{"gene":"SDCCAG8","run_date":"2026-04-28T20:42:07","timeline":{"discoveries":[{"year":2003,"finding":"SDCCAG8 (CCCAP) localizes to centrosomes during both interphase and mitosis, is resistant to nocodazole-induced microtubule depolymerization (indicating it is an integral centrosomal component rather than a microtubule-associated protein), and its C-terminal coiled-coil domain mediates homo-oligomerization as demonstrated by yeast two-hybrid. N- and C-terminal truncations abolish centrosomal localization.","method":"Immunofluorescence localization, nocodazole treatment, yeast two-hybrid, truncation mutagenesis","journal":"Gene","confidence":"Medium","confidence_rationale":"Tier 2 — direct localization with functional consequence (truncations abolish targeting), single lab, multiple orthogonal methods","pmids":["12559564"],"is_preprint":false},{"year":2010,"finding":"SDCCAG8 localizes at both centrioles and directly interacts with OFD1 (oral-facial-digital syndrome 1 protein). Depletion of sdccag8 in zebrafish causes kidney cysts and body axis defects, and induces cell polarity defects in 3D renal cell cultures.","method":"Immunofluorescence, direct protein interaction assay (co-immunoprecipitation/pulldown), zebrafish morpholino knockdown, 3D renal cell culture","journal":"Nature genetics","confidence":"High","confidence_rationale":"Tier 2 — reciprocal interaction demonstrated, in vivo loss-of-function with defined phenotypes, replicated across model systems","pmids":["20835237"],"is_preprint":false},{"year":2012,"finding":"RPGRIP1 is required for ciliary targeting of SDCCAG8 in photoreceptor neurons; loss of RPGRIP1 expression shifts SDCCAG8 subcellular partitioning to the endoplasmic reticulum membrane fraction and strongly decreases its ciliary localization in photoreceptors but not in kidney cells, revealing cell type-dependent regulation of SDCCAG8 ciliary targeting.","method":"Immunofluorescence, subcellular fractionation, Rpgrip1 mutant mouse model","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2 — direct localization with functional consequence in genetic loss-of-function model, single lab","pmids":["22825473"],"is_preprint":false},{"year":2014,"finding":"Loss of Sdccag8 in a mouse gene-trap model causes retinal degeneration with rhodopsin mislocalization in photoreceptors, and renal pathology associated with elevated DNA damage response signaling (elevated γH2AX and phosphorylated ATM). Cell culture studies confirmed aberrant activation of ATM-dependent DNA damage response signaling and cell cycle profile abnormalities in Sdccag8-deficient cells.","method":"Sdccag8 gene-trap mouse model, immunofluorescence, western blotting (γH2AX, pATM), flow cytometry cell cycle analysis","journal":"Journal of the American Society of Nephrology","confidence":"High","confidence_rationale":"Tier 2 — clean KO mouse with defined molecular phenotype, validated in cell culture with multiple markers, single lab but multiple orthogonal methods","pmids":["24722439"],"is_preprint":false},{"year":2014,"finding":"SDCCAG8 regulates centrosomal accumulation of pericentriolar material (γ-tubulin and pericentrin), microtubule organization, centrosome-nucleus coupling, and neuronal migration in the developing cortex. SDCCAG8 interacts and co-traffics with PCM1 (pericentriolar material 1), a centriolar satellite protein required for centrosomal protein targeting.","method":"shRNA knockdown, loss-of-function allele in mouse cortex, immunofluorescence, co-immunoprecipitation (SDCCAG8–PCM1 interaction), live imaging","journal":"Neuron","confidence":"High","confidence_rationale":"Tier 2 — reciprocal Co-IP demonstrating interaction, clean KD/KO with defined cellular phenotype (migration, centrosomal recruitment), multiple orthogonal approaches in single lab","pmids":["25088364"],"is_preprint":false},{"year":2016,"finding":"SDCCAG8 interacts with centriolar satellite proteins OFD1 and AZI1, endosomal sorting complex proteins RABEP2 and ERC1, and non-muscle myosin motor proteins MYH9, MYH10, and MYH14 at the centrosome, as identified by affinity proteomics. SDCCAG8 regulates centrosomal localization of RABEP2, and SDCCAG8 is required for ciliogenesis and Hedgehog signaling.","method":"Affinity proteomics/mass spectrometry, co-immunoprecipitation, siRNA knockdown, immunofluorescence, Sdccag8 gene-trap mouse model","journal":"PloS one","confidence":"High","confidence_rationale":"Tier 1–2 — affinity proteomics identifying multiple interaction partners validated with Co-IP, KO mouse and siRNA knockdown with defined ciliogenesis and Hh signaling phenotypes","pmids":["27224062"],"is_preprint":false},{"year":2019,"finding":"SOX11 transcription factor directly binds the SDCCAG8 gene promoter and transcriptionally activates SDCCAG8 expression; wild-type but not DNA-binding mutant SOX11 induces SDCCAG8 promoter activity. SDCCAG8 mediates pro-tumorigenic effects of SOX11 on HNSCC cell proliferation, migration, and invasion.","method":"Chromatin immunoprecipitation (ChIP), luciferase reporter assay, rescue assay, SOX11 mutant overexpression","journal":"Journal of experimental & clinical cancer research","confidence":"Medium","confidence_rationale":"Tier 2 — ChIP + reporter assay + rescue, single lab, multiple orthogonal methods","pmids":["30922366"],"is_preprint":false},{"year":2020,"finding":"Genome editing-mediated loss of SDCCAG8 causes defects in primary ciliogenesis and cilium-dependent cell signaling, and impairs neuronal cell migration and differentiation.","method":"Genome editing (CRISPR), immunofluorescence for cilia, transcriptomic analysis, neuronal migration/differentiation assays","journal":"Human molecular genetics","confidence":"Medium","confidence_rationale":"Tier 2 — genome editing with defined ciliogenesis and signaling phenotypes, single lab","pmids":["31868218"],"is_preprint":false},{"year":2022,"finding":"The C-terminal region of SDCCAG8 (Sdccag8-C) is essential for its localization to centrosomes and cilia formation. Sdccag8-C interacts with ciliopathy kinases ICK/CILK1 and MAK, which regulate ciliary protein trafficking and cilia length. Truncation of Sdccag8-C in mice causes cilia formation defects and ciliopathy-like phenotypes including cleft palate, polydactyly, retinal degeneration, cystic kidney, and spermatogenesis defects.","method":"CRISPR knock-in truncation mouse model, co-immunoprecipitation (Sdccag8-C with ICK/CILK1 and MAK), immunofluorescence for centrosomal localization and cilia","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1–2 — domain-specific interaction identified by Co-IP, CRISPR knock-in mouse with multiple defined phenotypes, multiple orthogonal methods in single lab","pmids":["35131266"],"is_preprint":false},{"year":2022,"finding":"Hypomorphic Sdccag8 truncation mutations in knock-in mice cause defective cilia in photoreceptors, renal epithelial cells, and mouse embryonic fibroblasts, with major phototransduction protein mislocalization outside outer segments, confirming SDCCAG8's essential role in ciliogenesis as a primary driver of retinal ciliopathy pathology.","method":"CRISPR/Cas9 knock-in mouse models, electron microscopy, immunofluorescence for cilia and phototransduction proteins","journal":"Zoological research","confidence":"Medium","confidence_rationale":"Tier 2 — knock-in mouse models with defined cellular phenotypes, single lab","pmids":["35503560"],"is_preprint":false},{"year":2025,"finding":"SDCCAG8 protein localizes to the sperm manchette and centrosomal region and interacts with PCM1 (the centriolar satellite scaffold protein) through its coiled-coil domains 5–7. Loss of CC domains 5–8 destabilizes PCM1 and prevents recruitment of BBS4 and CEP131 to centriolar satellites, causing defective sperm flagellum biogenesis and male infertility (MMAF phenotype).","method":"Sdccag8 CC-domain truncation knock-in mouse, co-immunoprecipitation (SDCCAG8–PCM1), immunofluorescence for PCM1/BBS4/CEP131 at satellites, electron microscopy of flagella","journal":"Cells","confidence":"High","confidence_rationale":"Tier 1–2 — domain-specific interaction by Co-IP, downstream satellite protein recruitment mechanistically demonstrated, clean genetic model with defined structural and fertility phenotypes","pmids":["40801568"],"is_preprint":false},{"year":2025,"finding":"Intronic mutations in SDCCAG8 cause cryptic exon inclusion with premature termination codons and loss of SDCCAG8 protein; antisense oligonucleotides targeting the cryptic exon splice sites restore correct exon 7–8 splicing and rescue SDCCAG8 protein expression to ~40% of wild-type in patient-derived fibroblasts.","method":"RT-PCR splicing assay, RNA sequencing, western blotting; ASO-mediated splice-switching in patient fibroblasts","journal":"bioRxiv","confidence":"Medium","confidence_rationale":"Tier 2 — molecular mechanism of splicing defect and correction established with multiple methods; preprint, single lab","pmids":["41279107"],"is_preprint":true}],"current_model":"SDCCAG8 is an integral centrosomal/basal body protein whose C-terminal coiled-coil domains are essential for centrosomal localization, interaction with ICK/CILK1, MAK, and PCM1 (centriolar satellite scaffold), and recruitment of pericentriolar material; it regulates ciliogenesis and cilium-dependent Hedgehog signaling, controls ciliary trafficking of proteins such as NPHP4, RPGR, and rhodopsin (in a cell type-specific manner dependent on RPGRIP1), maintains centriolar satellite integrity (via PCM1/BBS4/CEP131) for sperm flagellum biogenesis, participates in DNA damage response signaling at centrosomes, and supports neuronal migration through centrosome–nucleus coupling, with transcriptional activation of its expression mediated by SOX11."},"narrative":{"teleology":[{"year":2003,"claim":"Establishing that SDCCAG8 is an integral centrosomal protein whose coiled-coil domains are required for centrosomal localization and self-association resolved its subcellular identity as a core centrosome component rather than a microtubule-associated protein.","evidence":"Immunofluorescence with nocodazole treatment, yeast two-hybrid, and truncation mutagenesis in cultured cells","pmids":["12559564"],"confidence":"Medium","gaps":["No interaction partners beyond self-association identified","No functional consequence of centrosomal loss assessed","Single lab, not independently replicated at this time"]},{"year":2010,"claim":"Demonstrating that SDCCAG8 interacts with the ciliopathy protein OFD1 and that its depletion causes kidney cysts and body-axis defects in zebrafish established SDCCAG8 as a ciliopathy gene required for renal and planar cell polarity.","evidence":"Co-immunoprecipitation, zebrafish morpholino knockdown, 3D renal cell culture","pmids":["20835237"],"confidence":"High","gaps":["Mechanism by which SDCCAG8 loss leads to cystogenesis undefined","No mammalian loss-of-function model yet"]},{"year":2012,"claim":"Showing that RPGRIP1 is required for SDCCAG8 ciliary targeting specifically in photoreceptors but not kidney cells revealed cell-type-specific regulation of SDCCAG8 localization.","evidence":"Rpgrip1 mutant mouse, immunofluorescence, subcellular fractionation","pmids":["22825473"],"confidence":"Medium","gaps":["Molecular basis of RPGRIP1-dependent targeting not defined","Whether other cell types use analogous adaptors unknown","Single lab study"]},{"year":2014,"claim":"Two concurrent studies showed that SDCCAG8 recruits pericentriolar material and PCM1 to centrosomes for neuronal migration, and that its loss activates ATM-dependent DNA damage signaling alongside retinal and renal pathology, broadening its function beyond ciliogenesis to centrosome–nucleus coupling and genome maintenance.","evidence":"Sdccag8 gene-trap mouse, shRNA knockdown in cortex, co-immunoprecipitation of SDCCAG8–PCM1, γH2AX/pATM immunoblotting, flow cytometry","pmids":["24722439","25088364"],"confidence":"High","gaps":["Whether DNA damage response activation is direct or secondary to ciliary/centrosomal dysfunction unclear","Mechanism linking PCM1 co-trafficking to pericentriolar material recruitment not resolved"]},{"year":2016,"claim":"Affinity proteomics expanded the SDCCAG8 interactome to include endosomal sorting proteins (RABEP2, ERC1) and non-muscle myosins, and demonstrated that SDCCAG8 is required for Hedgehog signaling, linking it to cilium-dependent morphogen pathways.","evidence":"Tandem affinity purification/mass spectrometry, siRNA knockdown, Sdccag8 gene-trap mouse, Hedgehog reporter assays","pmids":["27224062"],"confidence":"High","gaps":["Functional significance of RABEP2 and myosin interactions for ciliogenesis untested","Hedgehog signaling rescue not demonstrated"]},{"year":2020,"claim":"CRISPR-mediated knockout in human cells confirmed SDCCAG8's cell-autonomous requirement for ciliogenesis, cilium-dependent signaling, and neuronal migration/differentiation, validating prior knockdown findings in a human context.","evidence":"CRISPR knockout in human cells, immunofluorescence, transcriptomics, neuronal differentiation assays","pmids":["31868218"],"confidence":"Medium","gaps":["Specific signaling pathways downstream of ciliary loss not fully dissected","Single lab"]},{"year":2022,"claim":"Precise C-terminal truncation in knock-in mice pinpointed the C-terminal coiled-coil region as the domain mediating interactions with ciliopathy kinases ICK/CILK1 and MAK and as essential for centrosomal localization, cilia formation, and prevention of multi-organ ciliopathy phenotypes.","evidence":"CRISPR knock-in truncation mouse models, co-immunoprecipitation with ICK and MAK, electron microscopy, immunofluorescence","pmids":["35131266","35503560"],"confidence":"High","gaps":["Whether ICK/MAK phosphorylate SDCCAG8 directly unknown","Structural basis of C-terminal domain interactions not determined"]},{"year":2025,"claim":"Mapping SDCCAG8's coiled-coil domains 5–7 as the PCM1-binding interface and showing that their loss destabilizes centriolar satellite proteins BBS4 and CEP131, causing defective sperm flagellum biogenesis, established a molecular mechanism linking SDCCAG8 to satellite integrity and male fertility.","evidence":"CC-domain truncation knock-in mouse, co-immunoprecipitation of SDCCAG8–PCM1 domain mapping, immunofluorescence for satellite markers, electron microscopy of flagella","pmids":["40801568"],"confidence":"High","gaps":["Whether satellite destabilization fully accounts for all ciliopathy phenotypes not tested","Direct stoichiometry or structure of SDCCAG8–PCM1 complex unknown"]},{"year":null,"claim":"Key unresolved questions include the structural basis of SDCCAG8's interactions with PCM1, ICK/MAK, and OFD1; whether the DNA damage response phenotype is a direct function or secondary to centrosomal/ciliary defects; and the full spectrum of ciliary cargo whose trafficking depends on SDCCAG8.","evidence":"","pmids":[],"confidence":"Low","gaps":["No atomic-resolution structural data for SDCCAG8 or its complexes","DNA damage response mechanism not separated from ciliary dysfunction","Complete inventory of SDCCAG8-dependent ciliary cargo lacking"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0008092","term_label":"cytoskeletal protein binding","supporting_discovery_ids":[4,10]},{"term_id":"GO:0005198","term_label":"structural molecule activity","supporting_discovery_ids":[0,4,10]}],"localization":[{"term_id":"GO:0005815","term_label":"microtubule organizing center","supporting_discovery_ids":[0,1,4,5,8,10]},{"term_id":"GO:0005929","term_label":"cilium","supporting_discovery_ids":[2,5,7,8,9]},{"term_id":"GO:0005856","term_label":"cytoskeleton","supporting_discovery_ids":[4,10]}],"pathway":[{"term_id":"R-HSA-1852241","term_label":"Organelle biogenesis and maintenance","supporting_discovery_ids":[0,1,5,8,9,10]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[5,7]},{"term_id":"R-HSA-73894","term_label":"DNA Repair","supporting_discovery_ids":[3]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[4,7]}],"complexes":["centriolar satellites (PCM1/BBS4/CEP131)"],"partners":["PCM1","OFD1","ICK","MAK","RABEP2","RPGRIP1","BBS4","CEP131"],"other_free_text":[]},"mechanistic_narrative":"SDCCAG8 is a centrosomal and basal body protein essential for ciliogenesis, centriolar satellite integrity, and cilium-dependent signaling across multiple tissue types. Its C-terminal coiled-coil domains mediate centrosomal targeting, homo-oligomerization, and direct interactions with ICK/CILK1, MAK, and the centriolar satellite scaffold protein PCM1, through which it recruits pericentriolar material (γ-tubulin, pericentrin) and satellite components (BBS4, CEP131) required for cilium and sperm flagellum assembly [PMID:12559564, PMID:25088364, PMID:35131266, PMID:40801568]. Loss of SDCCAG8 disrupts primary cilia formation, Hedgehog signaling, ciliary trafficking of photoreceptor proteins (rhodopsin, RPGR), centrosome–nucleus coupling during neuronal migration, and activates aberrant ATM-dependent DNA damage response signaling [PMID:24722439, PMID:27224062, PMID:31868218]. Biallelic mutations in SDCCAG8 cause a multi-organ ciliopathy in mice and humans characterized by retinal degeneration, cystic kidneys, polydactyly, cleft palate, and male infertility [PMID:20835237, PMID:35131266, PMID:35503560]."},"prefetch_data":{"uniprot":{"accession":"Q86SQ7","full_name":"Serologically defined colon cancer antigen 8","aliases":["Antigen NY-CO-8","Centrosomal colon cancer autoantigen protein","hCCCAP"],"length_aa":713,"mass_kda":82.7,"function":"Plays a role in the establishment of cell polarity and epithelial lumen formation (By similarity). Also plays an essential role in ciliogenesis and subsequent Hedgehog signaling pathway that requires the presence of intact primary cilia for pathway activation. Mechanistically, interacts with and mediates RABEP2 centrosomal localization which is critical for ciliogenesis (PubMed:27224062)","subcellular_location":"Cytoplasm","url":"https://www.uniprot.org/uniprotkb/Q86SQ7/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/SDCCAG8","classification":"Not Classified","n_dependent_lines":0,"n_total_lines":1208,"dependency_fraction":0.0},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/SDCCAG8","total_profiled":1310},"omim":[{"mim_id":"615993","title":"BARDET-BIEDL SYNDROME 16; BBS16","url":"https://www.omim.org/entry/615993"},{"mim_id":"614848","title":"CENTROSOMAL PROTEIN, 164-KD; CEP164","url":"https://www.omim.org/entry/614848"},{"mim_id":"613615","title":"SENIOR-LOKEN SYNDROME 7; SLSN7","url":"https://www.omim.org/entry/613615"},{"mim_id":"613524","title":"SHH SIGNALING AND CILIOGENESIS REGULATOR SDCCAG8; SDCCAG8","url":"https://www.omim.org/entry/613524"},{"mim_id":"604557","title":"ZINC FINGER PROTEIN 423; ZNF423","url":"https://www.omim.org/entry/604557"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Centrosome","reliability":"Supported"},{"location":"Basal body","reliability":"Supported"},{"location":"Primary cilium","reliability":"Additional"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/SDCCAG8"},"hgnc":{"alias_symbol":["NY-CO-8","CCCAP","SLSN7","NPHP10","BBS16"],"prev_symbol":[]},"alphafold":{"accession":"Q86SQ7","domains":[{"cath_id":"1.20.5","chopping":"553-577","consensus_level":"medium","plddt":87.3688,"start":553,"end":577}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q86SQ7","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q86SQ7-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q86SQ7-F1-predicted_aligned_error_v6.png","plddt_mean":77.94},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=SDCCAG8","jax_strain_url":"https://www.jax.org/strain/search?query=SDCCAG8"},"sequence":{"accession":"Q86SQ7","fasta_url":"https://rest.uniprot.org/uniprotkb/Q86SQ7.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q86SQ7/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q86SQ7"}},"corpus_meta":[{"pmid":"20835237","id":"PMC_20835237","title":"Candidate exome capture identifies mutation of SDCCAG8 as the cause of a retinal-renal ciliopathy.","date":"2010","source":"Nature genetics","url":"https://pubmed.ncbi.nlm.nih.gov/20835237","citation_count":269,"is_preprint":false},{"pmid":"22190896","id":"PMC_22190896","title":"Mutations in SDCCAG8/NPHP10 Cause Bardet-Biedl Syndrome and Are Associated with Penetrant Renal Disease and Absent Polydactyly.","date":"2011","source":"Molecular syndromology","url":"https://pubmed.ncbi.nlm.nih.gov/22190896","citation_count":67,"is_preprint":false},{"pmid":"24722439","id":"PMC_24722439","title":"Renal-retinal ciliopathy gene Sdccag8 regulates DNA damage response signaling.","date":"2014","source":"Journal of the American Society of Nephrology : JASN","url":"https://pubmed.ncbi.nlm.nih.gov/24722439","citation_count":61,"is_preprint":false},{"pmid":"25088364","id":"PMC_25088364","title":"SDCCAG8 regulates pericentriolar material recruitment and neuronal migration in the developing cortex.","date":"2014","source":"Neuron","url":"https://pubmed.ncbi.nlm.nih.gov/25088364","citation_count":46,"is_preprint":false},{"pmid":"22825473","id":"PMC_22825473","title":"Selective loss of RPGRIP1-dependent ciliary targeting of NPHP4, RPGR and SDCCAG8 underlies the degeneration of photoreceptor neurons.","date":"2012","source":"Cell death & disease","url":"https://pubmed.ncbi.nlm.nih.gov/22825473","citation_count":41,"is_preprint":false},{"pmid":"30922366","id":"PMC_30922366","title":"Sox11 promotes head and neck cancer progression via the regulation of SDCCAG8.","date":"2019","source":"Journal of experimental & clinical cancer research : CR","url":"https://pubmed.ncbi.nlm.nih.gov/30922366","citation_count":30,"is_preprint":false},{"pmid":"12559564","id":"PMC_12559564","title":"Identification and characterization of the novel centrosome-associated protein CCCAP.","date":"2003","source":"Gene","url":"https://pubmed.ncbi.nlm.nih.gov/12559564","citation_count":25,"is_preprint":false},{"pmid":"27224062","id":"PMC_27224062","title":"SDCCAG8 Interacts with RAB Effector Proteins RABEP2 and ERC1 and Is Required for Hedgehog Signaling.","date":"2016","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/27224062","citation_count":23,"is_preprint":false},{"pmid":"35131266","id":"PMC_35131266","title":"The carboxyl-terminal region of SDCCAG8 comprises a functional module essential for cilia formation as well as organ development and homeostasis.","date":"2022","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/35131266","citation_count":14,"is_preprint":false},{"pmid":"31868218","id":"PMC_31868218","title":"Altered gene regulation as a candidate mechanism by which ciliopathy gene SDCCAG8 contributes to schizophrenia and cognitive function.","date":"2020","source":"Human molecular genetics","url":"https://pubmed.ncbi.nlm.nih.gov/31868218","citation_count":12,"is_preprint":false},{"pmid":"32926352","id":"PMC_32926352","title":"A novel splice site mutation in the SDCCAG8 gene in an Iranian family with Bardet-Biedl syndrome.","date":"2020","source":"International ophthalmology","url":"https://pubmed.ncbi.nlm.nih.gov/32926352","citation_count":6,"is_preprint":false},{"pmid":"31534065","id":"PMC_31534065","title":"Rapidly Progressive Nephronophthisis in a 2-Year-Old Boy with a Homozygous SDCCAG8 Mutation.","date":"2019","source":"The Tohoku journal of experimental medicine","url":"https://pubmed.ncbi.nlm.nih.gov/31534065","citation_count":5,"is_preprint":false},{"pmid":"35503560","id":"PMC_35503560","title":"Characterization of two novel knock-in mouse models of syndromic retinal ciliopathy carrying hypomorphic Sdccag8 mutations.","date":"2022","source":"Zoological research","url":"https://pubmed.ncbi.nlm.nih.gov/35503560","citation_count":4,"is_preprint":false},{"pmid":"34375487","id":"PMC_34375487","title":"Genetic variants of SDCCAG8 and MAGI2 in mitosis-related pathway genes are independent predictors of cutaneous melanoma-specific survival.","date":"2021","source":"Cancer science","url":"https://pubmed.ncbi.nlm.nih.gov/34375487","citation_count":2,"is_preprint":false},{"pmid":"36090644","id":"PMC_36090644","title":"Locally advanced undifferentiated small round cell sarcoma of the lung with novel SDCCAG8-AKT3 fusion and type II tumor immunity in the microenvironment: a rare case report.","date":"2022","source":"Translational lung cancer research","url":"https://pubmed.ncbi.nlm.nih.gov/36090644","citation_count":2,"is_preprint":false},{"pmid":"40801568","id":"PMC_40801568","title":"Loss of C-Terminal Coiled-Coil Domains in SDCCAG8 Impairs Centriolar Satellites and Causes Defective Sperm Flagellum Biogenesis and Male Fertility.","date":"2025","source":"Cells","url":"https://pubmed.ncbi.nlm.nih.gov/40801568","citation_count":2,"is_preprint":false},{"pmid":"41279107","id":"PMC_41279107","title":"Splice-switching antisense oligonucleotides correct cryptic exon inclusion and restore SDCCAG8 protein in Bardet-Biedl Syndrome.","date":"2025","source":"bioRxiv : the preprint server for biology","url":"https://pubmed.ncbi.nlm.nih.gov/41279107","citation_count":0,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":10771,"output_tokens":3137,"usd":0.039684},"stage2":{"model":"claude-opus-4-6","input_tokens":6513,"output_tokens":2481,"usd":0.141885},"total_usd":0.181569,"stage1_batch_id":"msgbatch_011rkcQdVV1RaFq9XhcG6df6","stage2_batch_id":"msgbatch_01RzgrJafdF4EWHhj5mNi6dh","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2003,\n      \"finding\": \"SDCCAG8 (CCCAP) localizes to centrosomes during both interphase and mitosis, is resistant to nocodazole-induced microtubule depolymerization (indicating it is an integral centrosomal component rather than a microtubule-associated protein), and its C-terminal coiled-coil domain mediates homo-oligomerization as demonstrated by yeast two-hybrid. N- and C-terminal truncations abolish centrosomal localization.\",\n      \"method\": \"Immunofluorescence localization, nocodazole treatment, yeast two-hybrid, truncation mutagenesis\",\n      \"journal\": \"Gene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — direct localization with functional consequence (truncations abolish targeting), single lab, multiple orthogonal methods\",\n      \"pmids\": [\"12559564\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"SDCCAG8 localizes at both centrioles and directly interacts with OFD1 (oral-facial-digital syndrome 1 protein). Depletion of sdccag8 in zebrafish causes kidney cysts and body axis defects, and induces cell polarity defects in 3D renal cell cultures.\",\n      \"method\": \"Immunofluorescence, direct protein interaction assay (co-immunoprecipitation/pulldown), zebrafish morpholino knockdown, 3D renal cell culture\",\n      \"journal\": \"Nature genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal interaction demonstrated, in vivo loss-of-function with defined phenotypes, replicated across model systems\",\n      \"pmids\": [\"20835237\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"RPGRIP1 is required for ciliary targeting of SDCCAG8 in photoreceptor neurons; loss of RPGRIP1 expression shifts SDCCAG8 subcellular partitioning to the endoplasmic reticulum membrane fraction and strongly decreases its ciliary localization in photoreceptors but not in kidney cells, revealing cell type-dependent regulation of SDCCAG8 ciliary targeting.\",\n      \"method\": \"Immunofluorescence, subcellular fractionation, Rpgrip1 mutant mouse model\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — direct localization with functional consequence in genetic loss-of-function model, single lab\",\n      \"pmids\": [\"22825473\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"Loss of Sdccag8 in a mouse gene-trap model causes retinal degeneration with rhodopsin mislocalization in photoreceptors, and renal pathology associated with elevated DNA damage response signaling (elevated γH2AX and phosphorylated ATM). Cell culture studies confirmed aberrant activation of ATM-dependent DNA damage response signaling and cell cycle profile abnormalities in Sdccag8-deficient cells.\",\n      \"method\": \"Sdccag8 gene-trap mouse model, immunofluorescence, western blotting (γH2AX, pATM), flow cytometry cell cycle analysis\",\n      \"journal\": \"Journal of the American Society of Nephrology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — clean KO mouse with defined molecular phenotype, validated in cell culture with multiple markers, single lab but multiple orthogonal methods\",\n      \"pmids\": [\"24722439\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"SDCCAG8 regulates centrosomal accumulation of pericentriolar material (γ-tubulin and pericentrin), microtubule organization, centrosome-nucleus coupling, and neuronal migration in the developing cortex. SDCCAG8 interacts and co-traffics with PCM1 (pericentriolar material 1), a centriolar satellite protein required for centrosomal protein targeting.\",\n      \"method\": \"shRNA knockdown, loss-of-function allele in mouse cortex, immunofluorescence, co-immunoprecipitation (SDCCAG8–PCM1 interaction), live imaging\",\n      \"journal\": \"Neuron\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal Co-IP demonstrating interaction, clean KD/KO with defined cellular phenotype (migration, centrosomal recruitment), multiple orthogonal approaches in single lab\",\n      \"pmids\": [\"25088364\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"SDCCAG8 interacts with centriolar satellite proteins OFD1 and AZI1, endosomal sorting complex proteins RABEP2 and ERC1, and non-muscle myosin motor proteins MYH9, MYH10, and MYH14 at the centrosome, as identified by affinity proteomics. SDCCAG8 regulates centrosomal localization of RABEP2, and SDCCAG8 is required for ciliogenesis and Hedgehog signaling.\",\n      \"method\": \"Affinity proteomics/mass spectrometry, co-immunoprecipitation, siRNA knockdown, immunofluorescence, Sdccag8 gene-trap mouse model\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — affinity proteomics identifying multiple interaction partners validated with Co-IP, KO mouse and siRNA knockdown with defined ciliogenesis and Hh signaling phenotypes\",\n      \"pmids\": [\"27224062\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"SOX11 transcription factor directly binds the SDCCAG8 gene promoter and transcriptionally activates SDCCAG8 expression; wild-type but not DNA-binding mutant SOX11 induces SDCCAG8 promoter activity. SDCCAG8 mediates pro-tumorigenic effects of SOX11 on HNSCC cell proliferation, migration, and invasion.\",\n      \"method\": \"Chromatin immunoprecipitation (ChIP), luciferase reporter assay, rescue assay, SOX11 mutant overexpression\",\n      \"journal\": \"Journal of experimental & clinical cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — ChIP + reporter assay + rescue, single lab, multiple orthogonal methods\",\n      \"pmids\": [\"30922366\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Genome editing-mediated loss of SDCCAG8 causes defects in primary ciliogenesis and cilium-dependent cell signaling, and impairs neuronal cell migration and differentiation.\",\n      \"method\": \"Genome editing (CRISPR), immunofluorescence for cilia, transcriptomic analysis, neuronal migration/differentiation assays\",\n      \"journal\": \"Human molecular genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — genome editing with defined ciliogenesis and signaling phenotypes, single lab\",\n      \"pmids\": [\"31868218\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"The C-terminal region of SDCCAG8 (Sdccag8-C) is essential for its localization to centrosomes and cilia formation. Sdccag8-C interacts with ciliopathy kinases ICK/CILK1 and MAK, which regulate ciliary protein trafficking and cilia length. Truncation of Sdccag8-C in mice causes cilia formation defects and ciliopathy-like phenotypes including cleft palate, polydactyly, retinal degeneration, cystic kidney, and spermatogenesis defects.\",\n      \"method\": \"CRISPR knock-in truncation mouse model, co-immunoprecipitation (Sdccag8-C with ICK/CILK1 and MAK), immunofluorescence for centrosomal localization and cilia\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — domain-specific interaction identified by Co-IP, CRISPR knock-in mouse with multiple defined phenotypes, multiple orthogonal methods in single lab\",\n      \"pmids\": [\"35131266\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Hypomorphic Sdccag8 truncation mutations in knock-in mice cause defective cilia in photoreceptors, renal epithelial cells, and mouse embryonic fibroblasts, with major phototransduction protein mislocalization outside outer segments, confirming SDCCAG8's essential role in ciliogenesis as a primary driver of retinal ciliopathy pathology.\",\n      \"method\": \"CRISPR/Cas9 knock-in mouse models, electron microscopy, immunofluorescence for cilia and phototransduction proteins\",\n      \"journal\": \"Zoological research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — knock-in mouse models with defined cellular phenotypes, single lab\",\n      \"pmids\": [\"35503560\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"SDCCAG8 protein localizes to the sperm manchette and centrosomal region and interacts with PCM1 (the centriolar satellite scaffold protein) through its coiled-coil domains 5–7. Loss of CC domains 5–8 destabilizes PCM1 and prevents recruitment of BBS4 and CEP131 to centriolar satellites, causing defective sperm flagellum biogenesis and male infertility (MMAF phenotype).\",\n      \"method\": \"Sdccag8 CC-domain truncation knock-in mouse, co-immunoprecipitation (SDCCAG8–PCM1), immunofluorescence for PCM1/BBS4/CEP131 at satellites, electron microscopy of flagella\",\n      \"journal\": \"Cells\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — domain-specific interaction by Co-IP, downstream satellite protein recruitment mechanistically demonstrated, clean genetic model with defined structural and fertility phenotypes\",\n      \"pmids\": [\"40801568\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Intronic mutations in SDCCAG8 cause cryptic exon inclusion with premature termination codons and loss of SDCCAG8 protein; antisense oligonucleotides targeting the cryptic exon splice sites restore correct exon 7–8 splicing and rescue SDCCAG8 protein expression to ~40% of wild-type in patient-derived fibroblasts.\",\n      \"method\": \"RT-PCR splicing assay, RNA sequencing, western blotting; ASO-mediated splice-switching in patient fibroblasts\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — molecular mechanism of splicing defect and correction established with multiple methods; preprint, single lab\",\n      \"pmids\": [\"41279107\"],\n      \"is_preprint\": true\n    }\n  ],\n  \"current_model\": \"SDCCAG8 is an integral centrosomal/basal body protein whose C-terminal coiled-coil domains are essential for centrosomal localization, interaction with ICK/CILK1, MAK, and PCM1 (centriolar satellite scaffold), and recruitment of pericentriolar material; it regulates ciliogenesis and cilium-dependent Hedgehog signaling, controls ciliary trafficking of proteins such as NPHP4, RPGR, and rhodopsin (in a cell type-specific manner dependent on RPGRIP1), maintains centriolar satellite integrity (via PCM1/BBS4/CEP131) for sperm flagellum biogenesis, participates in DNA damage response signaling at centrosomes, and supports neuronal migration through centrosome–nucleus coupling, with transcriptional activation of its expression mediated by SOX11.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"SDCCAG8 is a centrosomal and basal body protein essential for ciliogenesis, centriolar satellite integrity, and cilium-dependent signaling across multiple tissue types. Its C-terminal coiled-coil domains mediate centrosomal targeting, homo-oligomerization, and direct interactions with ICK/CILK1, MAK, and the centriolar satellite scaffold protein PCM1, through which it recruits pericentriolar material (γ-tubulin, pericentrin) and satellite components (BBS4, CEP131) required for cilium and sperm flagellum assembly [PMID:12559564, PMID:25088364, PMID:35131266, PMID:40801568]. Loss of SDCCAG8 disrupts primary cilia formation, Hedgehog signaling, ciliary trafficking of photoreceptor proteins (rhodopsin, RPGR), centrosome–nucleus coupling during neuronal migration, and activates aberrant ATM-dependent DNA damage response signaling [PMID:24722439, PMID:27224062, PMID:31868218]. Biallelic mutations in SDCCAG8 cause a multi-organ ciliopathy in mice and humans characterized by retinal degeneration, cystic kidneys, polydactyly, cleft palate, and male infertility [PMID:20835237, PMID:35131266, PMID:35503560].\",\n  \"teleology\": [\n    {\n      \"year\": 2003,\n      \"claim\": \"Establishing that SDCCAG8 is an integral centrosomal protein whose coiled-coil domains are required for centrosomal localization and self-association resolved its subcellular identity as a core centrosome component rather than a microtubule-associated protein.\",\n      \"evidence\": \"Immunofluorescence with nocodazole treatment, yeast two-hybrid, and truncation mutagenesis in cultured cells\",\n      \"pmids\": [\"12559564\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No interaction partners beyond self-association identified\", \"No functional consequence of centrosomal loss assessed\", \"Single lab, not independently replicated at this time\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Demonstrating that SDCCAG8 interacts with the ciliopathy protein OFD1 and that its depletion causes kidney cysts and body-axis defects in zebrafish established SDCCAG8 as a ciliopathy gene required for renal and planar cell polarity.\",\n      \"evidence\": \"Co-immunoprecipitation, zebrafish morpholino knockdown, 3D renal cell culture\",\n      \"pmids\": [\"20835237\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism by which SDCCAG8 loss leads to cystogenesis undefined\", \"No mammalian loss-of-function model yet\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Showing that RPGRIP1 is required for SDCCAG8 ciliary targeting specifically in photoreceptors but not kidney cells revealed cell-type-specific regulation of SDCCAG8 localization.\",\n      \"evidence\": \"Rpgrip1 mutant mouse, immunofluorescence, subcellular fractionation\",\n      \"pmids\": [\"22825473\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Molecular basis of RPGRIP1-dependent targeting not defined\", \"Whether other cell types use analogous adaptors unknown\", \"Single lab study\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Two concurrent studies showed that SDCCAG8 recruits pericentriolar material and PCM1 to centrosomes for neuronal migration, and that its loss activates ATM-dependent DNA damage signaling alongside retinal and renal pathology, broadening its function beyond ciliogenesis to centrosome–nucleus coupling and genome maintenance.\",\n      \"evidence\": \"Sdccag8 gene-trap mouse, shRNA knockdown in cortex, co-immunoprecipitation of SDCCAG8–PCM1, γH2AX/pATM immunoblotting, flow cytometry\",\n      \"pmids\": [\"24722439\", \"25088364\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether DNA damage response activation is direct or secondary to ciliary/centrosomal dysfunction unclear\", \"Mechanism linking PCM1 co-trafficking to pericentriolar material recruitment not resolved\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Affinity proteomics expanded the SDCCAG8 interactome to include endosomal sorting proteins (RABEP2, ERC1) and non-muscle myosins, and demonstrated that SDCCAG8 is required for Hedgehog signaling, linking it to cilium-dependent morphogen pathways.\",\n      \"evidence\": \"Tandem affinity purification/mass spectrometry, siRNA knockdown, Sdccag8 gene-trap mouse, Hedgehog reporter assays\",\n      \"pmids\": [\"27224062\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Functional significance of RABEP2 and myosin interactions for ciliogenesis untested\", \"Hedgehog signaling rescue not demonstrated\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"CRISPR-mediated knockout in human cells confirmed SDCCAG8's cell-autonomous requirement for ciliogenesis, cilium-dependent signaling, and neuronal migration/differentiation, validating prior knockdown findings in a human context.\",\n      \"evidence\": \"CRISPR knockout in human cells, immunofluorescence, transcriptomics, neuronal differentiation assays\",\n      \"pmids\": [\"31868218\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Specific signaling pathways downstream of ciliary loss not fully dissected\", \"Single lab\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Precise C-terminal truncation in knock-in mice pinpointed the C-terminal coiled-coil region as the domain mediating interactions with ciliopathy kinases ICK/CILK1 and MAK and as essential for centrosomal localization, cilia formation, and prevention of multi-organ ciliopathy phenotypes.\",\n      \"evidence\": \"CRISPR knock-in truncation mouse models, co-immunoprecipitation with ICK and MAK, electron microscopy, immunofluorescence\",\n      \"pmids\": [\"35131266\", \"35503560\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether ICK/MAK phosphorylate SDCCAG8 directly unknown\", \"Structural basis of C-terminal domain interactions not determined\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Mapping SDCCAG8's coiled-coil domains 5–7 as the PCM1-binding interface and showing that their loss destabilizes centriolar satellite proteins BBS4 and CEP131, causing defective sperm flagellum biogenesis, established a molecular mechanism linking SDCCAG8 to satellite integrity and male fertility.\",\n      \"evidence\": \"CC-domain truncation knock-in mouse, co-immunoprecipitation of SDCCAG8–PCM1 domain mapping, immunofluorescence for satellite markers, electron microscopy of flagella\",\n      \"pmids\": [\"40801568\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether satellite destabilization fully accounts for all ciliopathy phenotypes not tested\", \"Direct stoichiometry or structure of SDCCAG8–PCM1 complex unknown\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"Key unresolved questions include the structural basis of SDCCAG8's interactions with PCM1, ICK/MAK, and OFD1; whether the DNA damage response phenotype is a direct function or secondary to centrosomal/ciliary defects; and the full spectrum of ciliary cargo whose trafficking depends on SDCCAG8.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No atomic-resolution structural data for SDCCAG8 or its complexes\", \"DNA damage response mechanism not separated from ciliary dysfunction\", \"Complete inventory of SDCCAG8-dependent ciliary cargo lacking\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0008092\", \"supporting_discovery_ids\": [4, 10]},\n      {\"term_id\": \"GO:0005198\", \"supporting_discovery_ids\": [0, 4, 10]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005815\", \"supporting_discovery_ids\": [0, 1, 4, 5, 8, 10]},\n      {\"term_id\": \"GO:0005929\", \"supporting_discovery_ids\": [2, 5, 7, 8, 9]},\n      {\"term_id\": \"GO:0005856\", \"supporting_discovery_ids\": [4, 10]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1852241\", \"supporting_discovery_ids\": [0, 1, 5, 8, 9, 10]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [5, 7]},\n      {\"term_id\": \"R-HSA-73894\", \"supporting_discovery_ids\": [3]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [4, 7]}\n    ],\n    \"complexes\": [\n      \"centriolar satellites (PCM1/BBS4/CEP131)\"\n    ],\n    \"partners\": [\n      \"PCM1\",\n      \"OFD1\",\n      \"ICK\",\n      \"MAK\",\n      \"RABEP2\",\n      \"RPGRIP1\",\n      \"BBS4\",\n      \"CEP131\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}