{"gene":"CCDC57","run_date":"2026-06-09T22:57:17","timeline":{"discoveries":[{"year":2020,"finding":"CCDC57 localizes to the proximal end of centrioles and interacts with the microcephaly protein CEP63, centriolar satellite proteins, and microtubules. Loss of CCDC57 causes defects in centriole duplication and failure to localize CEP63 and CEP152 to the centrosome. Its centrosome-targeting region is required for interaction with CEP63 and functions during centriole duplication and cilium assembly, whereas the microtubule-targeting region is required for mitotic functions. CCDC57 depletion also perturbs mitotic progression in both wild-type and centriole-less cells.","method":"Proximity mapping, superresolution imaging, Co-IP/pulldown, loss-of-function (siRNA depletion), domain mutagenesis","journal":"Cell reports","confidence":"High","confidence_rationale":"Tier 2 / Moderate — reciprocal interaction mapping, superresolution localization, domain-specific mutagenesis, and defined cellular phenotypes in a single rigorous study","pmids":["32402286"],"is_preprint":false},{"year":2023,"finding":"In zebrafish, Ccdc57 localizes to ciliary basal bodies and controls the planar polarity of ependymal cells by regulating microtubule network organization and proper positioning of basal bodies. Loss of ccdc57 causes uncoordinated cilia beating in ependymal cells, defective cerebrospinal fluid flow, hydrocephalus, and scoliosis. Mutant spinal cord showed altered expression of Urotensin neuropeptides consistent with spine curvature.","method":"Zebrafish mutant analysis, immunofluorescence localization, live imaging of cilia beating, CSF flow assay, in vivo loss-of-function","journal":"PLoS biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — ortholog (zebrafish), multiple orthogonal methods (localization, cilia beat imaging, CSF flow, mutant rescue), replicated by independent study (PMID:36669737)","pmids":["36862758"],"is_preprint":false},{"year":2023,"finding":"In zebrafish, Ccdc57 colocalizes with acetylated α-tubulin at cilia, and its loss specifically disrupts coordinated cilia beating of multiple cilia bundles in the brain ventricle, leading to impaired cerebrospinal fluid flow and spinal curvature. mRNA rescue or epinephrine treatment reverses spinal curvature and upregulates urotensin signaling, placing Ccdc57 upstream of urotensin in the pathway.","method":"Zebrafish mutant analysis (zygotic and maternal-zygotic), immunofluorescence colocalization, mRNA injection rescue, pharmacological rescue, cilia beat imaging","journal":"Journal of genetics and genomics","confidence":"High","confidence_rationale":"Tier 2 / Strong — ortholog (zebrafish), multiple orthogonal methods including genetic rescue and pharmacological rescue, consistent with independent study (PMID:36862758)","pmids":["36669737"],"is_preprint":false},{"year":2024,"finding":"CCDC57 localizes to basal bodies as a rotationally asymmetric punctum that polarizes away from the basal foot after rotational polarity is achieved. CCDC57 is required for coupling axonemal orientation to basal foot position during rotational polarization of basal bodies. Loss of CCDC57 in mice causes ependymal multicilia to lack basal foot–axonemal orientation coupling, resulting in directional beats only at the single-cell level (not coordinated across the epithelium), impaired CSF flow, severe hydrocephalus, and high mortality. Tracheal multicilia in Ccdc57−/− mice also fail to fully align their basal feet.","method":"Mouse knockout (Ccdc57−/−), superresolution imaging of basal body asymmetry, immunofluorescence of basal foot orientation, CSF flow measurement, in vivo loss-of-function phenotyping","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 / Strong — mouse knockout with defined structural mechanism (rotational asymmetry imaging), multiple tissue readouts, consistent with zebrafish ortholog studies","pmids":["39592607"],"is_preprint":false}],"current_model":"CCDC57 is a centrosomal/basal body-associated protein that localizes to the proximal end of centrioles and, as a rotationally asymmetric punctum, to basal bodies; it couples axonemal orientation to basal foot positioning during basal body rotational polarization, thereby coordinating directional ciliary beating across epithelia to drive CSF flow, and separately interacts with the microcephaly protein CEP63 and microtubules to regulate centriole duplication, CEP152/CEP63 centrosomal recruitment, and mitotic progression."},"narrative":{"mechanistic_narrative":"CCDC57 is a centriole- and basal body-associated protein that coordinates ciliary polarity and centrosome duplication across cell types [PMID:32402286, PMID:39592607]. At the proximal end of centrioles it interacts with the microcephaly protein CEP63, centriolar satellite proteins, and microtubules; its centrosome-targeting region mediates CEP63 binding and is required for centriole duplication and recruitment of CEP63 and CEP152 to the centrosome, while its microtubule-targeting region supports mitotic functions, and its loss perturbs mitotic progression even in centriole-less cells [PMID:32402286]. At basal bodies, CCDC57 is positioned as a rotationally asymmetric punctum that polarizes away from the basal foot, and it couples axonemal orientation to basal foot position during rotational polarization, thereby aligning ciliary beating across the epithelium [PMID:39592607]. Loss of CCDC57 disrupts coordinated multiciliary beating and cerebrospinal fluid flow, producing hydrocephalus and scoliosis, with rescue restoring spinal curvature and acting upstream of urotensin neuropeptide signaling [PMID:36862758, PMID:36669737, PMID:39592607].","teleology":[{"year":2020,"claim":"Established CCDC57 as a centriolar protein required for centriole duplication and for recruiting key centrosomal microcephaly factors, defining its earliest molecular role.","evidence":"Proximity mapping, superresolution imaging, Co-IP, siRNA depletion, and domain mutagenesis in human cells","pmids":["32402286"],"confidence":"High","gaps":["Mechanism by which CCDC57 promotes CEP63/CEP152 recruitment is not resolved","Structural basis of microtubule and CEP63 binding undefined","Separation of mitotic versus duplication functions only mapped to broad domains"]},{"year":2023,"claim":"Showed in vivo that CCDC57 controls planar polarity of ependymal cells and coordinated cilia beating, linking the protein to CSF flow and disease phenotypes (hydrocephalus, scoliosis).","evidence":"Zebrafish mutant analysis, immunofluorescence localization, cilia beat live imaging, CSF flow assay, and genetic/pharmacological rescue","pmids":["36862758","36669737"],"confidence":"High","gaps":["Molecular link between CCDC57 and microtubule network organization not detailed","How CCDC57 connects to downstream urotensin signaling is unresolved","Relationship between basal body positioning and planar polarity machinery undefined"]},{"year":2024,"claim":"Defined the structural mechanism: CCDC57 acts as a rotationally asymmetric basal body marker that couples axonemal orientation to basal foot position, explaining how it enforces epithelium-wide directional ciliary beating.","evidence":"Mouse Ccdc57 knockout, superresolution imaging of basal body asymmetry, basal foot orientation immunofluorescence, and CSF flow measurement across tissues","pmids":["39592607"],"confidence":"High","gaps":["Molecular partners establishing the asymmetric punctum are unidentified","How axonemal orientation signal is mechanically transmitted to the basal foot is unknown","Whether centriolar (CEP63/CEP152) functions and basal body polarity functions share a mechanism is unresolved"]},{"year":null,"claim":"How CCDC57's centriole-duplication/mitotic activities mechanistically relate to its basal body rotational-polarity function, and the molecular intermediaries to urotensin signaling, remain open.","evidence":"","pmids":[],"confidence":"High","gaps":["No structural model of CCDC57 or its complexes","No identified effectors bridging basal foot coupling to ciliary orientation","Mechanism connecting ciliary defects to urotensin pathway not established"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0008092","term_label":"cytoskeletal protein binding","supporting_discovery_ids":[0]}],"localization":[{"term_id":"GO:0005815","term_label":"microtubule organizing center","supporting_discovery_ids":[0]},{"term_id":"GO:0005929","term_label":"cilium","supporting_discovery_ids":[1,2,3]},{"term_id":"GO:0005856","term_label":"cytoskeleton","supporting_discovery_ids":[0,1]}],"pathway":[{"term_id":"R-HSA-1852241","term_label":"Organelle biogenesis and maintenance","supporting_discovery_ids":[0,3]},{"term_id":"R-HSA-1640170","term_label":"Cell Cycle","supporting_discovery_ids":[0]}],"complexes":[],"partners":["CEP63","CEP152"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q2TAC2","full_name":"Coiled-coil domain-containing protein 57","aliases":[],"length_aa":915,"mass_kda":103.0,"function":"Pleiotropic regulator of centriole duplication, mitosis, and ciliogenesis. Critical interface between centrosome and microtubule-mediated cellular processes. Centriole duplication protein required for recruitment of CEP63, CEP152, and PLK4 to the centrosome. Independent of its centrosomal targeting, localizes to and interacts with microtubules and regulates microtubule nucleation, stability, and mitotic progression","subcellular_location":"Cytoplasm, cytoskeleton, microtubule organizing center, centrosome; Cytoplasm, cytoskeleton, microtubule organizing center, centrosome, centriolar satellite; Cytoplasm, cytoskeleton, microtubule organizing center, centrosome, centriole; Cytoplasm, cytoskeleton, spindle","url":"https://www.uniprot.org/uniprotkb/Q2TAC2/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/CCDC57","classification":"Not Classified","n_dependent_lines":0,"n_total_lines":77,"dependency_fraction":0.0},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/CCDC57","total_profiled":1310},"omim":[{"mim_id":"150699","title":"LEIOMYOMA, UTERINE; UL","url":"https://www.omim.org/entry/150699"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Microtubules","reliability":"Approved"},{"location":"Centriolar satellite","reliability":"Additional"},{"location":"Cytosol","reliability":"Additional"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in many","driving_tissues":[],"url":"https://www.proteinatlas.org/search/CCDC57"},"hgnc":{"alias_symbol":["FLJ00130","FLJ23754"],"prev_symbol":[]},"alphafold":{"accession":"Q2TAC2","domains":[{"cath_id":"-","chopping":"8-206","consensus_level":"medium","plddt":95.4225,"start":8,"end":206}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q2TAC2","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q2TAC2-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q2TAC2-F1-predicted_aligned_error_v6.png","plddt_mean":70.19},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=CCDC57","jax_strain_url":"https://www.jax.org/strain/search?query=CCDC57"},"sequence":{"accession":"Q2TAC2","fasta_url":"https://rest.uniprot.org/uniprotkb/Q2TAC2.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q2TAC2/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q2TAC2"}},"corpus_meta":[{"pmid":"29164275","id":"PMC_29164275","title":"DNA methylation markers associated with type 2 diabetes, fasting glucose and HbA1c levels: a systematic review and replication in a case-control sample of the Lifelines study.","date":"2017","source":"Diabetologia","url":"https://pubmed.ncbi.nlm.nih.gov/29164275","citation_count":107,"is_preprint":false},{"pmid":"23040493","id":"PMC_23040493","title":"Genome-wide linkage and association analyses implicate FASN in predisposition to Uterine Leiomyomata.","date":"2012","source":"American journal of human genetics","url":"https://pubmed.ncbi.nlm.nih.gov/23040493","citation_count":71,"is_preprint":false},{"pmid":"24737029","id":"PMC_24737029","title":"DNA methylation status of a distinctively different subset of genes is associated with each histologic Lauren classification subtype in early gastric carcinogenesis.","date":"2014","source":"Oncology reports","url":"https://pubmed.ncbi.nlm.nih.gov/24737029","citation_count":31,"is_preprint":false},{"pmid":"36862758","id":"PMC_36862758","title":"Ependymal polarity defects coupled with disorganized ciliary beating drive abnormal cerebrospinal fluid flow and spine curvature in zebrafish.","date":"2023","source":"PLoS biology","url":"https://pubmed.ncbi.nlm.nih.gov/36862758","citation_count":23,"is_preprint":false},{"pmid":"32402286","id":"PMC_32402286","title":"CCDC57 Cooperates with Microtubules and Microcephaly Protein CEP63 and Regulates Centriole Duplication and Mitotic Progression.","date":"2020","source":"Cell reports","url":"https://pubmed.ncbi.nlm.nih.gov/32402286","citation_count":21,"is_preprint":false},{"pmid":"24315323","id":"PMC_24315323","title":"Fine mapping of a quantitative trait locus for bovine milk fat composition on Bos taurus autosome 19.","date":"2013","source":"Journal of dairy science","url":"https://pubmed.ncbi.nlm.nih.gov/24315323","citation_count":19,"is_preprint":false},{"pmid":"35094857","id":"PMC_35094857","title":"Genome-wide associations for heat stress response suggest potential candidate genes underlying milk fatty acid composition in dairy cattle.","date":"2022","source":"Journal of dairy science","url":"https://pubmed.ncbi.nlm.nih.gov/35094857","citation_count":19,"is_preprint":false},{"pmid":"32651461","id":"PMC_32651461","title":"Transcriptome-wide association study for restless legs syndrome identifies new susceptibility genes.","date":"2020","source":"Communications biology","url":"https://pubmed.ncbi.nlm.nih.gov/32651461","citation_count":18,"is_preprint":false},{"pmid":"26236334","id":"PMC_26236334","title":"Evaluation of GWAS candidate susceptibility loci for uterine leiomyoma in the multi-ethnic NIEHS uterine fibroid study.","date":"2015","source":"Frontiers in genetics","url":"https://pubmed.ncbi.nlm.nih.gov/26236334","citation_count":16,"is_preprint":false},{"pmid":"30265318","id":"PMC_30265318","title":"Genome-wide association study and prediction of genomic breeding values for fatty-acid composition in Korean Hanwoo cattle using a high-density single-nucleotide polymorphism 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protein CEP63, centriolar satellite proteins, and microtubules. Loss of CCDC57 causes defects in centriole duplication and failure to localize CEP63 and CEP152 to the centrosome. Its centrosome-targeting region is required for interaction with CEP63 and functions during centriole duplication and cilium assembly, whereas the microtubule-targeting region is required for mitotic functions. CCDC57 depletion also perturbs mitotic progression in both wild-type and centriole-less cells.\",\n      \"method\": \"Proximity mapping, superresolution imaging, Co-IP/pulldown, loss-of-function (siRNA depletion), domain mutagenesis\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal interaction mapping, superresolution localization, domain-specific mutagenesis, and defined cellular phenotypes in a single rigorous study\",\n      \"pmids\": [\"32402286\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"In zebrafish, Ccdc57 localizes to ciliary basal bodies and controls the planar polarity of ependymal cells by regulating microtubule network organization and proper positioning of basal bodies. Loss of ccdc57 causes uncoordinated cilia beating in ependymal cells, defective cerebrospinal fluid flow, hydrocephalus, and scoliosis. Mutant spinal cord showed altered expression of Urotensin neuropeptides consistent with spine curvature.\",\n      \"method\": \"Zebrafish mutant analysis, immunofluorescence localization, live imaging of cilia beating, CSF flow assay, in vivo loss-of-function\",\n      \"journal\": \"PLoS biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — ortholog (zebrafish), multiple orthogonal methods (localization, cilia beat imaging, CSF flow, mutant rescue), replicated by independent study (PMID:36669737)\",\n      \"pmids\": [\"36862758\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"In zebrafish, Ccdc57 colocalizes with acetylated α-tubulin at cilia, and its loss specifically disrupts coordinated cilia beating of multiple cilia bundles in the brain ventricle, leading to impaired cerebrospinal fluid flow and spinal curvature. mRNA rescue or epinephrine treatment reverses spinal curvature and upregulates urotensin signaling, placing Ccdc57 upstream of urotensin in the pathway.\",\n      \"method\": \"Zebrafish mutant analysis (zygotic and maternal-zygotic), immunofluorescence colocalization, mRNA injection rescue, pharmacological rescue, cilia beat imaging\",\n      \"journal\": \"Journal of genetics and genomics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — ortholog (zebrafish), multiple orthogonal methods including genetic rescue and pharmacological rescue, consistent with independent study (PMID:36862758)\",\n      \"pmids\": [\"36669737\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"CCDC57 localizes to basal bodies as a rotationally asymmetric punctum that polarizes away from the basal foot after rotational polarity is achieved. CCDC57 is required for coupling axonemal orientation to basal foot position during rotational polarization of basal bodies. Loss of CCDC57 in mice causes ependymal multicilia to lack basal foot–axonemal orientation coupling, resulting in directional beats only at the single-cell level (not coordinated across the epithelium), impaired CSF flow, severe hydrocephalus, and high mortality. Tracheal multicilia in Ccdc57−/− mice also fail to fully align their basal feet.\",\n      \"method\": \"Mouse knockout (Ccdc57−/−), superresolution imaging of basal body asymmetry, immunofluorescence of basal foot orientation, CSF flow measurement, in vivo loss-of-function phenotyping\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — mouse knockout with defined structural mechanism (rotational asymmetry imaging), multiple tissue readouts, consistent with zebrafish ortholog studies\",\n      \"pmids\": [\"39592607\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"CCDC57 is a centrosomal/basal body-associated protein that localizes to the proximal end of centrioles and, as a rotationally asymmetric punctum, to basal bodies; it couples axonemal orientation to basal foot positioning during basal body rotational polarization, thereby coordinating directional ciliary beating across epithelia to drive CSF flow, and separately interacts with the microcephaly protein CEP63 and microtubules to regulate centriole duplication, CEP152/CEP63 centrosomal recruitment, and mitotic progression.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"CCDC57 is a centriole- and basal body-associated protein that coordinates ciliary polarity and centrosome duplication across cell types [#0, #3]. At the proximal end of centrioles it interacts with the microcephaly protein CEP63, centriolar satellite proteins, and microtubules; its centrosome-targeting region mediates CEP63 binding and is required for centriole duplication and recruitment of CEP63 and CEP152 to the centrosome, while its microtubule-targeting region supports mitotic functions, and its loss perturbs mitotic progression even in centriole-less cells [#0]. At basal bodies, CCDC57 is positioned as a rotationally asymmetric punctum that polarizes away from the basal foot, and it couples axonemal orientation to basal foot position during rotational polarization, thereby aligning ciliary beating across the epithelium [#3]. Loss of CCDC57 disrupts coordinated multiciliary beating and cerebrospinal fluid flow, producing hydrocephalus and scoliosis, with rescue restoring spinal curvature and acting upstream of urotensin neuropeptide signaling [#1, #2, #3].\",\n  \"teleology\": [\n    {\n      \"year\": 2020,\n      \"claim\": \"Established CCDC57 as a centriolar protein required for centriole duplication and for recruiting key centrosomal microcephaly factors, defining its earliest molecular role.\",\n      \"evidence\": \"Proximity mapping, superresolution imaging, Co-IP, siRNA depletion, and domain mutagenesis in human cells\",\n      \"pmids\": [\"32402286\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism by which CCDC57 promotes CEP63/CEP152 recruitment is not resolved\", \"Structural basis of microtubule and CEP63 binding undefined\", \"Separation of mitotic versus duplication functions only mapped to broad domains\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Showed in vivo that CCDC57 controls planar polarity of ependymal cells and coordinated cilia beating, linking the protein to CSF flow and disease phenotypes (hydrocephalus, scoliosis).\",\n      \"evidence\": \"Zebrafish mutant analysis, immunofluorescence localization, cilia beat live imaging, CSF flow assay, and genetic/pharmacological rescue\",\n      \"pmids\": [\"36862758\", \"36669737\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular link between CCDC57 and microtubule network organization not detailed\", \"How CCDC57 connects to downstream urotensin signaling is unresolved\", \"Relationship between basal body positioning and planar polarity machinery undefined\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Defined the structural mechanism: CCDC57 acts as a rotationally asymmetric basal body marker that couples axonemal orientation to basal foot position, explaining how it enforces epithelium-wide directional ciliary beating.\",\n      \"evidence\": \"Mouse Ccdc57 knockout, superresolution imaging of basal body asymmetry, basal foot orientation immunofluorescence, and CSF flow measurement across tissues\",\n      \"pmids\": [\"39592607\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular partners establishing the asymmetric punctum are unidentified\", \"How axonemal orientation signal is mechanically transmitted to the basal foot is unknown\", \"Whether centriolar (CEP63/CEP152) functions and basal body polarity functions share a mechanism is unresolved\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How CCDC57's centriole-duplication/mitotic activities mechanistically relate to its basal body rotational-polarity function, and the molecular intermediaries to urotensin signaling, remain open.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No structural model of CCDC57 or its complexes\", \"No identified effectors bridging basal foot coupling to ciliary orientation\", \"Mechanism connecting ciliary defects to urotensin pathway not established\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0008092\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005815\", \"supporting_discovery_ids\": [0]},\n      {\"term_id\": \"GO:0005929\", \"supporting_discovery_ids\": [1, 2, 3]},\n      {\"term_id\": \"GO:0005856\", \"supporting_discovery_ids\": [0, 1]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1852241\", \"supporting_discovery_ids\": [0, 3]},\n      {\"term_id\": \"R-HSA-1640170\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"CEP63\", \"CEP152\"],\n    \"other_free_text\": []\n  }\n}\n```","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":4,"faith_total":4,"faith_pct":100.0}}