{"gene":"RTTN","run_date":"2026-06-10T07:46:28","timeline":{"discoveries":[{"year":2012,"finding":"RTTN (Rotatin) colocalizes with basal bodies at the primary cilium. Cultured fibroblasts from affected individuals carrying RTTN mutations show structural abnormalities of cilia and exhibit downregulation of BMP4, WNT5A, and WNT2B. Knockdown of RTTN in human fibroblasts and neural stem cells confirmed a role for RTTN in cilia structure and function.","method":"Immunofluorescence colocalization, knockdown experiments in human fibroblasts and neural stem cells, gene expression analysis","journal":"American journal of human genetics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct localization experiment with functional consequence, KD with defined cellular phenotype, two orthogonal methods in single lab","pmids":["22939636"],"is_preprint":false},{"year":2017,"finding":"RTTN is recruited to the proximal end of the procentriole at early S phase and is located at the inner luminal walls of centrioles. RTTN directly interacts with STIL and acts downstream of STIL-mediated centriole assembly. CRISPR/Cas9-mediated RTTN knockout induces amplification of primitive procentriole bodies lacking distal-half centriolar proteins POC5 and POC1B. RTTN serves as an upstream effector of CEP295, which mediates loading of POC1B and POC5 to distal-half centrioles. The microcephaly-associated mutant RTTN(A578P) shows low affinity for STIL binding and blocks centriole assembly.","method":"Super-resolution and electron microscopy, CRISPR/Cas9 knockout, Co-IP/direct interaction assays, active-site mutagenesis (A578P mutant), immunofluorescence","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — multiple orthogonal methods (super-resolution EM, CRISPR KO, direct interaction assay, functional mutant), epistasis pathway established, single lab with rigorous controls","pmids":["28811500"],"is_preprint":false},{"year":2018,"finding":"PPP1R35 acts downstream of RTTN and forms a complex with RTTN in the centriole elongation pathway. Loss of PPP1R35 results in shortened centrioles lacking distal and microtubule wall-associated proteins. RTTN is required for distal centriole elongation, and PPP1R35 is positioned proximal to the cartwheel, downstream of RTTN.","method":"Quantitative super-resolution microscopy, live-cell imaging, Co-IP/complex formation assay, loss-of-function (PPP1R35 depletion) with defined centriolar phenotype","journal":"eLife","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal complex demonstrated, super-resolution mapping, epistasis established by independent lab corroborating RTTN's upstream role in centriole elongation","pmids":["30168418"],"is_preprint":false},{"year":2021,"finding":"RTTN is required for normal mitotic progression and correct spindle positioning. Depletion of RTTN induces dispersion of pericentriolar γ-tubulin, and multiple mitotic abnormalities including monopolar, abnormal bipolar, and multipolar spindles. Loss of RTTN alters NuMA/p150Glued congression to spindle poles, perturbs NuMA cortical localization, and reduces the number and length of astral microtubules.","method":"siRNA depletion, immunofluorescence microscopy, spindle positioning assay","journal":"Cells","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — KD with defined cellular phenotypes, multiple mitotic readouts, single lab with multiple orthogonal phenotypic analyses","pmids":["34207628"],"is_preprint":false},{"year":2024,"finding":"In RTTN-depleted RPE1 cells and patient fibroblasts carrying the c.2953A>G variant, RTTN function at the centrosome is disrupted. In neural stem cells derived from CRISPR/Cas9-edited iPSCs, RTTN loss causes major cell cycle and mitotic abnormalities leading to aneuploidy, cell cycle arrest, and cell death. In cortical organoids, RTTN is required for self-organisation of neural stem cells into neural rosettes, with loss causing delayed apico-basal polarization of neural stem cells.","method":"CRISPR/Cas9 gene editing, iPSC-derived neural stem cells and cortical organoids, immunofluorescence, cell cycle analysis","journal":"PLoS genetics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — CRISPR-engineered cells and organoids, multiple functional readouts, single lab with orthogonal in vitro and organoid models","pmids":["39680576"],"is_preprint":false}],"current_model":"RTTN (Rotatin) is a centrosomal protein that localizes to the inner luminal walls of centrioles and basal bodies; it directly interacts with STIL and acts downstream of STIL to promote full-length centriole assembly by functioning as an upstream effector of CEP295-mediated loading of distal centriolar proteins POC1B and POC5, and also forms a complex with PPP1R35 to regulate centriole elongation; additionally, RTTN is required for proper mitotic spindle positioning through regulation of NuMA/p150Glued cortical localization and astral microtubule integrity, for primary cilia structure and BMP/WNT signaling, and for apico-basal polarization of neural stem cells during cortical development."},"narrative":{"mechanistic_narrative":"RTTN (Rotatin) is a centriolar protein that governs centriole assembly and elongation and, through this role, controls mitotic fidelity and the polarization of neural stem cells during cortical development [PMID:28811500, PMID:39680576]. Recruited to the proximal end of the procentriole in early S phase and residing at the inner luminal walls of centrioles, RTTN directly binds STIL and acts downstream of STIL-mediated centriole assembly; its loss generates amplified primitive procentriole bodies that lack the distal-half centriolar proteins POC5 and POC1B because RTTN functions as an upstream effector of CEP295-mediated loading of these proteins [PMID:28811500]. RTTN further forms a complex with PPP1R35, positioning it within a distal centriole elongation pathway in which PPP1R35 acts downstream of RTTN [PMID:30168418]. The microcephaly-associated RTTN(A578P) mutant has reduced STIL affinity and blocks centriole assembly, linking the molecular pathway to disease [PMID:28811500]. Beyond centriole biogenesis, RTTN is required for correct mitotic spindle positioning, regulating NuMA/p150Glued congression and cortical localization and maintaining astral microtubule number and length [PMID:34207628], and its loss in neural stem cells and cortical organoids causes aneuploidy, cell death, and delayed apico-basal polarization with failed neural rosette self-organization [PMID:39680576]. RTTN also localizes to basal bodies of the primary cilium, where it is needed for cilia structure and normal BMP/WNT signaling [PMID:22939636].","teleology":[{"year":2012,"claim":"Established the first cellular role for RTTN by linking it to ciliary structure and developmental signaling, addressing why RTTN mutations cause human disease.","evidence":"Immunofluorescence colocalization at basal bodies plus knockdown in patient fibroblasts and neural stem cells with BMP/WNT expression readouts","pmids":["22939636"],"confidence":"Medium","gaps":["Did not define a molecular partner or biochemical activity","Mechanism connecting RTTN to BMP/WNT downregulation unresolved"]},{"year":2017,"claim":"Defined RTTN's molecular position in centriole biogenesis, answering how it contributes to centriole assembly: it binds STIL and licenses distal centriole maturation via CEP295.","evidence":"Super-resolution/EM localization, CRISPR knockout, direct STIL interaction assay, and the A578P disease mutant in human cells","pmids":["28811500"],"confidence":"High","gaps":["Structural basis of the RTTN-STIL interaction not resolved","How RTTN promotes CEP295-mediated POC1B/POC5 loading mechanistically unclear"]},{"year":2018,"claim":"Extended the elongation pathway by placing PPP1R35 downstream of RTTN in a shared complex, clarifying how distal centriole elongation is executed.","evidence":"Quantitative super-resolution microscopy, live-cell imaging, and Co-IP complex formation with PPP1R35 depletion phenotyping","pmids":["30168418"],"confidence":"High","gaps":["Stoichiometry and architecture of the RTTN-PPP1R35 complex unknown","Whether PPP1R35 phosphatase regulatory activity is involved not addressed"]},{"year":2021,"claim":"Showed RTTN's centriolar role propagates to mitotic spindle control, explaining how its loss disrupts division through NuMA/p150Glued and astral microtubule defects.","evidence":"siRNA depletion with immunofluorescence and spindle positioning assays scoring spindle morphology and cortical NuMA","pmids":["34207628"],"confidence":"Medium","gaps":["Direct versus indirect effect on NuMA cortical localization not distinguished","No physical interaction with spindle factors demonstrated"]},{"year":2024,"claim":"Connected RTTN's centrosomal function to neurodevelopmental outcome, demonstrating that its loss drives aneuploidy and impaired neural stem cell polarization in organoid models of cortical development.","evidence":"CRISPR-edited iPSC-derived neural stem cells and cortical organoids with cell cycle analysis and immunofluorescence, plus patient fibroblasts","pmids":["39680576"],"confidence":"Medium","gaps":["Molecular link between centriole defect and apico-basal polarization not defined","Single-lab organoid models"]},{"year":null,"claim":"How RTTN structurally engages STIL, CEP295 and PPP1R35 to coordinate distal centriole elongation, and whether its biochemical activity is enzymatic or purely scaffolding, remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No structural model of RTTN or its complexes","No defined catalytic activity for RTTN","Mechanism coupling centriole defects to ciliary BMP/WNT signaling unknown"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[1,2]}],"localization":[{"term_id":"GO:0005815","term_label":"microtubule organizing center","supporting_discovery_ids":[3]},{"term_id":"GO:0005929","term_label":"cilium","supporting_discovery_ids":[0]}],"pathway":[{"term_id":"R-HSA-1852241","term_label":"Organelle biogenesis and maintenance","supporting_discovery_ids":[1,2]},{"term_id":"R-HSA-1640170","term_label":"Cell Cycle","supporting_discovery_ids":[3,4]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[4]}],"complexes":["RTTN-PPP1R35 complex"],"partners":["STIL","PPP1R35","CEP295"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q86VV8","full_name":"Rotatin","aliases":[],"length_aa":2226,"mass_kda":248.6,"function":"Involved in the genetic cascade that governs left-right specification. Plays a role in the maintenance of a normal ciliary structure. Required for correct asymmetric expression of NODAL, LEFTY and PITX2","subcellular_location":"Cytoplasm, cytoskeleton, cilium basal body; Cytoplasm, cytoskeleton, microtubule organizing center, centrosome","url":"https://www.uniprot.org/uniprotkb/Q86VV8/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/RTTN","classification":"Not Classified","n_dependent_lines":628,"n_total_lines":1208,"dependency_fraction":0.5198675496688742},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/RTTN","total_profiled":1310},"omim":[{"mim_id":"618937","title":"PROTEIN PHOSPHATASE 1, REGULATORY SUBUNIT 35; PPP1R35","url":"https://www.omim.org/entry/618937"},{"mim_id":"614833","title":"MICROCEPHALY, SHORT STATURE, AND POLYMICROGYRIA WITH OR WITHOUT SEIZURES; MSSP","url":"https://www.omim.org/entry/614833"},{"mim_id":"610436","title":"ROTATIN; RTTN","url":"https://www.omim.org/entry/610436"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Uncertain","locations":[{"location":"Cytosol","reliability":"Uncertain"},{"location":"Centrosome","reliability":"Additional"},{"location":"Basal body","reliability":"Additional"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in many","driving_tissues":[],"url":"https://www.proteinatlas.org/search/RTTN"},"hgnc":{"alias_symbol":["DKFZP434G145"],"prev_symbol":[]},"alphafold":{"accession":"Q86VV8","domains":[{"cath_id":"1.25.10.10","chopping":"2-114","consensus_level":"high","plddt":86.991,"start":2,"end":114},{"cath_id":"-","chopping":"379-533","consensus_level":"medium","plddt":90.5681,"start":379,"end":533},{"cath_id":"-","chopping":"764-840_860-964_975-996","consensus_level":"high","plddt":85.7094,"start":764,"end":996},{"cath_id":"-","chopping":"1227-1343","consensus_level":"medium","plddt":79.9174,"start":1227,"end":1343},{"cath_id":"1.25.10.10","chopping":"2054-2063_2072-2226","consensus_level":"high","plddt":82.2593,"start":2054,"end":2226},{"cath_id":"1.20.930","chopping":"181-277_370-377","consensus_level":"medium","plddt":84.6301,"start":181,"end":377},{"cath_id":"1.20.870","chopping":"590-718","consensus_level":"medium","plddt":87.7779,"start":590,"end":718},{"cath_id":"1.25.40","chopping":"1068-1188_1204-1222","consensus_level":"medium","plddt":80.3599,"start":1068,"end":1222}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q86VV8","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q86VV8-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q86VV8-F1-predicted_aligned_error_v6.png","plddt_mean":77.12},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=RTTN","jax_strain_url":"https://www.jax.org/strain/search?query=RTTN"},"sequence":{"accession":"Q86VV8","fasta_url":"https://rest.uniprot.org/uniprotkb/Q86VV8.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q86VV8/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q86VV8"}},"corpus_meta":[{"pmid":"22939636","id":"PMC_22939636","title":"RTTN mutations link primary cilia function to organization of the human cerebral cortex.","date":"2012","source":"American journal of human genetics","url":"https://pubmed.ncbi.nlm.nih.gov/22939636","citation_count":58,"is_preprint":false},{"pmid":"28811500","id":"PMC_28811500","title":"Human microcephaly protein RTTN interacts with STIL and is required to build full-length centrioles.","date":"2017","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/28811500","citation_count":39,"is_preprint":false},{"pmid":"26608784","id":"PMC_26608784","title":"RTTN Mutations Cause Primary Microcephaly and Primordial Dwarfism in Humans.","date":"2015","source":"American journal of human genetics","url":"https://pubmed.ncbi.nlm.nih.gov/26608784","citation_count":38,"is_preprint":false},{"pmid":"30168418","id":"PMC_30168418","title":"PPP1R35 is a novel centrosomal protein that regulates centriole length in concert with the microcephaly protein RTTN.","date":"2018","source":"eLife","url":"https://pubmed.ncbi.nlm.nih.gov/30168418","citation_count":29,"is_preprint":false},{"pmid":"26940245","id":"PMC_26940245","title":"Expanding the phenotype of RTTN variations: a new family with primary microcephaly, severe growth failure, brain malformations and dermatitis.","date":"2016","source":"Clinical genetics","url":"https://pubmed.ncbi.nlm.nih.gov/26940245","citation_count":21,"is_preprint":false},{"pmid":"30121372","id":"PMC_30121372","title":"Recurrent RTTN mutation leading to severe microcephaly, polymicrogyria and growth restriction.","date":"2018","source":"European journal of medical genetics","url":"https://pubmed.ncbi.nlm.nih.gov/30121372","citation_count":13,"is_preprint":false},{"pmid":"29883675","id":"PMC_29883675","title":"Biallelic mutations in RTTN are associated with microcephaly, short stature and a wide range of brain malformations.","date":"2018","source":"European journal of medical genetics","url":"https://pubmed.ncbi.nlm.nih.gov/29883675","citation_count":11,"is_preprint":false},{"pmid":"34207628","id":"PMC_34207628","title":"Human Microcephaly Protein RTTN Is Required for Proper Mitotic Progression and Correct Spindle Position.","date":"2021","source":"Cells","url":"https://pubmed.ncbi.nlm.nih.gov/34207628","citation_count":8,"is_preprint":false},{"pmid":"29356416","id":"PMC_29356416","title":"A neuropathological study of novel RTTN gene mutations causing a familial microcephaly with simplified gyral pattern.","date":"2018","source":"Birth defects research","url":"https://pubmed.ncbi.nlm.nih.gov/29356416","citation_count":8,"is_preprint":false},{"pmid":"37371259","id":"PMC_37371259","title":"Microcephaly, Short Stature, Intellectual Disability, Speech Absence and Cataract Are Associated with Novel Bi-Allelic Missense Variant in RTTN Gene: A Seckel Syndrome Case Report.","date":"2023","source":"Children (Basel, Switzerland)","url":"https://pubmed.ncbi.nlm.nih.gov/37371259","citation_count":7,"is_preprint":false},{"pmid":"34012324","id":"PMC_34012324","title":"Exome sequencing reveled a compound heterozygous mutations in RTTN gene causing developmental delay and primary microcephaly.","date":"2021","source":"Saudi journal of biological sciences","url":"https://pubmed.ncbi.nlm.nih.gov/34012324","citation_count":6,"is_preprint":false},{"pmid":"39680576","id":"PMC_39680576","title":"A Taybi-Linder syndrome-related RTTN variant impedes neural rosette formation in human cortical organoids.","date":"2024","source":"PLoS genetics","url":"https://pubmed.ncbi.nlm.nih.gov/39680576","citation_count":3,"is_preprint":false},{"pmid":"30927481","id":"PMC_30927481","title":"Primary microcephaly, primordial dwarfism, and brachydactyly in adult cases with biallelic skipping of RTTN exon 42.","date":"2019","source":"Human mutation","url":"https://pubmed.ncbi.nlm.nih.gov/30927481","citation_count":3,"is_preprint":false},{"pmid":"40151166","id":"PMC_40151166","title":"Radial Microbrain (Micrencephaly) Is Caused by a Recurrent Variant in the RTTN Gene.","date":"2025","source":"Neurology. Genetics","url":"https://pubmed.ncbi.nlm.nih.gov/40151166","citation_count":1,"is_preprint":false},{"pmid":"38178912","id":"PMC_38178912","title":"Case Report: Novel biallelic moderately damaging variants in RTTN in a patient with cerebellar dysplasia.","date":"2023","source":"Frontiers in pediatrics","url":"https://pubmed.ncbi.nlm.nih.gov/38178912","citation_count":1,"is_preprint":false},{"pmid":"41719742","id":"PMC_41719742","title":"Generation of the iPSC line CRNLi001-A from a patient with microcephaly and harbouring the most recurrent RTTN variant, c.2953A>G, at homozygous state.","date":"2026","source":"Stem cell research","url":"https://pubmed.ncbi.nlm.nih.gov/41719742","citation_count":0,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":9036,"output_tokens":1557,"usd":0.025232,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":8303,"output_tokens":2230,"usd":0.048633,"stage2_stop_reason":"end_turn"},"total_usd":0.073865,"stage1_batch_id":"msgbatch_013LWZZT6MWaqB9qyTSeQBmU","stage2_batch_id":"msgbatch_0194ZzQaTGNpruoNJBbEMbt3","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2012,\n      \"finding\": \"RTTN (Rotatin) colocalizes with basal bodies at the primary cilium. Cultured fibroblasts from affected individuals carrying RTTN mutations show structural abnormalities of cilia and exhibit downregulation of BMP4, WNT5A, and WNT2B. Knockdown of RTTN in human fibroblasts and neural stem cells confirmed a role for RTTN in cilia structure and function.\",\n      \"method\": \"Immunofluorescence colocalization, knockdown experiments in human fibroblasts and neural stem cells, gene expression analysis\",\n      \"journal\": \"American journal of human genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct localization experiment with functional consequence, KD with defined cellular phenotype, two orthogonal methods in single lab\",\n      \"pmids\": [\"22939636\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"RTTN is recruited to the proximal end of the procentriole at early S phase and is located at the inner luminal walls of centrioles. RTTN directly interacts with STIL and acts downstream of STIL-mediated centriole assembly. CRISPR/Cas9-mediated RTTN knockout induces amplification of primitive procentriole bodies lacking distal-half centriolar proteins POC5 and POC1B. RTTN serves as an upstream effector of CEP295, which mediates loading of POC1B and POC5 to distal-half centrioles. The microcephaly-associated mutant RTTN(A578P) shows low affinity for STIL binding and blocks centriole assembly.\",\n      \"method\": \"Super-resolution and electron microscopy, CRISPR/Cas9 knockout, Co-IP/direct interaction assays, active-site mutagenesis (A578P mutant), immunofluorescence\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — multiple orthogonal methods (super-resolution EM, CRISPR KO, direct interaction assay, functional mutant), epistasis pathway established, single lab with rigorous controls\",\n      \"pmids\": [\"28811500\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"PPP1R35 acts downstream of RTTN and forms a complex with RTTN in the centriole elongation pathway. Loss of PPP1R35 results in shortened centrioles lacking distal and microtubule wall-associated proteins. RTTN is required for distal centriole elongation, and PPP1R35 is positioned proximal to the cartwheel, downstream of RTTN.\",\n      \"method\": \"Quantitative super-resolution microscopy, live-cell imaging, Co-IP/complex formation assay, loss-of-function (PPP1R35 depletion) with defined centriolar phenotype\",\n      \"journal\": \"eLife\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal complex demonstrated, super-resolution mapping, epistasis established by independent lab corroborating RTTN's upstream role in centriole elongation\",\n      \"pmids\": [\"30168418\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"RTTN is required for normal mitotic progression and correct spindle positioning. Depletion of RTTN induces dispersion of pericentriolar γ-tubulin, and multiple mitotic abnormalities including monopolar, abnormal bipolar, and multipolar spindles. Loss of RTTN alters NuMA/p150Glued congression to spindle poles, perturbs NuMA cortical localization, and reduces the number and length of astral microtubules.\",\n      \"method\": \"siRNA depletion, immunofluorescence microscopy, spindle positioning assay\",\n      \"journal\": \"Cells\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — KD with defined cellular phenotypes, multiple mitotic readouts, single lab with multiple orthogonal phenotypic analyses\",\n      \"pmids\": [\"34207628\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"In RTTN-depleted RPE1 cells and patient fibroblasts carrying the c.2953A>G variant, RTTN function at the centrosome is disrupted. In neural stem cells derived from CRISPR/Cas9-edited iPSCs, RTTN loss causes major cell cycle and mitotic abnormalities leading to aneuploidy, cell cycle arrest, and cell death. In cortical organoids, RTTN is required for self-organisation of neural stem cells into neural rosettes, with loss causing delayed apico-basal polarization of neural stem cells.\",\n      \"method\": \"CRISPR/Cas9 gene editing, iPSC-derived neural stem cells and cortical organoids, immunofluorescence, cell cycle analysis\",\n      \"journal\": \"PLoS genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — CRISPR-engineered cells and organoids, multiple functional readouts, single lab with orthogonal in vitro and organoid models\",\n      \"pmids\": [\"39680576\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"RTTN (Rotatin) is a centrosomal protein that localizes to the inner luminal walls of centrioles and basal bodies; it directly interacts with STIL and acts downstream of STIL to promote full-length centriole assembly by functioning as an upstream effector of CEP295-mediated loading of distal centriolar proteins POC1B and POC5, and also forms a complex with PPP1R35 to regulate centriole elongation; additionally, RTTN is required for proper mitotic spindle positioning through regulation of NuMA/p150Glued cortical localization and astral microtubule integrity, for primary cilia structure and BMP/WNT signaling, and for apico-basal polarization of neural stem cells during cortical development.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"RTTN (Rotatin) is a centriolar protein that governs centriole assembly and elongation and, through this role, controls mitotic fidelity and the polarization of neural stem cells during cortical development [#1, #4]. Recruited to the proximal end of the procentriole in early S phase and residing at the inner luminal walls of centrioles, RTTN directly binds STIL and acts downstream of STIL-mediated centriole assembly; its loss generates amplified primitive procentriole bodies that lack the distal-half centriolar proteins POC5 and POC1B because RTTN functions as an upstream effector of CEP295-mediated loading of these proteins [#1]. RTTN further forms a complex with PPP1R35, positioning it within a distal centriole elongation pathway in which PPP1R35 acts downstream of RTTN [#2]. The microcephaly-associated RTTN(A578P) mutant has reduced STIL affinity and blocks centriole assembly, linking the molecular pathway to disease [#1]. Beyond centriole biogenesis, RTTN is required for correct mitotic spindle positioning, regulating NuMA/p150Glued congression and cortical localization and maintaining astral microtubule number and length [#3], and its loss in neural stem cells and cortical organoids causes aneuploidy, cell death, and delayed apico-basal polarization with failed neural rosette self-organization [#4]. RTTN also localizes to basal bodies of the primary cilium, where it is needed for cilia structure and normal BMP/WNT signaling [#0].\",\n  \"teleology\": [\n    {\n      \"year\": 2012,\n      \"claim\": \"Established the first cellular role for RTTN by linking it to ciliary structure and developmental signaling, addressing why RTTN mutations cause human disease.\",\n      \"evidence\": \"Immunofluorescence colocalization at basal bodies plus knockdown in patient fibroblasts and neural stem cells with BMP/WNT expression readouts\",\n      \"pmids\": [\"22939636\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Did not define a molecular partner or biochemical activity\", \"Mechanism connecting RTTN to BMP/WNT downregulation unresolved\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Defined RTTN's molecular position in centriole biogenesis, answering how it contributes to centriole assembly: it binds STIL and licenses distal centriole maturation via CEP295.\",\n      \"evidence\": \"Super-resolution/EM localization, CRISPR knockout, direct STIL interaction assay, and the A578P disease mutant in human cells\",\n      \"pmids\": [\"28811500\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of the RTTN-STIL interaction not resolved\", \"How RTTN promotes CEP295-mediated POC1B/POC5 loading mechanistically unclear\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Extended the elongation pathway by placing PPP1R35 downstream of RTTN in a shared complex, clarifying how distal centriole elongation is executed.\",\n      \"evidence\": \"Quantitative super-resolution microscopy, live-cell imaging, and Co-IP complex formation with PPP1R35 depletion phenotyping\",\n      \"pmids\": [\"30168418\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Stoichiometry and architecture of the RTTN-PPP1R35 complex unknown\", \"Whether PPP1R35 phosphatase regulatory activity is involved not addressed\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Showed RTTN's centriolar role propagates to mitotic spindle control, explaining how its loss disrupts division through NuMA/p150Glued and astral microtubule defects.\",\n      \"evidence\": \"siRNA depletion with immunofluorescence and spindle positioning assays scoring spindle morphology and cortical NuMA\",\n      \"pmids\": [\"34207628\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct versus indirect effect on NuMA cortical localization not distinguished\", \"No physical interaction with spindle factors demonstrated\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Connected RTTN's centrosomal function to neurodevelopmental outcome, demonstrating that its loss drives aneuploidy and impaired neural stem cell polarization in organoid models of cortical development.\",\n      \"evidence\": \"CRISPR-edited iPSC-derived neural stem cells and cortical organoids with cell cycle analysis and immunofluorescence, plus patient fibroblasts\",\n      \"pmids\": [\"39680576\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Molecular link between centriole defect and apico-basal polarization not defined\", \"Single-lab organoid models\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How RTTN structurally engages STIL, CEP295 and PPP1R35 to coordinate distal centriole elongation, and whether its biochemical activity is enzymatic or purely scaffolding, remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No structural model of RTTN or its complexes\", \"No defined catalytic activity for RTTN\", \"Mechanism coupling centriole defects to ciliary BMP/WNT signaling unknown\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [1, 2]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005814\", \"supporting_discovery_ids\": [1, 2]},\n      {\"term_id\": \"GO:0005815\", \"supporting_discovery_ids\": [3]},\n      {\"term_id\": \"GO:0005929\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1852241\", \"supporting_discovery_ids\": [1, 2]},\n      {\"term_id\": \"R-HSA-1640170\", \"supporting_discovery_ids\": [3, 4]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [4]}\n    ],\n    \"complexes\": [\"RTTN-PPP1R35 complex\"],\n    \"partners\": [\"STIL\", \"PPP1R35\", \"CEP295\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":6,"faith_total":6,"faith_pct":100.0}}