{"gene":"CPLANE1","run_date":"2026-06-09T22:57:19","timeline":{"discoveries":[{"year":2012,"finding":"Biallelic loss-of-function mutations in C5ORF42 (CPLANE1/JBTS17) cause Joubert syndrome in French Canadian patients, establishing CPLANE1 as a Joubert syndrome causative gene (JBTS17).","method":"Exome sequencing with Sanger validation; compound heterozygous mutations identified in 9/11 families; mutations absent in 477 French Canadian controls","journal":"American journal of human genetics","confidence":"High","confidence_rationale":"Tier 2 / Strong — exome sequencing with Sanger validation across multiple families, replicated across multiple affected individuals with no mutation in controls","pmids":["22425360"],"is_preprint":false},{"year":2013,"finding":"C5orf42 (CPLANE1) mutations are the major genetic cause of Oral-Facial-Digital Syndrome type VI (OFD VI), which is allelic to Joubert syndrome, establishing that CPLANE1 is a ciliopathy gene underlying both conditions.","method":"Exome sequencing in six unrelated families followed by Sanger sequencing; 14 novel mutations identified in 9/11 OFD VI families","journal":"Human genetics","confidence":"High","confidence_rationale":"Tier 2 / Strong — exome sequencing with Sanger confirmation across multiple unrelated families, replicated in independent cohorts","pmids":["24178751"],"is_preprint":false},{"year":2015,"finding":"JBTS17/CPLANE1 protein localizes to the cilia transition zone, and loss-of-function (S235P missense mutation in mouse) results in ciliogenesis defects and loss of NPHP1 and CEP290 from the transition zone, placing CPLANE1 upstream of these Joubert syndrome-associated transition zone proteins.","method":"Immunostaining of mouse fibroblasts and cerebellar cells; forward genetic screen; exome sequencing; fibroblast wound-healing assay; comparison of Hug mutant vs. patient-derived fibroblasts","journal":"Human molecular genetics","confidence":"High","confidence_rationale":"Tier 2 / Strong — direct localization experiment with functional consequence, genetic epistasis established via loss of downstream proteins, multiple orthogonal methods (immunostaining, wound-healing, ciliogenesis assay), replicated in both mouse model and human patient fibroblasts","pmids":["25877302"],"is_preprint":false},{"year":2015,"finding":"Loss of CPLANE1 (JBTS17) in the Hug mouse model results in ciliogenesis defects in cerebellar cells with reduced cerebellar foliation, and mutant cells fail to establish cell polarity required for directional cell migration in a wound-healing assay.","method":"Immunostaining of cerebellar sections; fibroblast wound-healing assay in Hug mutant mouse fibroblasts","journal":"Human molecular genetics","confidence":"High","confidence_rationale":"Tier 2 / Strong — direct functional assay with defined cellular phenotype (ciliation and directional migration), multiple orthogonal methods, replicated across mouse and human cells","pmids":["25877302"],"is_preprint":false},{"year":2018,"finding":"Silencing of C5orf42 (CPLANE1) in chicken embryos causes facial midline widening and axonal pathfinding errors similar to those observed after perturbation of Sonic Hedgehog (SHH) signaling, and patient-derived fibroblasts with C5orf42 mutations show abnormal primary cilia and diminished response to a SHH agonist.","method":"siRNA knockdown in chicken embryos; functional SHH pathway assay in patient-derived fibroblasts using SHH agonist; immunostaining of primary cilia","journal":"European journal of human genetics : EJHG","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional SHH pathway assay in patient fibroblasts and in vivo knockdown in chick, single lab, two orthogonal methods","pmids":["29321670"],"is_preprint":false},{"year":2019,"finding":"JBTS17 (CPLANE1) localizes to the kinetochore during mitosis in a cell-cycle-dependent manner (regulated by proteolysis), and its depletion disrupts chromosome alignment and spindle pole orientation causing mitotic delay. JBTS17 interacts with LIS1 and influences LIS1 localization. Depletion of Jbts17 in the developing mouse cortex impairs mitotic progression of neural progenitors and migration of postmitotic neurons.","method":"Immunostaining with anti-JBTS17 antibodies; expression vectors; siRNA knockdown in human cells; live imaging; in utero electroporation in mouse cortex","journal":"Annals of neurology","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (immunostaining, live imaging, co-localization, in utero electroporation), interaction with LIS1 demonstrated, functional consequence defined in both cell and in vivo contexts","pmids":["31004438"],"is_preprint":false},{"year":2022,"finding":"Knockdown of CPLANE1 in NIH/3T3 cells decreases the cell migration rate and reduces the number of cilia. Furthermore, CPLANE1 knockdown inhibits the Hedgehog (Hh) signaling pathway, and this inhibitory effect is reversed by the Hh pathway activator SAG.","method":"siRNA knockdown in NIH/3T3 cells; cilia counting by immunostaining; cell migration assay; Hh pathway reporter assay with SAG rescue","journal":"Journal of cellular and molecular medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional knockdown with defined cellular phenotypes (cilia number, migration, Hh signaling), rescue experiment, single lab","pmids":["35582950"],"is_preprint":false},{"year":2024,"finding":"Loss of Cplane1 function in chicken embryos causes defects in dorsal root ganglia development, with ganglia varying in size and failing to localize symmetrically along the spinal cord, demonstrating a role for CPLANE1 in peripheral nervous system development.","method":"Cplane1 loss-of-function in chicken embryos (in vivo knockdown/knockout); immunostaining and morphological analysis of dorsal root ganglia","journal":"Developmental biology","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — in vivo loss-of-function with defined anatomical phenotype, single lab, single organism model","pmids":["39694173"],"is_preprint":false},{"year":2025,"finding":"A missense variant in CPLANE1 (c.203C>T; p.Thr68Ile) causes exon 3 skipping leading to a frameshift, premature termination codon, and nonsense-mediated mRNA decay (NMD); inhibition of SMG1 (a key NMD pathway kinase) partially rescued mRNA expression in mutated cells, establishing that NMD contributes to CPLANE1 loss-of-function in this variant.","method":"Functional RNA splicing analysis in PBMCs; actinomycin D and puromycin treatment to assess mRNA stability; SMG1 inhibitor rescue experiment; Sanger sequencing confirmation","journal":"Journal of cellular and molecular medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional mRNA stability assay with pharmacological rescue, multiple orthogonal molecular methods, single lab","pmids":["40074699"],"is_preprint":false}],"current_model":"CPLANE1 (C5orf42/JBTS17) encodes a cilia transition zone component required for ciliogenesis and proper localization of downstream transition zone proteins NPHP1 and CEP290; it regulates Hedgehog/SHH signaling through primary cilia, controls directional cell migration and cell polarity, and has an extraciliary role at the kinetochore during mitosis where it interacts with LIS1 to support chromosome alignment, spindle orientation, and neural progenitor mitotic progression — with loss-of-function causing Joubert syndrome and OFD VI ciliopathies."},"narrative":{"mechanistic_narrative":"CPLANE1 (C5orf42/JBTS17) is a cilia transition zone component required for ciliogenesis and the assembly of a functional primary cilium that supports Hedgehog signaling, cell polarity, and directional migration [PMID:25877302, PMID:35582950]. At the transition zone it acts upstream of the Joubert syndrome-associated proteins NPHP1 and CEP290, whose localization is lost when CPLANE1 is mutated [PMID:25877302]. Through the primary cilium it is required for Sonic Hedgehog pathway responsiveness: patient fibroblasts and knockdown cells show diminished response to SHH/Hh agonists, and the defect is reversed by the pathway activator SAG [PMID:29321670, PMID:35582950]. Loss of CPLANE1 function impairs establishment of cell polarity and directional cell migration, and in developing embryos causes cerebellar foliation defects, facial midline widening, axonal pathfinding errors, and abnormal dorsal root ganglia development [PMID:25877302, PMID:29321670, PMID:39694173]. Beyond the cilium, CPLANE1 has an extraciliary mitotic role: it localizes to the kinetochore in a cell-cycle-dependent, proteolytically regulated manner, interacts with LIS1 and influences its localization, and is required for chromosome alignment, spindle orientation, and mitotic progression of neural progenitors [PMID:31004438]. Biallelic loss-of-function mutations in CPLANE1 cause Joubert syndrome (JBTS17) and the allelic Oral-Facial-Digital syndrome type VI, with at least one variant acting through splice disruption and nonsense-mediated mRNA decay [PMID:22425360, PMID:24178751, PMID:40074699].","teleology":[{"year":2012,"claim":"Established CPLANE1 as a disease gene by linking biallelic loss-of-function mutations to a defined human ciliopathy, framing all subsequent mechanistic work.","evidence":"Exome sequencing with Sanger validation across multiple French Canadian Joubert syndrome families, absent in 477 controls","pmids":["22425360"],"confidence":"High","gaps":["Did not define the protein's subcellular localization or molecular function","No mechanism connecting mutation to cilia phenotype"]},{"year":2013,"claim":"Extended the genetic spectrum by showing CPLANE1 mutations underlie the allelic disorder OFD VI, consolidating it as a core ciliopathy gene.","evidence":"Exome sequencing with Sanger confirmation across six unrelated OFD VI families","pmids":["24178751"],"confidence":"High","gaps":["Genotype-phenotype basis for OFD VI vs Joubert presentation unresolved","No protein-level mechanism"]},{"year":2015,"claim":"Localized the protein to the cilia transition zone and placed it upstream of NPHP1 and CEP290, providing the first molecular mechanism for the ciliopathy phenotype.","evidence":"Immunostaining, forward genetic screen and Hug mouse model, ciliogenesis and wound-healing assays in mouse and patient fibroblasts","pmids":["25877302"],"confidence":"High","gaps":["Mode of transition zone recruitment unknown","Direct physical interaction with NPHP1/CEP290 not demonstrated"]},{"year":2018,"claim":"Connected CPLANE1 loss to defective Sonic Hedgehog signaling, linking the ciliary defect to specific developmental phenotypes.","evidence":"siRNA knockdown in chicken embryos and SHH agonist response assay in patient fibroblasts","pmids":["29321670"],"confidence":"Medium","gaps":["Step in the SHH cascade affected not pinpointed","Single-lab functional assay"]},{"year":2019,"claim":"Uncovered an extraciliary mitotic function at the kinetochore and a LIS1 interaction, revealing a second pathway by which CPLANE1 affects neural development.","evidence":"Immunostaining, live imaging, siRNA knockdown in human cells and in utero electroporation in mouse cortex","pmids":["31004438"],"confidence":"High","gaps":["Structural basis of the LIS1 interaction unknown","How a transition zone protein is targeted to the kinetochore unresolved"]},{"year":2022,"claim":"Confirmed in an independent system that CPLANE1 supports ciliation, migration and Hh signaling, with rescue establishing the Hh defect as on-pathway.","evidence":"siRNA knockdown in NIH/3T3 cells with cilia counting, migration assay and Hh reporter with SAG rescue","pmids":["35582950"],"confidence":"Medium","gaps":["Molecular target of CPLANE1 within the Hh pathway not identified","Single-lab study"]},{"year":2024,"claim":"Extended the developmental requirement for CPLANE1 to peripheral nervous system patterning.","evidence":"Loss-of-function in chicken embryos with morphological analysis of dorsal root ganglia","pmids":["39694173"],"confidence":"Medium","gaps":["Whether the DRG defect is ciliary or extraciliary not determined","Single organism model"]},{"year":2025,"claim":"Demonstrated a specific loss-of-function mechanism in which a missense variant triggers exon skipping and NMD, refining how CPLANE1 mutations cause disease.","evidence":"RNA splicing analysis, mRNA stability assays and SMG1-inhibitor rescue in patient PBMCs","pmids":["40074699"],"confidence":"Medium","gaps":["Generalizability to other CPLANE1 variants unknown","Single-lab study"]},{"year":null,"claim":"How CPLANE1 is recruited to both the transition zone and the kinetochore, and the structural and biochemical basis of its function at each site, remains unresolved.","evidence":"","pmids":[],"confidence":"High","gaps":["No structural model of CPLANE1 or its complexes","Direct biochemical interactions with NPHP1/CEP290 not established","Mechanism switching CPLANE1 between ciliary and mitotic roles unknown"]}],"mechanism_profile":{"molecular_activity":[],"localization":[{"term_id":"GO:0005929","term_label":"cilium","supporting_discovery_ids":[2,3,6]},{"term_id":"GO:0005694","term_label":"chromosome","supporting_discovery_ids":[5]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[4,6]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[3,7]},{"term_id":"R-HSA-1640170","term_label":"Cell Cycle","supporting_discovery_ids":[5]}],"complexes":["cilia transition zone","kinetochore"],"partners":["LIS1","NPHP1","CEP290"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q9H799","full_name":"Ciliogenesis and planar polarity effector 1","aliases":["Protein JBTS17"],"length_aa":3197,"mass_kda":361.7,"function":"Involved in ciliogenesis (PubMed:25877302, PubMed:35582950). Involved in the establishment of cell polarity required for directional cell migration. Proposed to act in association with the CPLANE (ciliogenesis and planar polarity effectors) complex. Involved in recruitment of peripheral IFT-A proteins to basal bodies (By similarity)","subcellular_location":"Membrane; Cell projection, cilium","url":"https://www.uniprot.org/uniprotkb/Q9H799/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/CPLANE1","classification":"Not Classified","n_dependent_lines":7,"n_total_lines":1208,"dependency_fraction":0.005794701986754967},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/CPLANE1","total_profiled":1310},"omim":[{"mim_id":"614615","title":"JOUBERT SYNDROME 17; JBTS17","url":"https://www.omim.org/entry/614615"},{"mim_id":"614571","title":"CILIOGENESIS AND PLANAR POLARITY EFFECTOR COMPLEX, SUBUNIT 1; CPLANE1","url":"https://www.omim.org/entry/614571"},{"mim_id":"613580","title":"WD REPEAT-CONTAINING PLANAR CELL POLARITY EFFECTOR; WDPCP","url":"https://www.omim.org/entry/613580"},{"mim_id":"610622","title":"FUZZY PLANAR CELL POLARITY PROTEIN; FUZ","url":"https://www.omim.org/entry/610622"},{"mim_id":"610621","title":"INTURNED PLANAR CELL POLARITY PROTEIN; INTU","url":"https://www.omim.org/entry/610621"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Cytosol","reliability":"Approved"},{"location":"Mid piece","reliability":"Approved"},{"location":"Principal piece","reliability":"Approved"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in many","driving_tissues":[],"url":"https://www.proteinatlas.org/search/CPLANE1"},"hgnc":{"alias_symbol":["FLJ13231","JBTS17","Hug"],"prev_symbol":["C5orf42"]},"alphafold":{"accession":"Q9H799","domains":[],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9H799","model_url":"","pae_url":"","plddt_mean":null},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=CPLANE1","jax_strain_url":"https://www.jax.org/strain/search?query=CPLANE1"},"sequence":{"accession":"Q9H799","fasta_url":"https://rest.uniprot.org/uniprotkb/Q9H799.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q9H799/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9H799"}},"corpus_meta":[{"pmid":"21571150","id":"PMC_21571150","title":"Hydroxycarbamide in very young children with sickle-cell anaemia: a multicentre, randomised, controlled trial (BABY HUG).","date":"2011","source":"Lancet (London, England)","url":"https://pubmed.ncbi.nlm.nih.gov/21571150","citation_count":625,"is_preprint":false},{"pmid":"10477679","id":"PMC_10477679","title":"Safety of hydroxyurea in children with sickle cell anemia: results of the HUG-KIDS study, a phase I/II trial. 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compound heterozygous mutations identified in 9/11 families; mutations absent in 477 French Canadian controls\",\n      \"journal\": \"American journal of human genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — exome sequencing with Sanger validation across multiple families, replicated across multiple affected individuals with no mutation in controls\",\n      \"pmids\": [\"22425360\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"C5orf42 (CPLANE1) mutations are the major genetic cause of Oral-Facial-Digital Syndrome type VI (OFD VI), which is allelic to Joubert syndrome, establishing that CPLANE1 is a ciliopathy gene underlying both conditions.\",\n      \"method\": \"Exome sequencing in six unrelated families followed by Sanger sequencing; 14 novel mutations identified in 9/11 OFD VI families\",\n      \"journal\": \"Human genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — exome sequencing with Sanger confirmation across multiple unrelated families, replicated in independent cohorts\",\n      \"pmids\": [\"24178751\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"JBTS17/CPLANE1 protein localizes to the cilia transition zone, and loss-of-function (S235P missense mutation in mouse) results in ciliogenesis defects and loss of NPHP1 and CEP290 from the transition zone, placing CPLANE1 upstream of these Joubert syndrome-associated transition zone proteins.\",\n      \"method\": \"Immunostaining of mouse fibroblasts and cerebellar cells; forward genetic screen; exome sequencing; fibroblast wound-healing assay; comparison of Hug mutant vs. patient-derived fibroblasts\",\n      \"journal\": \"Human molecular genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — direct localization experiment with functional consequence, genetic epistasis established via loss of downstream proteins, multiple orthogonal methods (immunostaining, wound-healing, ciliogenesis assay), replicated in both mouse model and human patient fibroblasts\",\n      \"pmids\": [\"25877302\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Loss of CPLANE1 (JBTS17) in the Hug mouse model results in ciliogenesis defects in cerebellar cells with reduced cerebellar foliation, and mutant cells fail to establish cell polarity required for directional cell migration in a wound-healing assay.\",\n      \"method\": \"Immunostaining of cerebellar sections; fibroblast wound-healing assay in Hug mutant mouse fibroblasts\",\n      \"journal\": \"Human molecular genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — direct functional assay with defined cellular phenotype (ciliation and directional migration), multiple orthogonal methods, replicated across mouse and human cells\",\n      \"pmids\": [\"25877302\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Silencing of C5orf42 (CPLANE1) in chicken embryos causes facial midline widening and axonal pathfinding errors similar to those observed after perturbation of Sonic Hedgehog (SHH) signaling, and patient-derived fibroblasts with C5orf42 mutations show abnormal primary cilia and diminished response to a SHH agonist.\",\n      \"method\": \"siRNA knockdown in chicken embryos; functional SHH pathway assay in patient-derived fibroblasts using SHH agonist; immunostaining of primary cilia\",\n      \"journal\": \"European journal of human genetics : EJHG\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional SHH pathway assay in patient fibroblasts and in vivo knockdown in chick, single lab, two orthogonal methods\",\n      \"pmids\": [\"29321670\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"JBTS17 (CPLANE1) localizes to the kinetochore during mitosis in a cell-cycle-dependent manner (regulated by proteolysis), and its depletion disrupts chromosome alignment and spindle pole orientation causing mitotic delay. JBTS17 interacts with LIS1 and influences LIS1 localization. Depletion of Jbts17 in the developing mouse cortex impairs mitotic progression of neural progenitors and migration of postmitotic neurons.\",\n      \"method\": \"Immunostaining with anti-JBTS17 antibodies; expression vectors; siRNA knockdown in human cells; live imaging; in utero electroporation in mouse cortex\",\n      \"journal\": \"Annals of neurology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (immunostaining, live imaging, co-localization, in utero electroporation), interaction with LIS1 demonstrated, functional consequence defined in both cell and in vivo contexts\",\n      \"pmids\": [\"31004438\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Knockdown of CPLANE1 in NIH/3T3 cells decreases the cell migration rate and reduces the number of cilia. Furthermore, CPLANE1 knockdown inhibits the Hedgehog (Hh) signaling pathway, and this inhibitory effect is reversed by the Hh pathway activator SAG.\",\n      \"method\": \"siRNA knockdown in NIH/3T3 cells; cilia counting by immunostaining; cell migration assay; Hh pathway reporter assay with SAG rescue\",\n      \"journal\": \"Journal of cellular and molecular medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional knockdown with defined cellular phenotypes (cilia number, migration, Hh signaling), rescue experiment, single lab\",\n      \"pmids\": [\"35582950\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Loss of Cplane1 function in chicken embryos causes defects in dorsal root ganglia development, with ganglia varying in size and failing to localize symmetrically along the spinal cord, demonstrating a role for CPLANE1 in peripheral nervous system development.\",\n      \"method\": \"Cplane1 loss-of-function in chicken embryos (in vivo knockdown/knockout); immunostaining and morphological analysis of dorsal root ganglia\",\n      \"journal\": \"Developmental biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — in vivo loss-of-function with defined anatomical phenotype, single lab, single organism model\",\n      \"pmids\": [\"39694173\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"A missense variant in CPLANE1 (c.203C>T; p.Thr68Ile) causes exon 3 skipping leading to a frameshift, premature termination codon, and nonsense-mediated mRNA decay (NMD); inhibition of SMG1 (a key NMD pathway kinase) partially rescued mRNA expression in mutated cells, establishing that NMD contributes to CPLANE1 loss-of-function in this variant.\",\n      \"method\": \"Functional RNA splicing analysis in PBMCs; actinomycin D and puromycin treatment to assess mRNA stability; SMG1 inhibitor rescue experiment; Sanger sequencing confirmation\",\n      \"journal\": \"Journal of cellular and molecular medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional mRNA stability assay with pharmacological rescue, multiple orthogonal molecular methods, single lab\",\n      \"pmids\": [\"40074699\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"CPLANE1 (C5orf42/JBTS17) encodes a cilia transition zone component required for ciliogenesis and proper localization of downstream transition zone proteins NPHP1 and CEP290; it regulates Hedgehog/SHH signaling through primary cilia, controls directional cell migration and cell polarity, and has an extraciliary role at the kinetochore during mitosis where it interacts with LIS1 to support chromosome alignment, spindle orientation, and neural progenitor mitotic progression — with loss-of-function causing Joubert syndrome and OFD VI ciliopathies.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"CPLANE1 (C5orf42/JBTS17) is a cilia transition zone component required for ciliogenesis and the assembly of a functional primary cilium that supports Hedgehog signaling, cell polarity, and directional migration [#2, #6]. At the transition zone it acts upstream of the Joubert syndrome-associated proteins NPHP1 and CEP290, whose localization is lost when CPLANE1 is mutated [#2]. Through the primary cilium it is required for Sonic Hedgehog pathway responsiveness: patient fibroblasts and knockdown cells show diminished response to SHH/Hh agonists, and the defect is reversed by the pathway activator SAG [#4, #6]. Loss of CPLANE1 function impairs establishment of cell polarity and directional cell migration, and in developing embryos causes cerebellar foliation defects, facial midline widening, axonal pathfinding errors, and abnormal dorsal root ganglia development [#3, #4, #7]. Beyond the cilium, CPLANE1 has an extraciliary mitotic role: it localizes to the kinetochore in a cell-cycle-dependent, proteolytically regulated manner, interacts with LIS1 and influences its localization, and is required for chromosome alignment, spindle orientation, and mitotic progression of neural progenitors [#5]. Biallelic loss-of-function mutations in CPLANE1 cause Joubert syndrome (JBTS17) and the allelic Oral-Facial-Digital syndrome type VI, with at least one variant acting through splice disruption and nonsense-mediated mRNA decay [#0, #1, #8].\",\n  \"teleology\": [\n    {\n      \"year\": 2012,\n      \"claim\": \"Established CPLANE1 as a disease gene by linking biallelic loss-of-function mutations to a defined human ciliopathy, framing all subsequent mechanistic work.\",\n      \"evidence\": \"Exome sequencing with Sanger validation across multiple French Canadian Joubert syndrome families, absent in 477 controls\",\n      \"pmids\": [\"22425360\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not define the protein's subcellular localization or molecular function\", \"No mechanism connecting mutation to cilia phenotype\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Extended the genetic spectrum by showing CPLANE1 mutations underlie the allelic disorder OFD VI, consolidating it as a core ciliopathy gene.\",\n      \"evidence\": \"Exome sequencing with Sanger confirmation across six unrelated OFD VI families\",\n      \"pmids\": [\"24178751\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Genotype-phenotype basis for OFD VI vs Joubert presentation unresolved\", \"No protein-level mechanism\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Localized the protein to the cilia transition zone and placed it upstream of NPHP1 and CEP290, providing the first molecular mechanism for the ciliopathy phenotype.\",\n      \"evidence\": \"Immunostaining, forward genetic screen and Hug mouse model, ciliogenesis and wound-healing assays in mouse and patient fibroblasts\",\n      \"pmids\": [\"25877302\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mode of transition zone recruitment unknown\", \"Direct physical interaction with NPHP1/CEP290 not demonstrated\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Connected CPLANE1 loss to defective Sonic Hedgehog signaling, linking the ciliary defect to specific developmental phenotypes.\",\n      \"evidence\": \"siRNA knockdown in chicken embryos and SHH agonist response assay in patient fibroblasts\",\n      \"pmids\": [\"29321670\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Step in the SHH cascade affected not pinpointed\", \"Single-lab functional assay\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Uncovered an extraciliary mitotic function at the kinetochore and a LIS1 interaction, revealing a second pathway by which CPLANE1 affects neural development.\",\n      \"evidence\": \"Immunostaining, live imaging, siRNA knockdown in human cells and in utero electroporation in mouse cortex\",\n      \"pmids\": [\"31004438\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of the LIS1 interaction unknown\", \"How a transition zone protein is targeted to the kinetochore unresolved\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Confirmed in an independent system that CPLANE1 supports ciliation, migration and Hh signaling, with rescue establishing the Hh defect as on-pathway.\",\n      \"evidence\": \"siRNA knockdown in NIH/3T3 cells with cilia counting, migration assay and Hh reporter with SAG rescue\",\n      \"pmids\": [\"35582950\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Molecular target of CPLANE1 within the Hh pathway not identified\", \"Single-lab study\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Extended the developmental requirement for CPLANE1 to peripheral nervous system patterning.\",\n      \"evidence\": \"Loss-of-function in chicken embryos with morphological analysis of dorsal root ganglia\",\n      \"pmids\": [\"39694173\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether the DRG defect is ciliary or extraciliary not determined\", \"Single organism model\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Demonstrated a specific loss-of-function mechanism in which a missense variant triggers exon skipping and NMD, refining how CPLANE1 mutations cause disease.\",\n      \"evidence\": \"RNA splicing analysis, mRNA stability assays and SMG1-inhibitor rescue in patient PBMCs\",\n      \"pmids\": [\"40074699\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Generalizability to other CPLANE1 variants unknown\", \"Single-lab study\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How CPLANE1 is recruited to both the transition zone and the kinetochore, and the structural and biochemical basis of its function at each site, remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No structural model of CPLANE1 or its complexes\", \"Direct biochemical interactions with NPHP1/CEP290 not established\", \"Mechanism switching CPLANE1 between ciliary and mitotic roles unknown\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [],\n    \"localization\": [\n      {\"term_id\": \"GO:0005929\", \"supporting_discovery_ids\": [2, 3, 6]},\n      {\"term_id\": \"GO:0005694\", \"supporting_discovery_ids\": [5]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [4, 6]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [3, 7]},\n      {\"term_id\": \"R-HSA-1640170\", \"supporting_discovery_ids\": [5]}\n    ],\n    \"complexes\": [\"cilia transition zone\", \"kinetochore\"],\n    \"partners\": [\"LIS1\", \"NPHP1\", \"CEP290\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":6,"faith_total":6,"faith_pct":100.0}}