{"gene":"BBS10","run_date":"2026-06-09T22:02:44","timeline":{"discoveries":[{"year":2006,"finding":"BBS10 encodes a vertebrate-specific chaperonin-like protein that is required for normal ciliary/basal body function; in zebrafish, mild morpholino suppression of bbs10 exacerbated the phenotypes of other bbs morphants, placing BBS10 in a common genetic pathway with other BBS genes.","method":"Positional cloning, sequence analysis revealing chaperonin-like domain, zebrafish morpholino epistasis experiments","journal":"Nature genetics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — zebrafish epistasis establishes pathway position; chaperonin-like domain identified by sequence; single lab but multiple complementary approaches","pmids":["16582908"],"is_preprint":false},{"year":2015,"finding":"BBS10 protein forms part of a chaperone complex localized at the basal body of the primary cilium. Complete knockout of Bbs10 in mice (Bbs10−/−) caused obesity, retinal degeneration, glomerular structural defects, polyuria with elevated arginine vasopressin, and vacuolated renal epithelial cells, whereas renal-epithelium-specific knockout (Bbs10fl/fl; Cdh16-Cre) produced no detectable renal impairment, demonstrating that systemic rather than renal-intrinsic loss of BBS10 drives renal dysfunction.","method":"Conditional and complete mouse knockout (Cre-lox), histology, physiological measurements (urine output, AVP levels), immunofluorescence for cilia","journal":"Cilia","confidence":"High","confidence_rationale":"Tier 2 / Strong — clean KO mouse models (complete and tissue-specific) with multiple defined phenotypic readouts and direct functional consequence; systemic vs. conditional comparison is a rigorous epistatic design","pmids":["26273430"],"is_preprint":false},{"year":2015,"finding":"BBS10 iPSC line derived from a BBS patient with homozygous c.271insT (p.Cys91fsX95) confirmed that BBS6 and BBS12, together with BBS10, encode chaperonin-like proteins important for assembly of the BBSome multiprotein complex.","method":"iPSC generation and characterization; description of BBS10/BBS6/BBS12 as a chaperonin-like module for BBSome assembly","journal":"Stem cell research","confidence":"Low","confidence_rationale":"Tier 3 / Weak — iPSC line generation with molecular description; assembly role inferred from published literature cited in abstract, not directly demonstrated in this paper","pmids":["30312873"],"is_preprint":false},{"year":2022,"finding":"Mass spectrometry-based interactome analysis of BBS10 in IMCD3 cells (Bbs10 stably invalidated) identified multiple putative BBS10 interactors, indicating roles in renal metabolism, RNA processing, and cell proliferation beyond ciliary function. Bbs10-knockout IMCD3 cells showed increased proliferation, increased ATP production, and upregulation of aerobic glycolysis.","method":"MS-based interactome (co-IP/pull-down followed by mass spectrometry), stable cell line knockout, cell proliferation assay, ATP measurement, metabolomics","journal":"International journal of molecular sciences","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — MS interactome plus functional cellular phenotypes in KO cells; single lab with multiple orthogonal methods","pmids":["36012682"],"is_preprint":false},{"year":2025,"finding":"Truncating mutations in BBS10 (C-terminal deletions) reduce protein stability via accelerated degradation through the ubiquitin-proteasome pathway, impair protein-protein interactions with BBS12 and with the core BBSome subunit BBS7, and affect ciliary length, while mutant BBS10 still localizes to primary cilia similarly to wild-type.","method":"Transfection of mutant constructs in HEK293T and hTERT-RPE1 cells, Western blot (protein stability), co-immunoprecipitation (interaction with BBS12 and BBS7), immunofluorescence (ciliary localization and length measurement), proteasome inhibitor experiments","journal":"Experimental eye research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal co-IP, Western blot stability assay, and immunofluorescence in two cell lines; single lab with multiple orthogonal methods but no structural validation","pmids":["40914337"],"is_preprint":false}],"current_model":"BBS10 is a vertebrate-specific chaperonin-like protein that localizes to the basal body of the primary cilium, where it forms a chaperone complex with BBS6 and BBS12 required for BBSome assembly; its C-terminal domain mediates protein stability and direct interactions with BBS12 and the BBSome subunit BBS7, and loss of BBS10 drives obesity, retinal degeneration, and renal dysfunction through systemic rather than renal-cell-intrinsic mechanisms, with additional extraciliary roles in cellular metabolism and proliferation suggested by interactome studies."},"narrative":{"mechanistic_narrative":"BBS10 is a vertebrate-specific chaperonin-like protein that functions in a common genetic pathway with other Bardet-Biedl syndrome genes to support basal body and primary cilium function [PMID:16582908]. At the basal body, BBS10 acts within a chaperone complex required for assembly of the BBSome multiprotein complex [PMID:26273430]. Its C-terminal domain mediates protein stability and direct physical interactions with the chaperonin-like protein BBS12 and the core BBSome subunit BBS7; C-terminal truncating mutations accelerate degradation through the ubiquitin-proteasome pathway, impair these interactions, and alter ciliary length, although mutant protein still localizes normally to primary cilia [PMID:40914337]. Complete loss of BBS10 in mice produces obesity, retinal degeneration, and renal dysfunction, with renal-epithelium-specific knockout causing no renal impairment, establishing that renal phenotypes arise from systemic rather than renal-cell-intrinsic loss [PMID:26273430]. Interactome analysis in renal cells implicates BBS10 in extraciliary processes including cellular metabolism and proliferation, with knockout cells showing increased proliferation, elevated ATP production, and upregulated aerobic glycolysis [PMID:36012682].","teleology":[{"year":2006,"claim":"Established BBS10 as a Bardet-Biedl disease gene and placed it genetically within the shared BBS ciliary pathway rather than as an isolated factor.","evidence":"Positional cloning, sequence analysis identifying a chaperonin-like domain, and zebrafish morpholino epistasis with other bbs morphants","pmids":["16582908"],"confidence":"Medium","gaps":["Chaperonin-like activity inferred from sequence, not biochemically demonstrated","Direct molecular partners not yet identified","Mechanism by which it supports basal body function unresolved"]},{"year":2015,"claim":"Determined that BBS10 localizes to a basal body chaperone complex and that its systemic, not renal-intrinsic, loss drives renal dysfunction, resolving the tissue origin of the phenotype.","evidence":"Complete and renal-epithelium-specific Cre-lox mouse knockouts with histology, physiological readouts, and ciliary immunofluorescence","pmids":["26273430"],"confidence":"High","gaps":["Systemic factor mediating renal dysfunction not identified","Molecular composition of the chaperone complex not defined here","Link between basal body localization and the multi-organ phenotypes not mechanistically traced"]},{"year":2015,"claim":"Framed BBS10 together with BBS6 and BBS12 as a chaperonin-like module for BBSome assembly using a patient-derived cellular model.","evidence":"iPSC line generated from a BBS patient homozygous for c.271insT (p.Cys91fsX95)","pmids":["30312873"],"confidence":"Low","gaps":["BBSome assembly role cited from prior literature, not directly demonstrated in this study","No functional assay of the chaperonin module performed","Patient mutation phenotype not characterized at the protein level"]},{"year":2022,"claim":"Extended BBS10 function beyond cilia by linking it to metabolism and proliferation through interactome and cellular phenotyping.","evidence":"MS-based interactome of stably knocked-out Bbs10 IMCD3 cells with proliferation assays, ATP measurement, and metabolomics","pmids":["36012682"],"confidence":"Medium","gaps":["Interactors are putative and not individually validated","Causal link between specific interactors and the metabolic/proliferative phenotypes not established","Direct versus indirect nature of the metabolic role unclear"]},{"year":2025,"claim":"Defined the mechanistic basis of C-terminal truncating mutations: loss of protein stability and disrupted partner binding rather than mislocalization.","evidence":"Transfection of mutant constructs in HEK293T and hTERT-RPE1 cells with Western blot stability assays, reciprocal co-IP for BBS12 and BBS7, proteasome inhibition, and ciliary immunofluorescence","pmids":["40914337"],"confidence":"Medium","gaps":["No structural model of the C-terminal interaction interface","Stoichiometry and order of BBS10-BBS12-BBS7 assembly not determined","Whether reduced ciliary length is a direct consequence of impaired BBSome assembly not established"]},{"year":null,"claim":"How the BBS10/BBS6/BBS12 chaperonin-like module mechanically drives BBSome assembly, and what systemic signal links its loss to obesity and organ-specific degeneration, remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No reconstituted biochemical demonstration of chaperonin-like assembly activity","Systemic mediator of renal and metabolic phenotypes unidentified","No structural characterization of BBS10 or its complexes"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0044183","term_label":"protein folding chaperone","supporting_discovery_ids":[0,2]},{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[4]}],"localization":[{"term_id":"GO:0005815","term_label":"microtubule organizing center","supporting_discovery_ids":[1,4]},{"term_id":"GO:0005929","term_label":"cilium","supporting_discovery_ids":[1,4]}],"pathway":[{"term_id":"R-HSA-1852241","term_label":"Organelle biogenesis and maintenance","supporting_discovery_ids":[1,2]},{"term_id":"R-HSA-1430728","term_label":"Metabolism","supporting_discovery_ids":[3]}],"complexes":["BBSome assembly chaperone complex (BBS10/BBS6/BBS12)"],"partners":["BBS12","BBS7","BBS6"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q8TAM1","full_name":"BBSome complex assembly protein BBS10","aliases":["Bardet-Biedl syndrome 10 protein"],"length_aa":723,"mass_kda":80.8,"function":"Probable molecular chaperone that assists the folding of proteins upon ATP hydrolysis (PubMed:20080638). Plays a role in the assembly of BBSome, a complex involved in ciliogenesis regulating transports vesicles to the cilia (PubMed:20080638). Involved in adipogenic differentiation (PubMed:19190184)","subcellular_location":"Cell projection, cilium","url":"https://www.uniprot.org/uniprotkb/Q8TAM1/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/BBS10","classification":"Not Classified","n_dependent_lines":5,"n_total_lines":1208,"dependency_fraction":0.0041390728476821195},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/BBS10","total_profiled":1310},"omim":[{"mim_id":"617406","title":"BARDET-BIEDL SYNDROME 21; BBS21","url":"https://www.omim.org/entry/617406"},{"mim_id":"615994","title":"BARDET-BIEDL SYNDROME 17; BBS17","url":"https://www.omim.org/entry/615994"},{"mim_id":"615990","title":"BARDET-BIEDL SYNDROME 13; BBS13","url":"https://www.omim.org/entry/615990"},{"mim_id":"615989","title":"BARDET-BIEDL SYNDROME 12; BBS12","url":"https://www.omim.org/entry/615989"},{"mim_id":"615987","title":"BARDET-BIEDL SYNDROME 10; BBS10","url":"https://www.omim.org/entry/615987"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"","locations":[],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in many","driving_tissues":[],"url":"https://www.proteinatlas.org/search/BBS10"},"hgnc":{"alias_symbol":["FLJ23560"],"prev_symbol":["C12orf58"]},"alphafold":{"accession":"Q8TAM1","domains":[{"cath_id":"3.50.7.10","chopping":"240-268_278-394","consensus_level":"medium","plddt":86.9663,"start":240,"end":394}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q8TAM1","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q8TAM1-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q8TAM1-F1-predicted_aligned_error_v6.png","plddt_mean":71.31},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=BBS10","jax_strain_url":"https://www.jax.org/strain/search?query=BBS10"},"sequence":{"accession":"Q8TAM1","fasta_url":"https://rest.uniprot.org/uniprotkb/Q8TAM1.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q8TAM1/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q8TAM1"}},"corpus_meta":[{"pmid":"16582908","id":"PMC_16582908","title":"BBS10 encodes a vertebrate-specific chaperonin-like protein and is a major BBS locus.","date":"2006","source":"Nature genetics","url":"https://pubmed.ncbi.nlm.nih.gov/16582908","citation_count":223,"is_preprint":false},{"pmid":"16823392","id":"PMC_16823392","title":"Pitfalls of homozygosity mapping: an extended consanguineous Bardet-Biedl syndrome family with two mutant genes (BBS2, BBS10), three mutations, but no triallelism.","date":"2006","source":"European journal of human genetics : EJHG","url":"https://pubmed.ncbi.nlm.nih.gov/16823392","citation_count":41,"is_preprint":false},{"pmid":"26518167","id":"PMC_26518167","title":"Targeted multi-gene panel testing for the diagnosis of Bardet Biedl syndrome: Identification of nine novel mutations across BBS1, BBS2, BBS4, BBS7, BBS9, BBS10 genes.","date":"2015","source":"European journal of medical genetics","url":"https://pubmed.ncbi.nlm.nih.gov/26518167","citation_count":39,"is_preprint":false},{"pmid":"26273430","id":"PMC_26273430","title":"Comparing the Bbs10 complete knockout phenotype with a specific renal epithelial knockout one highlights the link between renal defects and systemic inactivation in mice.","date":"2015","source":"Cilia","url":"https://pubmed.ncbi.nlm.nih.gov/26273430","citation_count":28,"is_preprint":false},{"pmid":"25439097","id":"PMC_25439097","title":"A novel test for recessive contributions to complex diseases implicates Bardet-Biedl syndrome gene BBS10 in idiopathic type 2 diabetes and obesity.","date":"2014","source":"American journal of human genetics","url":"https://pubmed.ncbi.nlm.nih.gov/25439097","citation_count":27,"is_preprint":false},{"pmid":"17106446","id":"PMC_17106446","title":"Autozygosity mapping of Bardet-Biedl syndrome to 12q21.2 and confirmation of FLJ23560 as BBS10.","date":"2006","source":"European journal of human genetics : EJHG","url":"https://pubmed.ncbi.nlm.nih.gov/17106446","citation_count":22,"is_preprint":false},{"pmid":"20805367","id":"PMC_20805367","title":"BBS10 mutations are common in 'Meckel'-type cystic kidneys.","date":"2010","source":"Journal of medical genetics","url":"https://pubmed.ncbi.nlm.nih.gov/20805367","citation_count":20,"is_preprint":false},{"pmid":"23219996","id":"PMC_23219996","title":"Novel homozygous mutations in the genes ARL6 and BBS10 underlying Bardet-Biedl syndrome.","date":"2012","source":"Gene","url":"https://pubmed.ncbi.nlm.nih.gov/23219996","citation_count":20,"is_preprint":false},{"pmid":"36012682","id":"PMC_36012682","title":"Multi-Omics Studies Unveil Extraciliary Functions of BBS10 and Show Metabolic Aberrations Underlying Renal Disease in Bardet-Biedl Syndrome.","date":"2022","source":"International journal of molecular sciences","url":"https://pubmed.ncbi.nlm.nih.gov/36012682","citation_count":12,"is_preprint":false},{"pmid":"29666954","id":"PMC_29666954","title":"Clinical characteristics of a Japanese patient with Bardet-Biedl syndrome caused by BBS10 mutations.","date":"2018","source":"Japanese journal of ophthalmology","url":"https://pubmed.ncbi.nlm.nih.gov/29666954","citation_count":11,"is_preprint":false},{"pmid":"36312387","id":"PMC_36312387","title":"Computational and Structural Analysis to Assess the Pathogenicity of Bardet-Biedl Syndrome Related Missense Variants Identified in Bardet-Biedl Syndrome 10 Gene (BBS10).","date":"2022","source":"ACS omega","url":"https://pubmed.ncbi.nlm.nih.gov/36312387","citation_count":8,"is_preprint":false},{"pmid":"34900151","id":"PMC_34900151","title":"Identification of a Novel Homozygous Mutation in BBS10 Gene in an Iranian Family with Bardet-Biedl Syndrome.","date":"2021","source":"Avicenna journal of medical biotechnology","url":"https://pubmed.ncbi.nlm.nih.gov/34900151","citation_count":5,"is_preprint":false},{"pmid":"28808579","id":"PMC_28808579","title":"A novel BBS10 mutation identified in a patient with Bardet-Biedl syndrome with a violent emotional outbreak.","date":"2017","source":"Human genome variation","url":"https://pubmed.ncbi.nlm.nih.gov/28808579","citation_count":4,"is_preprint":false},{"pmid":"36340607","id":"PMC_36340607","title":"Prenatal diagnosis of Bardet‑Biedl syndrome due to novel variants in the BBS10 gene in a fetus with multiple anomalies: A case report.","date":"2022","source":"Experimental and therapeutic medicine","url":"https://pubmed.ncbi.nlm.nih.gov/36340607","citation_count":3,"is_preprint":false},{"pmid":"30312873","id":"PMC_30312873","title":"Generation of induced pluripotent stem cells, KCi002-A derived from a patient with Bardet-Biedl syndrome homozygous for the BBS10 variant c.271insT.","date":"2018","source":"Stem cell research","url":"https://pubmed.ncbi.nlm.nih.gov/30312873","citation_count":1,"is_preprint":false},{"pmid":"40914337","id":"PMC_40914337","title":"Truncating mutations in BBS10 and BBS12 impair proteostasis and ciliary architecture in Bardet-Biedl Syndrome.","date":"2025","source":"Experimental eye research","url":"https://pubmed.ncbi.nlm.nih.gov/40914337","citation_count":0,"is_preprint":false},{"pmid":"39315571","id":"PMC_39315571","title":"Integration of multi-omics reveals the important role of the BBS10 gene in reproduction.","date":"2024","source":"Journal of animal science","url":"https://pubmed.ncbi.nlm.nih.gov/39315571","citation_count":0,"is_preprint":false},{"pmid":"30335236","id":"PMC_30335236","title":"A pathogenic homozygous variant of the BBS10 gene in a patient with Bardet Biedl syndrome.","date":"2018","source":"Biomedica : revista del Instituto Nacional de Salud","url":"https://pubmed.ncbi.nlm.nih.gov/30335236","citation_count":0,"is_preprint":false},{"pmid":"41418239","id":"PMC_41418239","title":"Assessment of genetic variation(s) in BBS10, BBS6, and BBS12 in a family from Sindh, Pakistan diagnosed with Bardet-Biedl Syndrome.","date":"2025","source":"JPMA. The Journal of the Pakistan Medical Association","url":"https://pubmed.ncbi.nlm.nih.gov/41418239","citation_count":0,"is_preprint":false},{"pmid":"39250911","id":"PMC_39250911","title":"Neonatal Hydrocolpos in Bardet-Biedl Syndrome due to a Novel Frameshift Indel in the BBS10 Gene.","date":"2024","source":"Sexual development : genetics, molecular biology, evolution, endocrinology, embryology, and pathology of sex determination and differentiation","url":"https://pubmed.ncbi.nlm.nih.gov/39250911","citation_count":0,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":11513,"output_tokens":1433,"usd":0.028017,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":8157,"output_tokens":2219,"usd":0.04813,"stage2_stop_reason":"end_turn"},"total_usd":0.076147,"stage1_batch_id":"msgbatch_0179Z2pxRYBsXi2xADneafRw","stage2_batch_id":"msgbatch_01LaY9ZaVdgjWArcZo9eqQE5","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2006,\n      \"finding\": \"BBS10 encodes a vertebrate-specific chaperonin-like protein that is required for normal ciliary/basal body function; in zebrafish, mild morpholino suppression of bbs10 exacerbated the phenotypes of other bbs morphants, placing BBS10 in a common genetic pathway with other BBS genes.\",\n      \"method\": \"Positional cloning, sequence analysis revealing chaperonin-like domain, zebrafish morpholino epistasis experiments\",\n      \"journal\": \"Nature genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — zebrafish epistasis establishes pathway position; chaperonin-like domain identified by sequence; single lab but multiple complementary approaches\",\n      \"pmids\": [\"16582908\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"BBS10 protein forms part of a chaperone complex localized at the basal body of the primary cilium. Complete knockout of Bbs10 in mice (Bbs10−/−) caused obesity, retinal degeneration, glomerular structural defects, polyuria with elevated arginine vasopressin, and vacuolated renal epithelial cells, whereas renal-epithelium-specific knockout (Bbs10fl/fl; Cdh16-Cre) produced no detectable renal impairment, demonstrating that systemic rather than renal-intrinsic loss of BBS10 drives renal dysfunction.\",\n      \"method\": \"Conditional and complete mouse knockout (Cre-lox), histology, physiological measurements (urine output, AVP levels), immunofluorescence for cilia\",\n      \"journal\": \"Cilia\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — clean KO mouse models (complete and tissue-specific) with multiple defined phenotypic readouts and direct functional consequence; systemic vs. conditional comparison is a rigorous epistatic design\",\n      \"pmids\": [\"26273430\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"BBS10 iPSC line derived from a BBS patient with homozygous c.271insT (p.Cys91fsX95) confirmed that BBS6 and BBS12, together with BBS10, encode chaperonin-like proteins important for assembly of the BBSome multiprotein complex.\",\n      \"method\": \"iPSC generation and characterization; description of BBS10/BBS6/BBS12 as a chaperonin-like module for BBSome assembly\",\n      \"journal\": \"Stem cell research\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — iPSC line generation with molecular description; assembly role inferred from published literature cited in abstract, not directly demonstrated in this paper\",\n      \"pmids\": [\"30312873\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Mass spectrometry-based interactome analysis of BBS10 in IMCD3 cells (Bbs10 stably invalidated) identified multiple putative BBS10 interactors, indicating roles in renal metabolism, RNA processing, and cell proliferation beyond ciliary function. Bbs10-knockout IMCD3 cells showed increased proliferation, increased ATP production, and upregulation of aerobic glycolysis.\",\n      \"method\": \"MS-based interactome (co-IP/pull-down followed by mass spectrometry), stable cell line knockout, cell proliferation assay, ATP measurement, metabolomics\",\n      \"journal\": \"International journal of molecular sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — MS interactome plus functional cellular phenotypes in KO cells; single lab with multiple orthogonal methods\",\n      \"pmids\": [\"36012682\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Truncating mutations in BBS10 (C-terminal deletions) reduce protein stability via accelerated degradation through the ubiquitin-proteasome pathway, impair protein-protein interactions with BBS12 and with the core BBSome subunit BBS7, and affect ciliary length, while mutant BBS10 still localizes to primary cilia similarly to wild-type.\",\n      \"method\": \"Transfection of mutant constructs in HEK293T and hTERT-RPE1 cells, Western blot (protein stability), co-immunoprecipitation (interaction with BBS12 and BBS7), immunofluorescence (ciliary localization and length measurement), proteasome inhibitor experiments\",\n      \"journal\": \"Experimental eye research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal co-IP, Western blot stability assay, and immunofluorescence in two cell lines; single lab with multiple orthogonal methods but no structural validation\",\n      \"pmids\": [\"40914337\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"BBS10 is a vertebrate-specific chaperonin-like protein that localizes to the basal body of the primary cilium, where it forms a chaperone complex with BBS6 and BBS12 required for BBSome assembly; its C-terminal domain mediates protein stability and direct interactions with BBS12 and the BBSome subunit BBS7, and loss of BBS10 drives obesity, retinal degeneration, and renal dysfunction through systemic rather than renal-cell-intrinsic mechanisms, with additional extraciliary roles in cellular metabolism and proliferation suggested by interactome studies.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"BBS10 is a vertebrate-specific chaperonin-like protein that functions in a common genetic pathway with other Bardet-Biedl syndrome genes to support basal body and primary cilium function [#0]. At the basal body, BBS10 acts within a chaperone complex required for assembly of the BBSome multiprotein complex [#1]. Its C-terminal domain mediates protein stability and direct physical interactions with the chaperonin-like protein BBS12 and the core BBSome subunit BBS7; C-terminal truncating mutations accelerate degradation through the ubiquitin-proteasome pathway, impair these interactions, and alter ciliary length, although mutant protein still localizes normally to primary cilia [#4]. Complete loss of BBS10 in mice produces obesity, retinal degeneration, and renal dysfunction, with renal-epithelium-specific knockout causing no renal impairment, establishing that renal phenotypes arise from systemic rather than renal-cell-intrinsic loss [#1]. Interactome analysis in renal cells implicates BBS10 in extraciliary processes including cellular metabolism and proliferation, with knockout cells showing increased proliferation, elevated ATP production, and upregulated aerobic glycolysis [#3].\",\n  \"teleology\": [\n    {\n      \"year\": 2006,\n      \"claim\": \"Established BBS10 as a Bardet-Biedl disease gene and placed it genetically within the shared BBS ciliary pathway rather than as an isolated factor.\",\n      \"evidence\": \"Positional cloning, sequence analysis identifying a chaperonin-like domain, and zebrafish morpholino epistasis with other bbs morphants\",\n      \"pmids\": [\"16582908\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Chaperonin-like activity inferred from sequence, not biochemically demonstrated\", \"Direct molecular partners not yet identified\", \"Mechanism by which it supports basal body function unresolved\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Determined that BBS10 localizes to a basal body chaperone complex and that its systemic, not renal-intrinsic, loss drives renal dysfunction, resolving the tissue origin of the phenotype.\",\n      \"evidence\": \"Complete and renal-epithelium-specific Cre-lox mouse knockouts with histology, physiological readouts, and ciliary immunofluorescence\",\n      \"pmids\": [\"26273430\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Systemic factor mediating renal dysfunction not identified\", \"Molecular composition of the chaperone complex not defined here\", \"Link between basal body localization and the multi-organ phenotypes not mechanistically traced\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Framed BBS10 together with BBS6 and BBS12 as a chaperonin-like module for BBSome assembly using a patient-derived cellular model.\",\n      \"evidence\": \"iPSC line generated from a BBS patient homozygous for c.271insT (p.Cys91fsX95)\",\n      \"pmids\": [\"30312873\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"BBSome assembly role cited from prior literature, not directly demonstrated in this study\", \"No functional assay of the chaperonin module performed\", \"Patient mutation phenotype not characterized at the protein level\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Extended BBS10 function beyond cilia by linking it to metabolism and proliferation through interactome and cellular phenotyping.\",\n      \"evidence\": \"MS-based interactome of stably knocked-out Bbs10 IMCD3 cells with proliferation assays, ATP measurement, and metabolomics\",\n      \"pmids\": [\"36012682\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Interactors are putative and not individually validated\", \"Causal link between specific interactors and the metabolic/proliferative phenotypes not established\", \"Direct versus indirect nature of the metabolic role unclear\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Defined the mechanistic basis of C-terminal truncating mutations: loss of protein stability and disrupted partner binding rather than mislocalization.\",\n      \"evidence\": \"Transfection of mutant constructs in HEK293T and hTERT-RPE1 cells with Western blot stability assays, reciprocal co-IP for BBS12 and BBS7, proteasome inhibition, and ciliary immunofluorescence\",\n      \"pmids\": [\"40914337\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No structural model of the C-terminal interaction interface\", \"Stoichiometry and order of BBS10-BBS12-BBS7 assembly not determined\", \"Whether reduced ciliary length is a direct consequence of impaired BBSome assembly not established\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How the BBS10/BBS6/BBS12 chaperonin-like module mechanically drives BBSome assembly, and what systemic signal links its loss to obesity and organ-specific degeneration, remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No reconstituted biochemical demonstration of chaperonin-like assembly activity\", \"Systemic mediator of renal and metabolic phenotypes unidentified\", \"No structural characterization of BBS10 or its complexes\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0044183\", \"supporting_discovery_ids\": [0, 2]},\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [4]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005815\", \"supporting_discovery_ids\": [1, 4]},\n      {\"term_id\": \"GO:0005929\", \"supporting_discovery_ids\": [1, 4]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1852241\", \"supporting_discovery_ids\": [1, 2]},\n      {\"term_id\": \"R-HSA-1430728\", \"supporting_discovery_ids\": [3]}\n    ],\n    \"complexes\": [\"BBSome assembly chaperone complex (BBS10/BBS6/BBS12)\"],\n    \"partners\": [\"BBS12\", \"BBS7\", \"BBS6\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":4,"faith_total":5,"faith_pct":80.0}}