \"teleology\": [\n    {\n      \"year\": 2001,\n      \"claim\": \"Identification of the Chlamydomonas VFL1 gene product established that a leucine-rich repeat/coiled-coil protein resides asymmetrically in the distal basal body lumen and is required for correct rotational orientation of basal bodies, providing the first molecular handle on centriolar rotational asymmetry.\",\n      \"evidence\": \"Epitope-tagged rescue, immunogold EM, and co-purification with basal body apparatuses in Chlamydomonas\",\n      \"pmids\": [\"11285274\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Whether the mammalian ortholog shares the same localization and function was unknown\",\n        \"Direct interacting partners within the basal body lumen were not identified\",\n        \"How Vfl1 asymmetric positioning is established remained unresolved\"\n      ]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Characterization of the human ortholog CLERC/LRRCC1 demonstrated that the protein associates with centrosomes throughout the cell cycle and is required to prevent centrosome splitting and multipolar spindle formation, extending the centriolar integrity function to mammalian cells.\",\n      \"evidence\": \"RNAi depletion in human cells with immunofluorescence and spindle pole analysis\",\n      \"pmids\": [\"18728398\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Sub-centriolar localization at nanometer resolution was not determined\",\n        \"Whether LRRCC1 is required for ciliogenesis in mammalian cells was untested\",\n        \"Mechanism by which LRRCC1 loss causes centrosome splitting was unknown\"\n      ]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Work in planaria showed that the LRRCC1 ortholog SMED-VFL1 is required for centriole appendage assembly and bilaterally symmetric patterning of centrioles across tissues, generalizing the rotational asymmetry function to a metazoan context.\",\n      \"evidence\": \"RNAi knockdown in planarian ventral epidermis with centriole positioning analysis\",\n      \"pmids\": [\"31743665\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Single study in a non-standard model organism; independent confirmation in other metazoans needed\",\n        \"The molecular targets or appendage components regulated by SMED-VFL1 were not identified\",\n        \"Relationship to ciliary function in planaria was not directly assessed\"\n      ]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Super-resolution expansion microscopy revealed that LRRCC1 occupies two consecutive triplets of the human distal centriolar lumen and cooperates with C2CD3 in an acorn-like structure required for centriole integrity, ciliogenesis, and ciliary signaling, resolving the nanoscale architecture and linking LRRCC1 to the ciliary signaling pathway.\",\n      \"evidence\": \"U-ExM, RNAi depletion, co-localization/co-recruitment assays, and Hedgehog signaling readouts in human cells\",\n      \"pmids\": [\"35319462\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Whether LRRCC1 directly binds C2CD3 or is co-recruited independently was unresolved\",\n        \"The full molecular composition of the human acorn structure was not determined\",\n        \"Structural basis for LRRCC1 asymmetric positioning on specific triplets was unknown\"\n      ]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Functional studies in Xenopus multiciliated cells established that Lrrcc1 at the basal body proximal junction is essential for basal body docking, spacing, rotational polarization, and cilia-driven fluid flow, demonstrating its requirement in motile cilia function.\",\n      \"evidence\": \"Morpholino knockdown in Xenopus embryonic ciliated epidermis with beat frequency and flow assays\",\n      \"pmids\": [\"35067717\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Whether basal body docking defects are secondary to loss of rotational asymmetry or a separable function was not distinguished\",\n        \"Interaction partners at the proximal junction/rootlet interface were not identified\"\n      ]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Epistatic KO analysis placed LRRCC1 downstream of C2CD3 and SSNA1 in a hierarchical targeting axis for distal lumen organization, defining the recruitment logic for the human acorn complex.\",\n      \"evidence\": \"(preprint) KO-validated antibodies, interactor screening, expansion microscopy, and epistatic KO analysis in human cells\",\n      \"pmids\": [\"bio_10.1101_2025.04.28.648957\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Preprint not yet peer-reviewed\",\n        \"Whether SSNA1 directly recruits LRRCC1 or acts indirectly through C2CD3 was not resolved\",\n        \"Structural basis for the hierarchical targeting was not determined\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The direct binding interfaces among LRRCC1, C2CD3, and SSNA1, the structural basis for LRRCC1's asymmetric positioning on specific centriolar triplets, and whether LRRCC1 mutations are causative for human ciliopathies remain to be established.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"No crystal or cryo-EM structure of LRRCC1 or the acorn complex exists\",\n        \"No confirmed causative LRRCC1 mutations in human disease families\",\n        \"Mechanism by which LRRCC1 loss leads to multipolar spindles is unknown\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0005198\", \"supporting_discovery_ids\": [0, 1, 2]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005815\", \"supporting_discovery_ids\": [0, 1, 2, 3]},\n      {\"term_id\": \"GO:0005929\", \"supporting_discovery_ids\": [2, 3]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1852241\", \"supporting_discovery_ids\": [0, 1, 2, 3]},\n      {\"term_id\": \"R-HSA-1640170\", \"supporting_discovery_ids\": [1]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"C2CD3\", \"SSNA1\"],\n    \"other_free_text\": []\n  }\n}\n```"}