{"gene":"FLNB","run_date":"2026-04-28T17:46:03","timeline":{"discoveries":[{"year":2004,"finding":"Missense mutations in FLNB cause autosomal dominant Larsen syndrome and the perinatal lethal atelosteogenesis I and III phenotypes, while homozygous/compound heterozygous stop-codon mutations cause autosomal recessive spondylocarpotarsal syndrome (SCT). Filamin B was shown to be expressed in human growth plate chondrocytes and developing vertebral bodies in mouse, establishing an unexpected role in vertebral segmentation, joint formation, and endochondral ossification for this ubiquitously expressed cytoskeletal actin-crosslinking protein.","method":"Mutation screening (sequencing) in patient cohorts combined with in situ hybridization/expression analysis in human and mouse tissue","journal":"Nature genetics","confidence":"High","confidence_rationale":"Tier 2 — foundational human genetics paper with multiple disease phenotypes and expression validation, highly cited and independently replicated","pmids":["14991055"],"is_preprint":false},{"year":2001,"finding":"Filamins (including filamin B) function as large actin-binding proteins that stabilize three-dimensional actin webs, link actin networks to cellular membranes, anchor transmembrane proteins to the cytoskeleton, and provide a scaffold for cytoplasmic signaling proteins. They are essential for cell locomotion and fetal development.","method":"Review synthesizing biochemical binding studies, cell biology experiments (knockout/knockdown, cytoskeletal imaging), and structural analyses from multiple labs","journal":"Nature reviews. Molecular cell biology","confidence":"High","confidence_rationale":"Tier 2 — mechanistic framework supported by multiple independent labs with diverse methods","pmids":["11252955"],"is_preprint":false},{"year":2001,"finding":"Filamins organize filamentous actin into networks and stress fibers, anchor various transmembrane proteins to the actin cytoskeleton, and serve as scaffolds for cytoplasmic signaling proteins. The three human filamin paralogs (including filamin B) share this architecture with splice variants contributing to functional complexity.","method":"Structural domain analysis, binding partner studies, and functional cell biology experiments reviewed across multiple systems","journal":"Biochimica et biophysica acta","confidence":"High","confidence_rationale":"Tier 2 — multiple orthogonal methods across multiple labs establishing core filamin biology applicable to FLNB","pmids":["11336782"],"is_preprint":false},{"year":2006,"finding":"Mutations in FLNB causing Larsen syndrome cluster in two regions: the actin-binding domain (calponin homology 2 domain, CH2) and filamin repeats 13–17, with missense mutations or small in-frame deletions being the exclusive mutation type. The non-random clustering of mutations in specific functional domains indicates that disruption of actin-binding domain function and specific filamin repeat regions is mechanistically responsible for the dominant skeletal dysplasia phenotype.","method":"Mutation screening by dHPLC, direct sequencing, and restriction endonuclease digestion in 20 Larsen syndrome probands; genotype-phenotype correlation","journal":"Journal of medical genetics","confidence":"High","confidence_rationale":"Tier 2 — large multi-center cohort with non-random mutational clustering pointing to functional domain requirements; replicated by independent study","pmids":["16801345"],"is_preprint":false},{"year":2005,"finding":"Mutations L171R and S235P in the calponin homology 2 (CH2) region of the actin-binding domain of filamin B cause boomerang dysplasia, expanding the phenotypic spectrum of FLNB mutations. The affected residues are evolutionarily conserved, indicating critical functional importance of this region for skeletogenesis.","method":"Mutation identification by sequencing in patients with boomerang dysplasia; evolutionary conservation analysis","journal":"Journal of medical genetics","confidence":"Medium","confidence_rationale":"Tier 2 — human genetics with functional domain mapping, but limited to two patients","pmids":["15994868"],"is_preprint":false},{"year":2006,"finding":"Mutations causing atelosteogenesis I and III cluster in two regions of filamin B: exons 2–3 encoding the CH2 domain of the actin-binding region, and exons 28–29 encoding repeats 14 and 15. This bimodal clustering of 14 novel missense mutations in 15 patients demonstrates that dysfunction of these two specific FLNB domains underlies AOI/AOIII.","method":"Mutation screening and sequencing in 15 unrelated AOI/AOIII patients; genotype-phenotype correlation","journal":"Human mutation","confidence":"High","confidence_rationale":"Tier 2 — large cohort confirming non-random domain clustering, independently replicated across studies","pmids":["16752402"],"is_preprint":false},{"year":2007,"finding":"Homozygous disruption of Flnb in mice causes progressive vertebral fusions, short stature, and carpal/sternal joint fusions phenocopying human spondylocarpotarsal synostosis syndrome (SCT). Filamin B protein was absent in cells from SCT patients with nonsense mutations, confirming loss-of-function as the disease mechanism. The Flnb-/- phenotype showed that spinal segmentation can occur without filamin B, but the protein is required for maintenance of intervertebral, carpal and sternal joints — with fusion initiating antenatally.","method":"Gene targeting/knockout mouse model (Flnb-/-); skeletal analysis, histology, Western blotting of patient-derived cells","journal":"Human molecular genetics","confidence":"High","confidence_rationale":"Tier 2 — clean KO mouse model with defined cellular/skeletal phenotype plus human patient protein expression data; phenocopies human disease","pmids":["17635842"],"is_preprint":false},{"year":2018,"finding":"Alternative splicing of FLNB exon 30, regulated by RNA-binding proteins QKI and RBFOX1, plays a causal role in the epithelial-to-mesenchymal transition (EMT). Specifically, skipping of FLNB exon 30 induces EMT by releasing the FOXC1 transcription factor. QKI and RBFOX1 coordinately regulate FLNB splicing, and exon 30 skipping is strongly associated with EMT gene signatures in basal-like breast cancer.","method":"Genome-scale expression screen, RNA-seq, eCLIP analysis, loss-of-function and gain-of-function experiments for QKI/RBFOX1, FOXC1 reporter/rescue assays, patient sample analysis","journal":"eLife","confidence":"High","confidence_rationale":"Tier 2 — multiple orthogonal methods (eCLIP, RNA-seq, functional rescue, patient data) establishing causal mechanism","pmids":["30059005"],"is_preprint":false},{"year":2006,"finding":"Mutations in FLNB causing Larsen syndrome cluster in the calponin homology 2 domain, repeat 14, and repeat 15 of filamin B, confirming that as few as five of 46 coding exons harbor the majority of disease-causing variants. This non-random distribution indicates these domains are critical for filamin B's role in joint formation and skeletogenesis.","method":"Mutation screening by sequencing in five independent Larsen syndrome cases; compilation and statistical analysis of mutation clusters across two studies","journal":"Journal of medical genetics","confidence":"Medium","confidence_rationale":"Tier 3 — corroborating mutation clustering study, consistent with prior findings from Bicknell et al.","pmids":["16648377"],"is_preprint":false}],"current_model":"Filamin B (FLNB) is a large cytoplasmic actin-crosslinking protein that stabilizes three-dimensional actin networks, anchors transmembrane proteins to the cytoskeleton, and scaffolds signaling molecules; disease-causing mutations cluster in its actin-binding domain (CH2 region) and filamin repeats 14–15, loss of function causes joint and vertebral fusions in mice and humans (SCT), gain-of-function missense mutations cause dominant skeletal dysplasias (Larsen syndrome, atelosteogenesis), and alternative splicing of exon 30 (regulated by QKI/RBFOX1) controls EMT by releasing the FOXC1 transcription factor."},"narrative":{"teleology":[{"year":2001,"claim":"Establishing the foundational biochemistry of filamins — including filamin B — as actin-crosslinkers, membrane–cytoskeleton linkers, and signaling scaffolds provided the mechanistic framework for interpreting later disease genetics.","evidence":"Integrative review of biochemical binding studies, cytoskeletal imaging, and structural analyses across multiple laboratories","pmids":["11252955","11336782"],"confidence":"High","gaps":["Paralog-specific (FLNB vs. FLNA/FLNC) functions were not resolved","No in vivo genetic model yet available for FLNB"]},{"year":2004,"claim":"The discovery that FLNB mutations cause multiple distinct skeletal dysplasias (Larsen syndrome, atelosteogenesis I/III, and SCT) established FLNB as a non-redundant regulator of vertebral segmentation, joint formation, and endochondral ossification.","evidence":"Mutation screening in patient cohorts; in situ hybridization in human growth plate and mouse developing vertebral bodies","pmids":["14991055"],"confidence":"High","gaps":["Mechanism by which specific mutations produce gain-of-function vs. loss-of-function remained unknown","No animal model yet to confirm loss-of-function phenotype"]},{"year":2005,"claim":"Identification of CH2-domain mutations (L171R, S235P) causing boomerang dysplasia expanded the allelic series and pinpointed the actin-binding domain as a recurrent hotspot for dominant skeletal phenotypes.","evidence":"Sequencing of two boomerang dysplasia patients with evolutionary conservation analysis","pmids":["15994868"],"confidence":"Medium","gaps":["Only two patients identified; broader cohort confirmation needed","Effect of these mutations on actin-binding affinity not biochemically tested"]},{"year":2006,"claim":"Systematic genotype–phenotype mapping across Larsen syndrome and atelosteogenesis cohorts revealed that disease-causing mutations cluster non-randomly in two domains — the CH2 actin-binding domain and filamin repeats 14–15 — indicating these regions are critical for FLNB's skeletal function.","evidence":"Mutation screening by dHPLC and sequencing in independent multi-center cohorts (20 Larsen, 15 AOI/AOIII probands); statistical clustering analysis","pmids":["16801345","16752402","16648377"],"confidence":"High","gaps":["Structural basis for why repeats 14–15 are uniquely sensitive to missense mutations not determined","Whether mutations alter protein folding, dimerization, or partner binding is unknown"]},{"year":2007,"claim":"A Flnb-knockout mouse phenocopied human SCT — progressive vertebral and joint fusions — and patient cells with nonsense mutations lacked filamin B protein, formally establishing loss of function as the SCT disease mechanism and demonstrating that filamin B is dispensable for initial segmentation but essential for joint maintenance.","evidence":"Flnb−/− knockout mouse; skeletal analysis, histology; Western blotting of SCT patient-derived cells","pmids":["17635842"],"confidence":"High","gaps":["Cell-autonomous vs. non-cell-autonomous role of FLNB in chondrocytes/perichondrium not resolved","Downstream signaling pathways disrupted by FLNB loss not identified"]},{"year":2018,"claim":"Discovery that QKI/RBFOX1-regulated skipping of FLNB exon 30 causes EMT by releasing FOXC1 revealed a non-cytoskeletal, splice-isoform–dependent transcriptional role for FLNB in epithelial plasticity and breast cancer.","evidence":"Genome-scale expression screen, RNA-seq, eCLIP, QKI/RBFOX1 loss/gain-of-function, FOXC1 reporter/rescue assays, patient tumor analysis","pmids":["30059005"],"confidence":"High","gaps":["Mechanism by which the exon 30-skipped FLNB isoform releases FOXC1 (direct binding vs. indirect) is not fully resolved","Whether FLNB splicing-driven EMT contributes to metastasis in vivo has not been tested","Relationship between the EMT-related splice function and the skeletal phenotypes of FLNB mutations is unexplored"]},{"year":null,"claim":"Key open questions include the structural basis for domain-specific pathogenicity of FLNB mutations, the downstream signaling pathways disrupted in chondrocytes, and how the cytoskeletal-scaffolding and FOXC1-regulatory roles of FLNB are coordinated across tissues.","evidence":"","pmids":[],"confidence":"High","gaps":["No high-resolution structure of full-length filamin B or disease-relevant domains with mutations","Signaling pathways downstream of FLNB in growth plate chondrocytes remain uncharacterized","Integration of the EMT/splicing axis with skeletal biology has not been attempted"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0008092","term_label":"cytoskeletal protein binding","supporting_discovery_ids":[1,2]},{"term_id":"GO:0005198","term_label":"structural molecule activity","supporting_discovery_ids":[1,2]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[1,2]}],"localization":[{"term_id":"GO:0005856","term_label":"cytoskeleton","supporting_discovery_ids":[1,2]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[1,2]}],"pathway":[{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[0,6]},{"term_id":"R-HSA-1474244","term_label":"Extracellular matrix organization","supporting_discovery_ids":[0,6]}],"complexes":[],"partners":["QKI","RBFOX1","FOXC1"],"other_free_text":[]},"mechanistic_narrative":"Filamin B (FLNB) is a large actin-crosslinking protein that stabilizes three-dimensional actin networks, anchors transmembrane proteins to the cytoskeleton, and scaffolds cytoplasmic signaling molecules essential for cell locomotion and fetal development [PMID:11252955, PMID:11336782]. Dominant missense mutations clustering in the calponin homology 2 (CH2) domain and filamin repeats 14–15 cause gain-of-function skeletal dysplasias including Larsen syndrome, atelosteogenesis I/III, and boomerang dysplasia, while homozygous loss-of-function mutations cause autosomal recessive spondylocarpotarsal synostosis syndrome (SCT), a phenotype recapitulated by Flnb-knockout mice that develop progressive vertebral and joint fusions [PMID:14991055, PMID:16752402, PMID:17635842]. Alternative splicing of FLNB exon 30, regulated by the RNA-binding proteins QKI and RBFOX1, drives epithelial-to-mesenchymal transition by releasing the transcription factor FOXC1, linking FLNB isoform switching to breast cancer mesenchymal programs [PMID:30059005]."},"prefetch_data":{"uniprot":{"accession":"O75369","full_name":"Filamin-B","aliases":["ABP-278","ABP-280 homolog","Actin-binding-like protein","Beta-filamin","Filamin homolog 1","Fh1","Filamin-3","Thyroid autoantigen","Truncated actin-binding protein","Truncated ABP"],"length_aa":2602,"mass_kda":278.2,"function":"Connects cell membrane constituents to the actin cytoskeleton. May promote orthogonal branching of actin filaments and links actin filaments to membrane glycoproteins. Anchors various transmembrane proteins to the actin cytoskeleton. Interaction with FLNA may allow neuroblast migration from the ventricular zone into the cortical plate. Various interactions and localizations of isoforms affect myotube morphology and myogenesis. Isoform 6 accelerates muscle differentiation in vitro","subcellular_location":"Cytoplasm, cytoskeleton","url":"https://www.uniprot.org/uniprotkb/O75369/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/FLNB","classification":"Not Classified","n_dependent_lines":4,"n_total_lines":1208,"dependency_fraction":0.0033112582781456954},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"CALD1","stoichiometry":0.2},{"gene":"CALM3","stoichiometry":0.2},{"gene":"CAPZB","stoichiometry":0.2},{"gene":"CTTN","stoichiometry":0.2},{"gene":"PHAX","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/FLNB","total_profiled":1310},"omim":[{"mim_id":"620757","title":"THROMBOCYTOPENIA 12 WITH OR WITHOUT MYOPATHY; THC12","url":"https://www.omim.org/entry/620757"},{"mim_id":"618469","title":"CONTRACTURES, PTERYGIA, AND SPONDYLOCARPOTARSAL FUSION SYNDROME 1B; CPSFS1B","url":"https://www.omim.org/entry/618469"},{"mim_id":"615928","title":"REFILIN B; RFLNB","url":"https://www.omim.org/entry/615928"},{"mim_id":"615927","title":"REFILIN A; RFLNA","url":"https://www.omim.org/entry/615927"},{"mim_id":"608097","title":"PERIVENTRICULAR HETEROTOPIA WITH MICROCEPHALY, AUTOSOMAL RECESSIVE; ARPHM","url":"https://www.omim.org/entry/608097"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Plasma membrane","reliability":"Supported"},{"location":"Golgi apparatus","reliability":"Additional"},{"location":"Actin filaments","reliability":"Additional"},{"location":"Cytosol","reliability":"Additional"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/FLNB"},"hgnc":{"alias_symbol":["TAP","TABP","ABP-278","FH1"],"prev_symbol":["FLN1L","LRS1"]},"alphafold":{"accession":"O75369","domains":[{"cath_id":"1.10.418.10","chopping":"4-240","consensus_level":"medium","plddt":85.218,"start":4,"end":240},{"cath_id":"2.60.40.10","chopping":"255-349","consensus_level":"medium","plddt":77.1309,"start":255,"end":349},{"cath_id":"2.60.40.10","chopping":"359-448","consensus_level":"medium","plddt":74.6984,"start":359,"end":448},{"cath_id":"2.60.40.10","chopping":"451-547","consensus_level":"medium","plddt":82.289,"start":451,"end":547},{"cath_id":"2.60.40.10","chopping":"744-840","consensus_level":"high","plddt":79.6454,"start":744,"end":840},{"cath_id":"2.60.40.10","chopping":"846-937","consensus_level":"high","plddt":72.7808,"start":846,"end":937},{"cath_id":"2.60.40.10","chopping":"949-1036","consensus_level":"medium","plddt":70.5293,"start":949,"end":1036},{"cath_id":"2.60.40.10","chopping":"1041-1129","consensus_level":"high","plddt":79.8183,"start":1041,"end":1129},{"cath_id":"2.60.40.10","chopping":"1131-1226","consensus_level":"medium","plddt":77.2606,"start":1131,"end":1226},{"cath_id":"2.60.40.10","chopping":"1328-1419","consensus_level":"medium","plddt":78.7559,"start":1328,"end":1419},{"cath_id":"2.60.40.10","chopping":"1438-1512","consensus_level":"high","plddt":81.0677,"start":1438,"end":1512},{"cath_id":"2.60.40.10","chopping":"1568-1705","consensus_level":"medium","plddt":81.1944,"start":1568,"end":1705},{"cath_id":"2.60.40.10","chopping":"1748-1911","consensus_level":"medium","plddt":67.402,"start":1748,"end":1911},{"cath_id":"2.60.40.10","chopping":"1919-2015_2024-2091","consensus_level":"medium","plddt":71.4071,"start":1919,"end":2091},{"cath_id":"2.60.40.10","chopping":"2283-2377","consensus_level":"medium","plddt":73.0077,"start":2283,"end":2377},{"cath_id":"2.60.40.10","chopping":"2382-2496","consensus_level":"medium","plddt":74.4084,"start":2382,"end":2496},{"cath_id":"2.60.40.10","chopping":"2513-2602","consensus_level":"medium","plddt":82.0043,"start":2513,"end":2602}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/O75369","model_url":"https://alphafold.ebi.ac.uk/files/AF-O75369-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-O75369-F1-predicted_aligned_error_v6.png","plddt_mean":76.25},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=FLNB","jax_strain_url":"https://www.jax.org/strain/search?query=FLNB"},"sequence":{"accession":"O75369","fasta_url":"https://rest.uniprot.org/uniprotkb/O75369.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/O75369/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/O75369"}},"corpus_meta":[{"pmid":"11403571","id":"PMC_11403571","title":"The 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maturation.","date":"2011","source":"Nature cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/21423176","citation_count":490,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"35271311","id":"PMC_35271311","title":"OpenCell: Endogenous tagging for the cartography of human cellular organization.","date":"2022","source":"Science (New York, N.Y.)","url":"https://pubmed.ncbi.nlm.nih.gov/35271311","citation_count":432,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"26344197","id":"PMC_26344197","title":"Panorama of ancient metazoan macromolecular complexes.","date":"2015","source":"Nature","url":"https://pubmed.ncbi.nlm.nih.gov/26344197","citation_count":407,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"16009940","id":"PMC_16009940","title":"Human ISG15 conjugation targets both IFN-induced and constitutively expressed proteins functioning in diverse cellular pathways.","date":"2005","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/16009940","citation_count":383,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"14744259","id":"PMC_14744259","title":"14-3-3-affinity purification of over 200 human phosphoproteins reveals new links to regulation of cellular metabolism, proliferation and trafficking.","date":"2004","source":"The Biochemical journal","url":"https://pubmed.ncbi.nlm.nih.gov/14744259","citation_count":372,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"11336782","id":"PMC_11336782","title":"Structural and functional aspects of filamins.","date":"2001","source":"Biochimica et biophysica acta","url":"https://pubmed.ncbi.nlm.nih.gov/11336782","citation_count":354,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"32322062","id":"PMC_32322062","title":"The gluconeogenic enzyme PCK1 phosphorylates INSIG1/2 for 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fibrosis.","date":"2015","source":"Nature","url":"https://pubmed.ncbi.nlm.nih.gov/26618866","citation_count":209,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"19738201","id":"PMC_19738201","title":"Proteomic analysis of integrin-associated complexes identifies RCC2 as a dual regulator of Rac1 and Arf6.","date":"2009","source":"Science signaling","url":"https://pubmed.ncbi.nlm.nih.gov/19738201","citation_count":207,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"14991055","id":"PMC_14991055","title":"Mutations in the gene encoding filamin B disrupt vertebral segmentation, joint formation and skeletogenesis.","date":"2004","source":"Nature genetics","url":"https://pubmed.ncbi.nlm.nih.gov/14991055","citation_count":203,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"21653829","id":"PMC_21653829","title":"Protein interactome reveals converging molecular pathways among autism disorders.","date":"2011","source":"Science translational medicine","url":"https://pubmed.ncbi.nlm.nih.gov/21653829","citation_count":180,"is_preprint":false,"source_track":"gene2pubmed"}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":42751,"output_tokens":1459,"usd":0.075069},"stage2":{"model":"claude-opus-4-6","input_tokens":4708,"output_tokens":1502,"usd":0.091635},"total_usd":0.389157,"stage1_batch_id":"msgbatch_0118RScg3WGaGkaZRtWZbtce","stage2_batch_id":"msgbatch_01Cpfzvtbj42aqp5oYZ5Te2s","note":"batch pricing = 50% of standard","round2_stage1":{"model":"claude-sonnet-4-6","input_tokens":54572,"output_tokens":2725,"usd":0.102295},"round2_rules_fired":"R3","round2_stage2":{"model":"claude-opus-4-6","input_tokens":5836,"output_tokens":2037,"usd":0.120158}},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2018,\n      \"finding\": \"Alternative splicing of FLNB exon 30, regulated by RNA-binding proteins QKI and RBFOX1, controls epithelial-to-mesenchymal transition (EMT). Skipping of FLNB exon 30 releases the FOXC1 transcription factor, which then induces EMT gene expression. QKI and RBFOX1 coordinately regulate this splicing event as shown by RNA-seq and eCLIP analysis.\",\n      \"method\": \"RNA-seq, eCLIP analysis, RNA-binding protein knockdown/overexpression, genome-scale expression screen\",\n      \"journal\": \"eLife\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods (eCLIP, RNA-seq, functional rescue) in a single rigorous study establishing causal mechanism\",\n      \"pmids\": [\"30059005\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"Missense mutations and small in-frame deletions in FLNB cause autosomal dominant Larsen syndrome. Mutations cluster non-randomly in the actin-binding domain (calponin homology 2 region) and filamin repeats 13–17, indicating these domains are critical for FLNB function in skeletogenesis.\",\n      \"method\": \"Mutation screening by dHPLC, direct sequencing, restriction endonuclease digestion; clinical and radiographic phenotype analysis\",\n      \"journal\": \"Journal of medical genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — replicated across multiple independent studies (Bicknell 2006, Zhang 2006, Farrington-Rock 2006) linking specific FLNB domains to skeletal dysplasia\",\n      \"pmids\": [\"16801345\", \"16648377\", \"16752402\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"Mutations in FLNB cause boomerang dysplasia. The causative substitutions (L171R and S235P) lie within the calponin homology 2 (CH2) region of the actin-binding domain of filamin B at evolutionarily conserved sites, expanding the FLNB mutation spectrum to include perinatally lethal skeletal dysplasia.\",\n      \"method\": \"Mutation identification and sequencing in patient samples; evolutionary conservation analysis\",\n      \"journal\": \"Journal of medical genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — direct patient mutation mapping to defined functional domain, consistent with broader disease spectrum\",\n      \"pmids\": [\"15994868\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"Homozygous loss-of-function (knockout) of Flnb in mice results in progressive vertebral fusions, carpal and sternal joint fusions, and short stature, phenocopying human spondylocarpotarsal synostosis syndrome. Cells from SCT patients with FLNB nonsense mutations lack filamin B protein, demonstrating that loss of filamin B protein causes SCT. The data show filamin B is required for maintenance of intervertebral, carpal, and sternal joints.\",\n      \"method\": \"Flnb knockout mouse generation, skeletal analysis, Western blot of patient-derived cells\",\n      \"journal\": \"Human molecular genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — clean KO mouse with defined skeletal phenotype corroborated by patient cell protein analysis\",\n      \"pmids\": [\"17635842\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"Mutations in FLNB causing atelosteogenesis type I (AOI) and atelosteogenesis type III (AOIII) cluster in two regions: the CH2 domain of the actin-binding region (exons 2 and 3) and repeats 14 and 15 (exons 28 and 29), establishing these as critical functional domains for FLNB's role in skeletogenesis.\",\n      \"method\": \"Mutation screening and sequencing in 15 unrelated AOI/AOIII patients\",\n      \"journal\": \"Human mutation\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — domain mapping replicated across patient cohorts, consistent with other FLNB disease studies\",\n      \"pmids\": [\"16752402\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"FLNB gene variation (SNP rs9834312) is associated with stature variation in multiple independent population cohorts (Caucasian and Chinese), consistent with FLNB's known functional role in skeletal linear growth.\",\n      \"method\": \"Genome-wide association study with independent replication in multiple cohorts\",\n      \"journal\": \"Human molecular genetics\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 4 — GWAS/genetic association without direct mechanistic experiment on FLNB function\",\n      \"pmids\": [\"19039035\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"FLNB (filamin B) is a cytoskeletal actin-binding protein whose functional domains—including the calponin homology 2 (CH2) actin-binding domain and filamin repeats 13–17—are critical for skeletal development and joint maintenance, as established by loss-of-function mouse models and clustering of disease-causing mutations; additionally, alternative splicing of FLNB exon 30 (regulated by QKI and RBFOX1) controls epithelial-to-mesenchymal transition by releasing the FOXC1 transcription factor.\"\n}\n```\n\n--- ROUND 2 (R2/R3, augmented corpus) ---\n\nI'll classify each paper first, then extract discoveries only from KEEP papers.\n\n**Classification:**\n- Papers about FLNB (filamin B, the canonical cytoskeletal protein): KEEP\n  - PMID:30059005 (FLNB splicing/EMT)\n  - PMID:16801345 (Larsen syndrome mutations in FLNB)\n  - PMID:15994868 (boomerang dysplasia mutations in FLNB)\n  - PMID:17635842 (Flnb knockout mouse/SCT)\n  - PMID:16752402 (atelosteogenesis mutations in FLNB)\n  - PMID:16648377 (Larsen syndrome mutations in FLNB)\n  - PMID:14991055 (mutations in filamin B gene)\n  - PMID:11252955 (filamins as integrators - general filamin review, includes FLNB)\n  - PMID:11336782 (structural/functional aspects of filamins)\n  - PMID:19039035 (GWAS identifying FLNB locus for stature - expression/GWAS, exclude mechanistic)\n  - PMID:29682400 (serum protein panel FLNB - biomarker, exclude)\n\nFrom gene2pubmed curated papers:\n  - PMID:14991055 (KEEP - foundational FLNB paper)\n  - PMID:11252955 (KEEP - filamin biology)\n  - PMID:11336782 (KEEP - filamin structure/function)\n\nAll other papers are about TAP (antigen processing), formins (non-FLNB), tap water, or other unrelated proteins → EXCLUDE.\n\n```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2004,\n      \"finding\": \"Missense mutations in FLNB cause autosomal dominant Larsen syndrome and the perinatal lethal atelosteogenesis I and III phenotypes, while homozygous/compound heterozygous stop-codon mutations cause autosomal recessive spondylocarpotarsal syndrome (SCT). Filamin B was shown to be expressed in human growth plate chondrocytes and developing vertebral bodies in mouse, establishing an unexpected role in vertebral segmentation, joint formation, and endochondral ossification for this ubiquitously expressed cytoskeletal actin-crosslinking protein.\",\n      \"method\": \"Mutation screening (sequencing) in patient cohorts combined with in situ hybridization/expression analysis in human and mouse tissue\",\n      \"journal\": \"Nature genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — foundational human genetics paper with multiple disease phenotypes and expression validation, highly cited and independently replicated\",\n      \"pmids\": [\"14991055\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"Filamins (including filamin B) function as large actin-binding proteins that stabilize three-dimensional actin webs, link actin networks to cellular membranes, anchor transmembrane proteins to the cytoskeleton, and provide a scaffold for cytoplasmic signaling proteins. They are essential for cell locomotion and fetal development.\",\n      \"method\": \"Review synthesizing biochemical binding studies, cell biology experiments (knockout/knockdown, cytoskeletal imaging), and structural analyses from multiple labs\",\n      \"journal\": \"Nature reviews. Molecular cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — mechanistic framework supported by multiple independent labs with diverse methods\",\n      \"pmids\": [\"11252955\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"Filamins organize filamentous actin into networks and stress fibers, anchor various transmembrane proteins to the actin cytoskeleton, and serve as scaffolds for cytoplasmic signaling proteins. The three human filamin paralogs (including filamin B) share this architecture with splice variants contributing to functional complexity.\",\n      \"method\": \"Structural domain analysis, binding partner studies, and functional cell biology experiments reviewed across multiple systems\",\n      \"journal\": \"Biochimica et biophysica acta\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods across multiple labs establishing core filamin biology applicable to FLNB\",\n      \"pmids\": [\"11336782\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"Mutations in FLNB causing Larsen syndrome cluster in two regions: the actin-binding domain (calponin homology 2 domain, CH2) and filamin repeats 13–17, with missense mutations or small in-frame deletions being the exclusive mutation type. The non-random clustering of mutations in specific functional domains indicates that disruption of actin-binding domain function and specific filamin repeat regions is mechanistically responsible for the dominant skeletal dysplasia phenotype.\",\n      \"method\": \"Mutation screening by dHPLC, direct sequencing, and restriction endonuclease digestion in 20 Larsen syndrome probands; genotype-phenotype correlation\",\n      \"journal\": \"Journal of medical genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — large multi-center cohort with non-random mutational clustering pointing to functional domain requirements; replicated by independent study\",\n      \"pmids\": [\"16801345\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"Mutations L171R and S235P in the calponin homology 2 (CH2) region of the actin-binding domain of filamin B cause boomerang dysplasia, expanding the phenotypic spectrum of FLNB mutations. The affected residues are evolutionarily conserved, indicating critical functional importance of this region for skeletogenesis.\",\n      \"method\": \"Mutation identification by sequencing in patients with boomerang dysplasia; evolutionary conservation analysis\",\n      \"journal\": \"Journal of medical genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — human genetics with functional domain mapping, but limited to two patients\",\n      \"pmids\": [\"15994868\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"Mutations causing atelosteogenesis I and III cluster in two regions of filamin B: exons 2–3 encoding the CH2 domain of the actin-binding region, and exons 28–29 encoding repeats 14 and 15. This bimodal clustering of 14 novel missense mutations in 15 patients demonstrates that dysfunction of these two specific FLNB domains underlies AOI/AOIII.\",\n      \"method\": \"Mutation screening and sequencing in 15 unrelated AOI/AOIII patients; genotype-phenotype correlation\",\n      \"journal\": \"Human mutation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — large cohort confirming non-random domain clustering, independently replicated across studies\",\n      \"pmids\": [\"16752402\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"Homozygous disruption of Flnb in mice causes progressive vertebral fusions, short stature, and carpal/sternal joint fusions phenocopying human spondylocarpotarsal synostosis syndrome (SCT). Filamin B protein was absent in cells from SCT patients with nonsense mutations, confirming loss-of-function as the disease mechanism. The Flnb-/- phenotype showed that spinal segmentation can occur without filamin B, but the protein is required for maintenance of intervertebral, carpal and sternal joints — with fusion initiating antenatally.\",\n      \"method\": \"Gene targeting/knockout mouse model (Flnb-/-); skeletal analysis, histology, Western blotting of patient-derived cells\",\n      \"journal\": \"Human molecular genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — clean KO mouse model with defined cellular/skeletal phenotype plus human patient protein expression data; phenocopies human disease\",\n      \"pmids\": [\"17635842\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Alternative splicing of FLNB exon 30, regulated by RNA-binding proteins QKI and RBFOX1, plays a causal role in the epithelial-to-mesenchymal transition (EMT). Specifically, skipping of FLNB exon 30 induces EMT by releasing the FOXC1 transcription factor. QKI and RBFOX1 coordinately regulate FLNB splicing, and exon 30 skipping is strongly associated with EMT gene signatures in basal-like breast cancer.\",\n      \"method\": \"Genome-scale expression screen, RNA-seq, eCLIP analysis, loss-of-function and gain-of-function experiments for QKI/RBFOX1, FOXC1 reporter/rescue assays, patient sample analysis\",\n      \"journal\": \"eLife\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods (eCLIP, RNA-seq, functional rescue, patient data) establishing causal mechanism\",\n      \"pmids\": [\"30059005\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"Mutations in FLNB causing Larsen syndrome cluster in the calponin homology 2 domain, repeat 14, and repeat 15 of filamin B, confirming that as few as five of 46 coding exons harbor the majority of disease-causing variants. This non-random distribution indicates these domains are critical for filamin B's role in joint formation and skeletogenesis.\",\n      \"method\": \"Mutation screening by sequencing in five independent Larsen syndrome cases; compilation and statistical analysis of mutation clusters across two studies\",\n      \"journal\": \"Journal of medical genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — corroborating mutation clustering study, consistent with prior findings from Bicknell et al.\",\n      \"pmids\": [\"16648377\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"Filamin B (FLNB) is a large cytoplasmic actin-crosslinking protein that stabilizes three-dimensional actin networks, anchors transmembrane proteins to the cytoskeleton, and scaffolds signaling molecules; disease-causing mutations cluster in its actin-binding domain (CH2 region) and filamin repeats 14–15, loss of function causes joint and vertebral fusions in mice and humans (SCT), gain-of-function missense mutations cause dominant skeletal dysplasias (Larsen syndrome, atelosteogenesis), and alternative splicing of exon 30 (regulated by QKI/RBFOX1) controls EMT by releasing the FOXC1 transcription factor.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"FLNB encodes filamin B, a cytoskeletal actin-binding protein essential for vertebrate skeletal development and joint maintenance. Disease-causing missense mutations cluster in the calponin homology 2 (CH2) actin-binding domain and filamin repeats 13–17, establishing these regions as critical functional domains; gain-of-function mutations in these domains cause autosomal dominant Larsen syndrome, atelosteogenesis types I and III, and boomerang dysplasia, while loss-of-function mutations cause autosomal recessive spondylocarpotarsal synostosis syndrome, as confirmed by Flnb-knockout mice that develop progressive vertebral and joint fusions [PMID:16801345, PMID:15994868, PMID:16752402, PMID:17635842]. Beyond its structural role, alternative splicing of FLNB exon 30, regulated by the RNA-binding proteins QKI and RBFOX1, controls epithelial-to-mesenchymal transition by releasing the transcription factor FOXC1 to induce EMT gene expression [PMID:30059005].\",\n  \"teleology\": [\n    {\n      \"year\": 2005,\n      \"claim\": \"Identifying FLNB CH2-domain mutations as the cause of the lethal skeletal disorder boomerang dysplasia extended the gene's disease spectrum and pinpointed the actin-binding domain as functionally indispensable for skeletogenesis.\",\n      \"evidence\": \"Sequencing of patient DNA identified conserved CH2-domain substitutions L171R and S235P\",\n      \"pmids\": [\"15994868\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"No functional assay tested the effect of these mutations on actin binding or filamin B dimerization\",\n        \"How CH2-domain mutations cause a more severe phenotype than repeat-region mutations is unexplained\"\n      ]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Systematic mutation mapping across multiple skeletal dysplasias (Larsen syndrome, AOI, AOIII) established that pathogenic FLNB mutations cluster non-randomly in two hotspots — the CH2 actin-binding domain and filamin repeats 13–17 — revealing the domain architecture critical for skeletal function.\",\n      \"evidence\": \"dHPLC mutation screening and direct sequencing across independent patient cohorts with Larsen syndrome, AOI, and AOIII\",\n      \"pmids\": [\"16801345\", \"16648377\", \"16752402\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Whether these gain-of-function mutations alter actin crosslinking, protein interactions, or signaling has not been biochemically resolved\",\n        \"The specific signaling pathways downstream of mutant FLNB in chondrocytes remain uncharacterized\"\n      ]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"A Flnb-knockout mouse established that complete loss of filamin B causes progressive joint fusions phenocopying human spondylocarpotarsal synostosis syndrome, demonstrating that filamin B is required for joint maintenance rather than only joint formation.\",\n      \"evidence\": \"Flnb-null mice analyzed by skeletal staining and histology; Western blot confirmed absent filamin B in SCT patient cells with nonsense mutations\",\n      \"pmids\": [\"17635842\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"The cellular mechanism by which loss of filamin B leads to joint fusion is not defined\",\n        \"Whether filamin B acts through mechanotransduction, signaling scaffold function, or cytoskeletal organization in joints is unresolved\"\n      ]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Discovery that alternative splicing of FLNB exon 30 — regulated by QKI and RBFOX1 — controls EMT by releasing the transcription factor FOXC1 revealed a non-structural, gene-regulatory function for FLNB distinct from its cytoskeletal role.\",\n      \"evidence\": \"RNA-seq, eCLIP, and knockdown/overexpression of QKI and RBFOX1 with functional rescue in a genome-scale expression screen\",\n      \"pmids\": [\"30059005\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"How the FLNB protein isoform lacking exon 30 mechanistically releases FOXC1 is not defined at the structural level\",\n        \"Whether this EMT-regulatory splicing event is relevant in vivo during development or disease is untested\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"Key unresolved questions include the biochemical consequences of gain-of-function mutations on actin crosslinking and signaling scaffold activity, the structural basis by which FLNB isoforms sequester or release FOXC1, and the downstream signaling pathways through which filamin B maintains joint integrity.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"No structural model of disease-mutant FLNB domains exists\",\n        \"No reconstituted biochemical assay has tested mutant vs. wild-type actin-crosslinking activity\",\n        \"The relationship between FLNB's cytoskeletal and EMT-regulatory functions is unexplored\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0008092\", \"supporting_discovery_ids\": [1, 2, 3, 4]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005856\", \"supporting_discovery_ids\": [1, 2, 4]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [1, 2, 3, 4]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\n      \"FOXC1\",\n      \"QKI\",\n      \"RBFOX1\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```\n\n--- ROUND 2 (R2/R3, augmented corpus) ---\n\n```json\n{\n  \"mechanistic_narrative\": \"Filamin B (FLNB) is a large actin-crosslinking protein that stabilizes three-dimensional actin networks, anchors transmembrane proteins to the cytoskeleton, and scaffolds cytoplasmic signaling molecules essential for cell locomotion and fetal development [PMID:11252955, PMID:11336782]. Dominant missense mutations clustering in the calponin homology 2 (CH2) domain and filamin repeats 14–15 cause gain-of-function skeletal dysplasias including Larsen syndrome, atelosteogenesis I/III, and boomerang dysplasia, while homozygous loss-of-function mutations cause autosomal recessive spondylocarpotarsal synostosis syndrome (SCT), a phenotype recapitulated by Flnb-knockout mice that develop progressive vertebral and joint fusions [PMID:14991055, PMID:16752402, PMID:17635842]. Alternative splicing of FLNB exon 30, regulated by the RNA-binding proteins QKI and RBFOX1, drives epithelial-to-mesenchymal transition by releasing the transcription factor FOXC1, linking FLNB isoform switching to breast cancer mesenchymal programs [PMID:30059005].\",\n  \"teleology\": [\n    {\n      \"year\": 2001,\n      \"claim\": \"Establishing the foundational biochemistry of filamins — including filamin B — as actin-crosslinkers, membrane–cytoskeleton linkers, and signaling scaffolds provided the mechanistic framework for interpreting later disease genetics.\",\n      \"evidence\": \"Integrative review of biochemical binding studies, cytoskeletal imaging, and structural analyses across multiple laboratories\",\n      \"pmids\": [\"11252955\", \"11336782\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Paralog-specific (FLNB vs. FLNA/FLNC) functions were not resolved\",\n        \"No in vivo genetic model yet available for FLNB\"\n      ]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"The discovery that FLNB mutations cause multiple distinct skeletal dysplasias (Larsen syndrome, atelosteogenesis I/III, and SCT) established FLNB as a non-redundant regulator of vertebral segmentation, joint formation, and endochondral ossification.\",\n      \"evidence\": \"Mutation screening in patient cohorts; in situ hybridization in human growth plate and mouse developing vertebral bodies\",\n      \"pmids\": [\"14991055\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Mechanism by which specific mutations produce gain-of-function vs. loss-of-function remained unknown\",\n        \"No animal model yet to confirm loss-of-function phenotype\"\n      ]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Identification of CH2-domain mutations (L171R, S235P) causing boomerang dysplasia expanded the allelic series and pinpointed the actin-binding domain as a recurrent hotspot for dominant skeletal phenotypes.\",\n      \"evidence\": \"Sequencing of two boomerang dysplasia patients with evolutionary conservation analysis\",\n      \"pmids\": [\"15994868\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Only two patients identified; broader cohort confirmation needed\",\n        \"Effect of these mutations on actin-binding affinity not biochemically tested\"\n      ]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Systematic genotype–phenotype mapping across Larsen syndrome and atelosteogenesis cohorts revealed that disease-causing mutations cluster non-randomly in two domains — the CH2 actin-binding domain and filamin repeats 14–15 — indicating these regions are critical for FLNB's skeletal function.\",\n      \"evidence\": \"Mutation screening by dHPLC and sequencing in independent multi-center cohorts (20 Larsen, 15 AOI/AOIII probands); statistical clustering analysis\",\n      \"pmids\": [\"16801345\", \"16752402\", \"16648377\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Structural basis for why repeats 14–15 are uniquely sensitive to missense mutations not determined\",\n        \"Whether mutations alter protein folding, dimerization, or partner binding is unknown\"\n      ]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"A Flnb-knockout mouse phenocopied human SCT — progressive vertebral and joint fusions — and patient cells with nonsense mutations lacked filamin B protein, formally establishing loss of function as the SCT disease mechanism and demonstrating that filamin B is dispensable for initial segmentation but essential for joint maintenance.\",\n      \"evidence\": \"Flnb−/− knockout mouse; skeletal analysis, histology; Western blotting of SCT patient-derived cells\",\n      \"pmids\": [\"17635842\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Cell-autonomous vs. non-cell-autonomous role of FLNB in chondrocytes/perichondrium not resolved\",\n        \"Downstream signaling pathways disrupted by FLNB loss not identified\"\n      ]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Discovery that QKI/RBFOX1-regulated skipping of FLNB exon 30 causes EMT by releasing FOXC1 revealed a non-cytoskeletal, splice-isoform–dependent transcriptional role for FLNB in epithelial plasticity and breast cancer.\",\n      \"evidence\": \"Genome-scale expression screen, RNA-seq, eCLIP, QKI/RBFOX1 loss/gain-of-function, FOXC1 reporter/rescue assays, patient tumor analysis\",\n      \"pmids\": [\"30059005\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Mechanism by which the exon 30-skipped FLNB isoform releases FOXC1 (direct binding vs. indirect) is not fully resolved\",\n        \"Whether FLNB splicing-driven EMT contributes to metastasis in vivo has not been tested\",\n        \"Relationship between the EMT-related splice function and the skeletal phenotypes of FLNB mutations is unexplored\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"Key open questions include the structural basis for domain-specific pathogenicity of FLNB mutations, the downstream signaling pathways disrupted in chondrocytes, and how the cytoskeletal-scaffolding and FOXC1-regulatory roles of FLNB are coordinated across tissues.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"No high-resolution structure of full-length filamin B or disease-relevant domains with mutations\",\n        \"Signaling pathways downstream of FLNB in growth plate chondrocytes remain uncharacterized\",\n        \"Integration of the EMT/splicing axis with skeletal biology has not been attempted\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0008092\", \"supporting_discovery_ids\": [1, 2]},\n      {\"term_id\": \"GO:0005198\", \"supporting_discovery_ids\": [1, 2]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [1, 2]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005856\", \"supporting_discovery_ids\": [1, 2]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [1, 2]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [0, 6]},\n      {\"term_id\": \"R-HSA-1474244\", \"supporting_discovery_ids\": [0, 6]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\n      \"QKI\",\n      \"RBFOX1\",\n      \"FOXC1\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}