{"gene":"LRRC45","run_date":"2026-04-28T18:30:27","timeline":{"discoveries":[{"year":2018,"finding":"LRRC45 is recruited to the mother centriole distal appendages by the core appendage proteins Cep83 and SCLT1, and once there, LRRC45 recruits the keratin-binding protein FBF1.","method":"Genetic epistasis and co-localization/recruitment assays in cultured cells with loss-of-function knockdowns","journal":"Journal of cell science","confidence":"High","confidence_rationale":"Tier 2 — recruitment hierarchy established by multiple knockdowns with clear functional epistasis, replicated in multiple cell types","pmids":["30131441"],"is_preprint":false},{"year":2018,"finding":"LRRC45 promotes cilia biogenesis in CP110-uncapped centrioles by organizing centriolar satellites, establishing the transition zone, and promoting docking of Rab8 GTPase-positive vesicles, but is not essential for early ciliary vesicle docking or CP110 removal.","method":"Loss-of-function knockdown with defined phenotypic readouts (ciliogenesis assays, vesicle docking, CP110 removal, transition zone markers) in differentiated and stem cells","journal":"Journal of cell science","confidence":"High","confidence_rationale":"Tier 2 — multiple orthogonal functional assays in one study with clear mechanistic placement","pmids":["30131441"],"is_preprint":false},{"year":2018,"finding":"CCDC102B interacts with the centrosome linker component LRRC45 and is required for maintaining centrosome cohesion; CCDC102B is recruited to the centrosome by C-Nap1 and facilitates rootletin filament formation.","method":"Co-immunoprecipitation and functional knockdown assays in human cells","journal":"Journal of cell science","confidence":"Medium","confidence_rationale":"Tier 3 — interaction established by co-IP and knockdown phenotype, but LRRC45 is a binding partner rather than the focus of the study","pmids":["30404835"],"is_preprint":false},{"year":2020,"finding":"LRRC45 localization at the centrosome linker is independent of Cep44; Cep44 depletion does not affect LRRC45 stability or its centrosomal recruitment, demonstrating LRRC45 is part of an independently assembled linker module.","method":"Knockdown/depletion experiments with immunofluorescence and western blot in human cells","journal":"Journal of cell science","confidence":"Medium","confidence_rationale":"Tier 2 — clean loss-of-function with defined negative epistasis result, single study","pmids":["31974111"],"is_preprint":false},{"year":2025,"finding":"LRRC45 localizes to the distal appendages of the mother centriole; CRISPR-Cas9 knockout analysis placed LRRC45 within the hierarchical distal appendage assembly pathway downstream of the CEP83-SCLT1 and CEP164-TTBK2 modules.","method":"CRISPR-Cas9 knockout with super-resolution localization and functional ciliogenesis assays","journal":"eLife","confidence":"High","confidence_rationale":"Tier 2 — comprehensive CRISPR knockout panel with super-resolution imaging and multiple functional assays, replicated from preprint","pmids":["39882846"],"is_preprint":false},{"year":2024,"finding":"LRRC45 competitively interacts with KEAP1, inhibiting ubiquitin-proteasome-mediated degradation of NRF2, thereby enhancing NRF2 nuclear translocation and anti-ferroptotic activity in bladder cancer cells.","method":"Co-immunoprecipitation, competitive binding assays, ubiquitination assays, and nuclear fractionation in bladder cancer cell lines","journal":"Free radical biology & medicine","confidence":"Medium","confidence_rationale":"Tier 2-3 — mechanistic interaction demonstrated by co-IP and functional readouts, single lab study","pmids":["39522565"],"is_preprint":false},{"year":2024,"finding":"Biallelic loss-of-function variants in LRRC45 in patient-derived fibroblasts cause significantly reduced primary cilia frequency and length, and an aberrant splice variant leads to drastically reduced LRRC45 mRNA and protein, directly linking LRRC45 to ciliogenesis in human disease.","method":"Patient fibroblast analysis with exome sequencing, RT-PCR for aberrant splicing, western blot, and primary cilia immunofluorescence quantification","journal":"Clinical genetics","confidence":"Medium","confidence_rationale":"Tier 2 — human loss-of-function validated in patient-derived cells with direct ciliogenesis phenotype readout, single study","pmids":["39638757"],"is_preprint":false},{"year":2024,"finding":"LRRC45 silencing in lung adenocarcinoma cells reduces c-MYC, Slug, MMP2, and MMP9 expression; overexpression of c-MYC/Slug or MMP2/MMP9 rescues the proliferation and metastasis defects caused by LRRC45 deficiency, placing LRRC45 upstream of these oncogenic effectors.","method":"siRNA knockdown, rescue overexpression, colony formation, migration assays, and xenograft mouse model","journal":"Advances in medical sciences","confidence":"Medium","confidence_rationale":"Tier 2-3 — epistasis established by rescue experiments in vitro and in vivo, single lab study","pmids":["39326735"],"is_preprint":false}],"current_model":"LRRC45 is a centrosome-associated protein with dual roles: at the proximal centriole it forms part of the proteinaceous centrosome linker (interacting with rootletin, C-Nap1, and CCDC102B) to maintain centrosome cohesion, while at the distal appendages of the mother centriole it is recruited by CEP83-SCLT1, in turn recruits FBF1, organizes centriolar satellites, establishes the transition zone, and promotes Rab8-positive vesicle docking to drive early steps of ciliogenesis; additionally, LRRC45 can competitively bind KEAP1 to stabilize NRF2 and modulate ferroptosis in cancer contexts."},"narrative":{"teleology":[{"year":2018,"claim":"Determining where LRRC45 sits in the distal appendage hierarchy and its downstream effector resolved a key gap in understanding centriolar appendage assembly: LRRC45 is recruited by CEP83–SCLT1 and in turn recruits FBF1.","evidence":"Genetic epistasis via sequential knockdowns with co-localization in cultured cells","pmids":["30131441"],"confidence":"High","gaps":["Direct biochemical interaction between LRRC45 and SCLT1/CEP83 not demonstrated","Structural basis of LRRC45–FBF1 interaction unknown"]},{"year":2018,"claim":"Defining the specific ciliogenesis steps controlled by LRRC45 established that it acts after CP110 removal to organize satellites, build the transition zone, and dock Rab8 vesicles, rather than initiating ciliary vesicle capture.","evidence":"Multi-readout loss-of-function assays (transition zone markers, Rab8 vesicle docking, CP110 status) in differentiated and stem cells","pmids":["30131441"],"confidence":"High","gaps":["Mechanism by which LRRC45 organizes centriolar satellites is unknown","Whether LRRC45 directly interacts with Rab8 or acts indirectly not resolved"]},{"year":2018,"claim":"Identifying LRRC45 as a physical interactor of CCDC102B within the centrosome linker revealed a second, spatially distinct function at proximal centrioles maintaining centrosome cohesion.","evidence":"Co-immunoprecipitation and centrosome cohesion knockdown assays in human cells","pmids":["30404835"],"confidence":"Medium","gaps":["LRRC45–CCDC102B interaction not validated by reciprocal pull-down or in vitro reconstitution","How LRRC45 integrates with rootletin filaments structurally is unknown"]},{"year":2020,"claim":"Showing that LRRC45 centrosome linker localization is independent of Cep44 delineated LRRC45 as part of a separately assembled linker module, clarifying the modularity of centrosome architecture.","evidence":"Depletion of Cep44 with immunofluorescence and western blot in human cells","pmids":["31974111"],"confidence":"Medium","gaps":["Identity of the factor that recruits LRRC45 to the linker remains unresolved","Functional consequence of LRRC45 linker loss on centriole separation timing not measured"]},{"year":2024,"claim":"Discovery that biallelic LRRC45 loss-of-function variants in patients cause reduced cilia frequency and length translated cell-biological findings into human disease, establishing LRRC45 as a ciliopathy gene.","evidence":"Exome sequencing, RT-PCR for aberrant splicing, western blot, and cilia quantification in patient-derived fibroblasts","pmids":["39638757"],"confidence":"Medium","gaps":["Clinical spectrum of LRRC45-associated ciliopathy not fully defined","Rescue of patient cells with wild-type LRRC45 not reported","Only a single family reported"]},{"year":2024,"claim":"Demonstrating that LRRC45 competitively binds KEAP1 to stabilize NRF2 and inhibit ferroptosis revealed an unexpected non-centrosomal signaling role in bladder cancer cells.","evidence":"Co-IP, competitive binding assays, ubiquitination assays, and nuclear fractionation in bladder cancer cell lines","pmids":["39522565"],"confidence":"Medium","gaps":["Whether LRRC45–KEAP1 interaction occurs in non-cancer contexts is unknown","ETGE/DLG-like motif in LRRC45 mediating KEAP1 binding not mapped","Independent replication in additional cell types not reported"]},{"year":2024,"claim":"Placing LRRC45 upstream of c-MYC, Slug, MMP2, and MMP9 in lung adenocarcinoma provided an epistatic framework for its pro-proliferative and pro-metastatic activity in cancer.","evidence":"siRNA knockdown and rescue overexpression with colony formation, migration assays, and xenograft models","pmids":["39326735"],"confidence":"Medium","gaps":["Direct molecular link between LRRC45 and c-MYC/Slug transcription not identified","Whether these cancer phenotypes relate to centrosome or cilia function is unclear","Single lab study without independent validation"]},{"year":2025,"claim":"Comprehensive CRISPR knockout with super-resolution imaging confirmed and refined LRRC45 placement within the distal appendage assembly hierarchy downstream of CEP83–SCLT1 and the CEP164–TTBK2 module.","evidence":"CRISPR-Cas9 knockout panel with super-resolution localization and ciliogenesis assays","pmids":["39882846"],"confidence":"High","gaps":["Precise sub-appendage nanoscale position of LRRC45 relative to FBF1 not fully resolved","Direct interactions within the distal appendage assembly not reconstituted biochemically"]},{"year":null,"claim":"The structural basis of LRRC45 interactions at both the centrosome linker and distal appendages, the molecular mechanism connecting LRRC45 to satellite organization and transition zone assembly, and the relationship between its centrosomal and non-centrosomal (KEAP1/NRF2) functions remain unresolved.","evidence":"","pmids":[],"confidence":"Low","gaps":["No crystal or cryo-EM structure of LRRC45 or its complexes","Mechanism of satellite organization by LRRC45 unknown","Whether centrosomal and KEAP1-related functions are context-dependent or coexistent is untested"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0005198","term_label":"structural molecule activity","supporting_discovery_ids":[0,2,4]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[5]}],"localization":[{"term_id":"GO:0005815","term_label":"microtubule organizing center","supporting_discovery_ids":[0,2,3,4]},{"term_id":"GO:0005929","term_label":"cilium","supporting_discovery_ids":[1,4,6]}],"pathway":[{"term_id":"R-HSA-1852241","term_label":"Organelle biogenesis and maintenance","supporting_discovery_ids":[0,1,4,6]},{"term_id":"R-HSA-8953897","term_label":"Cellular responses to stimuli","supporting_discovery_ids":[5]}],"complexes":["centrosome linker"],"partners":["CEP83","SCLT1","FBF1","CCDC102B","KEAP1","NFE2L2"],"other_free_text":[]},"mechanistic_narrative":"LRRC45 is a centrosome-associated leucine-rich repeat protein that functions in both centrosome cohesion and primary ciliogenesis. At the proximal centriole, LRRC45 participates in the proteinaceous centrosome linker together with rootletin, C-Nap1, and CCDC102B to maintain centrosome cohesion [PMID:30404835, PMID:31974111]. At the mother centriole, LRRC45 is recruited to distal appendages by CEP83–SCLT1, where it recruits FBF1, organizes centriolar satellites, establishes the ciliary transition zone, and promotes Rab8-positive vesicle docking to drive ciliogenesis [PMID:30131441, PMID:39882846]. Biallelic loss-of-function variants in LRRC45 cause reduced primary cilia frequency and length in patient-derived fibroblasts, establishing LRRC45 as a human ciliopathy gene [PMID:39638757]."},"prefetch_data":{"uniprot":{"accession":"Q96CN5","full_name":"Leucine-rich repeat-containing protein 45","aliases":[],"length_aa":670,"mass_kda":76.0,"function":"Component of the proteinaceous fiber-like linker between two centrioles, required for centrosome cohesion","subcellular_location":"Cytoplasm, cytoskeleton, microtubule organizing center, centrosome","url":"https://www.uniprot.org/uniprotkb/Q96CN5/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/LRRC45","classification":"Not Classified","n_dependent_lines":35,"n_total_lines":1208,"dependency_fraction":0.028973509933774833},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/LRRC45","total_profiled":1310},"omim":[{"mim_id":"621312","title":"LEUCINE-RICH REPEAT-CONTAINING PROTEIN 45; LRRC45","url":"https://www.omim.org/entry/621312"},{"mim_id":"621147","title":"COILED-COIL DOMAIN-CONTAINING PROTEIN 102B; CCDC102B","url":"https://www.omim.org/entry/621147"},{"mim_id":"611399","title":"SODIUM CHANNEL AND CLATHRIN LINKER 1; SCLT1","url":"https://www.omim.org/entry/611399"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Centrosome","reliability":"Approved"},{"location":"Basal body","reliability":"Approved"},{"location":"Cytosol","reliability":"Approved"},{"location":"Plasma membrane","reliability":"Additional"},{"location":"Mid piece","reliability":"Additional"},{"location":"Principal piece","reliability":"Additional"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in many","driving_tissues":[],"url":"https://www.proteinatlas.org/search/LRRC45"},"hgnc":{"alias_symbol":["MGC20806"],"prev_symbol":[]},"alphafold":{"accession":"Q96CN5","domains":[{"cath_id":"3.80.10.10","chopping":"33-252","consensus_level":"medium","plddt":92.4432,"start":33,"end":252},{"cath_id":"1.20.5","chopping":"566-611","consensus_level":"medium","plddt":77.1857,"start":566,"end":611}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q96CN5","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q96CN5-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q96CN5-F1-predicted_aligned_error_v6.png","plddt_mean":83.38},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=LRRC45","jax_strain_url":"https://www.jax.org/strain/search?query=LRRC45"},"sequence":{"accession":"Q96CN5","fasta_url":"https://rest.uniprot.org/uniprotkb/Q96CN5.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q96CN5/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q96CN5"}},"corpus_meta":[{"pmid":"30131441","id":"PMC_30131441","title":"LRRC45 contributes to early steps of axoneme extension.","date":"2018","source":"Journal of cell science","url":"https://pubmed.ncbi.nlm.nih.gov/30131441","citation_count":42,"is_preprint":false},{"pmid":"39882846","id":"PMC_39882846","title":"A hierarchical pathway for assembly of the distal appendages that organize primary cilia.","date":"2025","source":"eLife","url":"https://pubmed.ncbi.nlm.nih.gov/39882846","citation_count":23,"is_preprint":false},{"pmid":"30404835","id":"PMC_30404835","title":"CCDC102B functions in centrosome linker assembly and centrosome cohesion.","date":"2018","source":"Journal of cell science","url":"https://pubmed.ncbi.nlm.nih.gov/30404835","citation_count":20,"is_preprint":false},{"pmid":"31260916","id":"PMC_31260916","title":"Association between long-term air pollution exposure and DNA methylation: The REGICOR study.","date":"2019","source":"Environmental research","url":"https://pubmed.ncbi.nlm.nih.gov/31260916","citation_count":20,"is_preprint":false},{"pmid":"34716235","id":"PMC_34716235","title":"Molecular diagnoses in the congenital malformations caused by ciliopathies cohort of the 100,000 Genomes Project.","date":"2021","source":"Journal of medical genetics","url":"https://pubmed.ncbi.nlm.nih.gov/34716235","citation_count":18,"is_preprint":false},{"pmid":"31974111","id":"PMC_31974111","title":"Cep44 functions in centrosome cohesion by stabilizing rootletin.","date":"2020","source":"Journal of cell science","url":"https://pubmed.ncbi.nlm.nih.gov/31974111","citation_count":13,"is_preprint":false},{"pmid":"36711481","id":"PMC_36711481","title":"A hierarchical pathway for assembly of the distal appendages that organize primary cilia.","date":"2023","source":"bioRxiv : the preprint server for biology","url":"https://pubmed.ncbi.nlm.nih.gov/36711481","citation_count":12,"is_preprint":false},{"pmid":"32599975","id":"PMC_32599975","title":"Genome-Wide Association Study for the Identification of Novel Genetic Variants Associated with the Risk of Neuroblastoma in Korean Children.","date":"2020","source":"Cancer research and treatment","url":"https://pubmed.ncbi.nlm.nih.gov/32599975","citation_count":11,"is_preprint":false},{"pmid":"39522565","id":"PMC_39522565","title":"LRRC45 accelerates bladder cancer development and ferroptosis inhibition via stabilizing NRF2 by competitively KEAP1 interaction.","date":"2024","source":"Free radical biology & medicine","url":"https://pubmed.ncbi.nlm.nih.gov/39522565","citation_count":5,"is_preprint":false},{"pmid":"39326735","id":"PMC_39326735","title":"LRRC45 promotes lung cancer proliferation and progression by enhancing c-MYC, slug, MMP2, and MMP9 expression.","date":"2024","source":"Advances in medical sciences","url":"https://pubmed.ncbi.nlm.nih.gov/39326735","citation_count":5,"is_preprint":false},{"pmid":"39638757","id":"PMC_39638757","title":"Biallelic Variants in LRRC45 Impair Ciliogenesis and Cause a Severe Neurological Disorder.","date":"2024","source":"Clinical genetics","url":"https://pubmed.ncbi.nlm.nih.gov/39638757","citation_count":1,"is_preprint":false},{"pmid":"41227295","id":"PMC_41227295","title":"Astrocyte Transcriptomics in a Three-Dimensional Tissue-Engineered Rostral Migratory Stream.","date":"2025","source":"Cells","url":"https://pubmed.ncbi.nlm.nih.gov/41227295","citation_count":1,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":7409,"output_tokens":1814,"usd":0.024719},"stage2":{"model":"claude-opus-4-6","input_tokens":5086,"output_tokens":2306,"usd":0.12462},"total_usd":0.149339,"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\": 2018,\n      \"finding\": \"LRRC45 is recruited to the mother centriole distal appendages by the core appendage proteins Cep83 and SCLT1, and once there, LRRC45 recruits the keratin-binding protein FBF1.\",\n      \"method\": \"Genetic epistasis and co-localization/recruitment assays in cultured cells with loss-of-function knockdowns\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — recruitment hierarchy established by multiple knockdowns with clear functional epistasis, replicated in multiple cell types\",\n      \"pmids\": [\"30131441\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"LRRC45 promotes cilia biogenesis in CP110-uncapped centrioles by organizing centriolar satellites, establishing the transition zone, and promoting docking of Rab8 GTPase-positive vesicles, but is not essential for early ciliary vesicle docking or CP110 removal.\",\n      \"method\": \"Loss-of-function knockdown with defined phenotypic readouts (ciliogenesis assays, vesicle docking, CP110 removal, transition zone markers) in differentiated and stem cells\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal functional assays in one study with clear mechanistic placement\",\n      \"pmids\": [\"30131441\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"CCDC102B interacts with the centrosome linker component LRRC45 and is required for maintaining centrosome cohesion; CCDC102B is recruited to the centrosome by C-Nap1 and facilitates rootletin filament formation.\",\n      \"method\": \"Co-immunoprecipitation and functional knockdown assays in human cells\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — interaction established by co-IP and knockdown phenotype, but LRRC45 is a binding partner rather than the focus of the study\",\n      \"pmids\": [\"30404835\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"LRRC45 localization at the centrosome linker is independent of Cep44; Cep44 depletion does not affect LRRC45 stability or its centrosomal recruitment, demonstrating LRRC45 is part of an independently assembled linker module.\",\n      \"method\": \"Knockdown/depletion experiments with immunofluorescence and western blot in human cells\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — clean loss-of-function with defined negative epistasis result, single study\",\n      \"pmids\": [\"31974111\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"LRRC45 localizes to the distal appendages of the mother centriole; CRISPR-Cas9 knockout analysis placed LRRC45 within the hierarchical distal appendage assembly pathway downstream of the CEP83-SCLT1 and CEP164-TTBK2 modules.\",\n      \"method\": \"CRISPR-Cas9 knockout with super-resolution localization and functional ciliogenesis assays\",\n      \"journal\": \"eLife\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — comprehensive CRISPR knockout panel with super-resolution imaging and multiple functional assays, replicated from preprint\",\n      \"pmids\": [\"39882846\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"LRRC45 competitively interacts with KEAP1, inhibiting ubiquitin-proteasome-mediated degradation of NRF2, thereby enhancing NRF2 nuclear translocation and anti-ferroptotic activity in bladder cancer cells.\",\n      \"method\": \"Co-immunoprecipitation, competitive binding assays, ubiquitination assays, and nuclear fractionation in bladder cancer cell lines\",\n      \"journal\": \"Free radical biology & medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — mechanistic interaction demonstrated by co-IP and functional readouts, single lab study\",\n      \"pmids\": [\"39522565\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Biallelic loss-of-function variants in LRRC45 in patient-derived fibroblasts cause significantly reduced primary cilia frequency and length, and an aberrant splice variant leads to drastically reduced LRRC45 mRNA and protein, directly linking LRRC45 to ciliogenesis in human disease.\",\n      \"method\": \"Patient fibroblast analysis with exome sequencing, RT-PCR for aberrant splicing, western blot, and primary cilia immunofluorescence quantification\",\n      \"journal\": \"Clinical genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — human loss-of-function validated in patient-derived cells with direct ciliogenesis phenotype readout, single study\",\n      \"pmids\": [\"39638757\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"LRRC45 silencing in lung adenocarcinoma cells reduces c-MYC, Slug, MMP2, and MMP9 expression; overexpression of c-MYC/Slug or MMP2/MMP9 rescues the proliferation and metastasis defects caused by LRRC45 deficiency, placing LRRC45 upstream of these oncogenic effectors.\",\n      \"method\": \"siRNA knockdown, rescue overexpression, colony formation, migration assays, and xenograft mouse model\",\n      \"journal\": \"Advances in medical sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — epistasis established by rescue experiments in vitro and in vivo, single lab study\",\n      \"pmids\": [\"39326735\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"LRRC45 is a centrosome-associated protein with dual roles: at the proximal centriole it forms part of the proteinaceous centrosome linker (interacting with rootletin, C-Nap1, and CCDC102B) to maintain centrosome cohesion, while at the distal appendages of the mother centriole it is recruited by CEP83-SCLT1, in turn recruits FBF1, organizes centriolar satellites, establishes the transition zone, and promotes Rab8-positive vesicle docking to drive early steps of ciliogenesis; additionally, LRRC45 can competitively bind KEAP1 to stabilize NRF2 and modulate ferroptosis in cancer contexts.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"LRRC45 is a centrosome-associated leucine-rich repeat protein that functions in both centrosome cohesion and primary ciliogenesis. At the proximal centriole, LRRC45 participates in the proteinaceous centrosome linker together with rootletin, C-Nap1, and CCDC102B to maintain centrosome cohesion [PMID:30404835, PMID:31974111]. At the mother centriole, LRRC45 is recruited to distal appendages by CEP83–SCLT1, where it recruits FBF1, organizes centriolar satellites, establishes the ciliary transition zone, and promotes Rab8-positive vesicle docking to drive ciliogenesis [PMID:30131441, PMID:39882846]. Biallelic loss-of-function variants in LRRC45 cause reduced primary cilia frequency and length in patient-derived fibroblasts, establishing LRRC45 as a human ciliopathy gene [PMID:39638757].\",\n  \"teleology\": [\n    {\n      \"year\": 2018,\n      \"claim\": \"Determining where LRRC45 sits in the distal appendage hierarchy and its downstream effector resolved a key gap in understanding centriolar appendage assembly: LRRC45 is recruited by CEP83–SCLT1 and in turn recruits FBF1.\",\n      \"evidence\": \"Genetic epistasis via sequential knockdowns with co-localization in cultured cells\",\n      \"pmids\": [\"30131441\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Direct biochemical interaction between LRRC45 and SCLT1/CEP83 not demonstrated\",\n        \"Structural basis of LRRC45–FBF1 interaction unknown\"\n      ]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Defining the specific ciliogenesis steps controlled by LRRC45 established that it acts after CP110 removal to organize satellites, build the transition zone, and dock Rab8 vesicles, rather than initiating ciliary vesicle capture.\",\n      \"evidence\": \"Multi-readout loss-of-function assays (transition zone markers, Rab8 vesicle docking, CP110 status) in differentiated and stem cells\",\n      \"pmids\": [\"30131441\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Mechanism by which LRRC45 organizes centriolar satellites is unknown\",\n        \"Whether LRRC45 directly interacts with Rab8 or acts indirectly not resolved\"\n      ]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Identifying LRRC45 as a physical interactor of CCDC102B within the centrosome linker revealed a second, spatially distinct function at proximal centrioles maintaining centrosome cohesion.\",\n      \"evidence\": \"Co-immunoprecipitation and centrosome cohesion knockdown assays in human cells\",\n      \"pmids\": [\"30404835\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"LRRC45–CCDC102B interaction not validated by reciprocal pull-down or in vitro reconstitution\",\n        \"How LRRC45 integrates with rootletin filaments structurally is unknown\"\n      ]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Showing that LRRC45 centrosome linker localization is independent of Cep44 delineated LRRC45 as part of a separately assembled linker module, clarifying the modularity of centrosome architecture.\",\n      \"evidence\": \"Depletion of Cep44 with immunofluorescence and western blot in human cells\",\n      \"pmids\": [\"31974111\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Identity of the factor that recruits LRRC45 to the linker remains unresolved\",\n        \"Functional consequence of LRRC45 linker loss on centriole separation timing not measured\"\n      ]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Discovery that biallelic LRRC45 loss-of-function variants in patients cause reduced cilia frequency and length translated cell-biological findings into human disease, establishing LRRC45 as a ciliopathy gene.\",\n      \"evidence\": \"Exome sequencing, RT-PCR for aberrant splicing, western blot, and cilia quantification in patient-derived fibroblasts\",\n      \"pmids\": [\"39638757\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Clinical spectrum of LRRC45-associated ciliopathy not fully defined\",\n        \"Rescue of patient cells with wild-type LRRC45 not reported\",\n        \"Only a single family reported\"\n      ]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Demonstrating that LRRC45 competitively binds KEAP1 to stabilize NRF2 and inhibit ferroptosis revealed an unexpected non-centrosomal signaling role in bladder cancer cells.\",\n      \"evidence\": \"Co-IP, competitive binding assays, ubiquitination assays, and nuclear fractionation in bladder cancer cell lines\",\n      \"pmids\": [\"39522565\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Whether LRRC45–KEAP1 interaction occurs in non-cancer contexts is unknown\",\n        \"ETGE/DLG-like motif in LRRC45 mediating KEAP1 binding not mapped\",\n        \"Independent replication in additional cell types not reported\"\n      ]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Placing LRRC45 upstream of c-MYC, Slug, MMP2, and MMP9 in lung adenocarcinoma provided an epistatic framework for its pro-proliferative and pro-metastatic activity in cancer.\",\n      \"evidence\": \"siRNA knockdown and rescue overexpression with colony formation, migration assays, and xenograft models\",\n      \"pmids\": [\"39326735\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Direct molecular link between LRRC45 and c-MYC/Slug transcription not identified\",\n        \"Whether these cancer phenotypes relate to centrosome or cilia function is unclear\",\n        \"Single lab study without independent validation\"\n      ]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Comprehensive CRISPR knockout with super-resolution imaging confirmed and refined LRRC45 placement within the distal appendage assembly hierarchy downstream of CEP83–SCLT1 and the CEP164–TTBK2 module.\",\n      \"evidence\": \"CRISPR-Cas9 knockout panel with super-resolution localization and ciliogenesis assays\",\n      \"pmids\": [\"39882846\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Precise sub-appendage nanoscale position of LRRC45 relative to FBF1 not fully resolved\",\n        \"Direct interactions within the distal appendage assembly not reconstituted biochemically\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The structural basis of LRRC45 interactions at both the centrosome linker and distal appendages, the molecular mechanism connecting LRRC45 to satellite organization and transition zone assembly, and the relationship between its centrosomal and non-centrosomal (KEAP1/NRF2) functions remain unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"No crystal or cryo-EM structure of LRRC45 or its complexes\",\n        \"Mechanism of satellite organization by LRRC45 unknown\",\n        \"Whether centrosomal and KEAP1-related functions are context-dependent or coexistent is untested\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0005198\", \"supporting_discovery_ids\": [0, 2, 4]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [5]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005815\", \"supporting_discovery_ids\": [0, 2, 3, 4]},\n      {\"term_id\": \"GO:0005929\", \"supporting_discovery_ids\": [1, 4, 6]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1852241\", \"supporting_discovery_ids\": [0, 1, 4, 6]},\n      {\"term_id\": \"R-HSA-8953897\", \"supporting_discovery_ids\": [5]}\n    ],\n    \"complexes\": [\n      \"centrosome linker\"\n    ],\n    \"partners\": [\n      \"CEP83\",\n      \"SCLT1\",\n      \"FBF1\",\n      \"CCDC102B\",\n      \"KEAP1\",\n      \"NFE2L2\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}