{"gene":"FLNB","run_date":"2026-06-09T23:54:43","timeline":{"discoveries":[{"year":2007,"finding":"Flnb-knockout mice phenocopy spondylocarpotarsal synostosis syndrome (SCT), exhibiting progressive vertebral fusions, carpal and sternal joint fusions. Protein extracts from SCT patients with nonsense FLNB mutations lacked filamin B, demonstrating SCT results from complete absence of the protein. The skeletal fusions begin antenatally and are progressive, indicating filamin B is required for maintenance (not initial formation) of intervertebral, carpal and sternal joints.","method":"Flnb knockout mouse model; western blot of patient cell extracts; skeletal histology and micro-CT","journal":"Human molecular genetics","confidence":"High","confidence_rationale":"Tier 2 / Strong — clean KO mouse with defined skeletal phenotype plus patient protein-level validation, replicated across multiple skeletal sites","pmids":["17635842"],"is_preprint":false},{"year":2018,"finding":"The RNA-binding proteins QKI and RBFOX1 coordinately regulate alternative splicing of FLNB exon 30; skipping of exon 30 promotes EMT by releasing the FOXC1 transcription factor. This splicing switch is necessary and sufficient to induce an intermediate mesenchymal cell state and increased tumorigenicity in breast cancer cells.","method":"RNA-seq, eCLIP analysis, gain/loss-of-function experiments with QKI and RBFOX1, genome-scale expression screen for EMT inducers","journal":"eLife","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (RNA-seq, eCLIP, functional rescue), necessity and sufficiency demonstrated, mechanistic pathway defined","pmids":["30059005"],"is_preprint":false},{"year":2017,"finding":"FlnA and FlnB physically interact in the cytoplasm of chondrocytes. FlnB loss promotes actin stress fiber formation and enhanced cell spreading on integrin-activating substrates, whereas FlnA inhibition decreases actin formation. FlnA more strongly binds RhoA and promotes RhoA activation, while FlnB indirectly inhibits the RhoA pathway. FlnB loss promotes β1-integrin expression, while FlnA loss diminishes it. FlnA and FlnB have antagonistic roles in regulating RhoA activity and actin stress fiber remodeling.","method":"Co-immunoprecipitation of FlnA/FlnB; RhoA activation assays; loss-of-function with integrin substrates; immunofluorescence of actin and RhoA","journal":"Human molecular genetics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP plus functional assays (RhoA activation, cell spreading), single lab with multiple orthogonal methods","pmids":["28175289"],"is_preprint":false},{"year":2005,"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, defining the actin-binding domain as critical for FLNB function in skeletogenesis.","method":"Molecular genetic analysis; sequencing; identification of mutation clustering in CH2 actin-binding domain","journal":"Journal of medical genetics","confidence":"Medium","confidence_rationale":"Tier 3 / Strong — mutation clustering in functional domain across multiple independent cases, convergent genetic evidence, but no direct biochemical assay","pmids":["15994868"],"is_preprint":false},{"year":2006,"finding":"Mutations causing atelosteogenesis I and III cluster in two regions of FLNB: the CH2 domain of the actin-binding region (exons 2–3) and filamin repeats 14–15 (exons 28–29). This non-random mutation distribution identifies these two structural domains as functionally critical for FLNB's role in skeletogenesis.","method":"Sequencing of 15 unrelated AOI/AOIII patients; mapping of mutations to FLNB protein domains","journal":"Human mutation","confidence":"Medium","confidence_rationale":"Tier 3 / Strong — convergent mutation mapping across multiple independent patients and labs defines functional domains, but no direct in vitro biochemical assay","pmids":["16752402"],"is_preprint":false},{"year":2006,"finding":"Larsen syndrome-causing FLNB mutations cluster in the actin-binding domain (CH2 region) and filamin repeats 13–17, defining these as functional hotspots. All affected individuals are heterozygous for missense or small in-frame deletions, consistent with a dominant gain-of-function or dominant-negative mechanism.","method":"DHPLC, direct sequencing, restriction endonuclease digestion across 20 Larsen syndrome probands","journal":"Journal of medical genetics","confidence":"Medium","confidence_rationale":"Tier 3 / Strong — convergent mutation analysis across multiple labs and patients, but no direct biochemical functional assay","pmids":["16801345"],"is_preprint":false},{"year":2017,"finding":"Novel biallelic FLNB mutations (p.F964L, p.A1577V) increase binding of FLNB protein to the MAP3K1 and RAC1 signal transduction complex, activate β-catenin signaling, and affect phosphorylation of MAP kinase pathway intermediates and SOX9 expression, causing 46,XY gonadal dysgenesis alongside skeletal dysplasia.","method":"Whole exome sequencing; qPCR; flow variant assays; TOPFLASH reporter assay for β-catenin activity; protein interaction assays","journal":"Clinical genetics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — TOPFLASH reporter plus binding assays plus phosphorylation analysis, single lab with multiple complementary methods","pmids":["29095481"],"is_preprint":false},{"year":2018,"finding":"BD-associated FLNB mutation L171R causes globular protein aggregation and increased cellular apoptosis in ATDC5 chondrogenic cells, while LS-associated FLNB G1586R causes evenly distributed protein but decreased cellular migration. Both mutations increase Runx2 expression. These differing cellular phenotypes correlate with clinical severity differences between boomerang dysplasia and Larsen syndrome.","method":"ATDC5 chondrogenic cell transfection model; immunofluorescence of FLNB localization; apoptosis assay; cell migration assay; Runx2 expression analysis","journal":"American journal of translational research","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — direct comparison of mutant protein behaviors in relevant chondrogenic cell line with multiple readouts, single lab","pmids":["29887954"],"is_preprint":false},{"year":2020,"finding":"AIS-associated FLNB variants alter protein conformation, subcellular localization, and interaction with TTC26 and OFD1 (proteins involved in primary cilia and AIS). FLNB was identified as the top signal in a gene-based burden test for adolescent idiopathic scoliosis.","method":"Exome sequencing of AIS trios; gene-based burden test; functional studies of protein conformation, subcellular localization, and co-immunoprecipitation with TTC26 and OFD1","journal":"Journal of medical genetics","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — Co-IP plus localization studies in disease context, single lab, moderate mechanistic follow-up","pmids":["32381728"],"is_preprint":false},{"year":2024,"finding":"FLNB disruption by a Larsen syndrome-associated point mutation (G1586R, generated by CRISPR-Cas9) causes downregulation of HOXD10 in the carpal region and HOXB2 in the cervical spine region at E12.5, leading to tarsal bone fusions. This places FLNB upstream of HOX gene transcription during skeletal segmentation.","method":"CRISPR-Cas9 knock-in mouse model; micro-CT; HE staining; whole skeletal preparation; in situ hybridization for HOX genes in embryos","journal":"Bone reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — CRISPR knock-in mouse with defined phenotype and in situ hybridization pathway placement, single lab","pmids":["38463381"],"is_preprint":false},{"year":2023,"finding":"Loss-of-function FLNB variants (p.P441T, p.G565R) are less potent than wild-type FLNB in inducing cell stretches in mammalian cells. Flnb-null embryos display cleft palates, demonstrating FLNB is required for palate development.","method":"Mammalian cell transfection with WT and variant FLNB; cell morphology assay; Flnb knockout mouse embryo analysis; immunohistochemistry of palatal tissues","journal":"Journal of genetics and genomics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — loss-of-function in cells plus mouse KO with specific palate phenotype, single lab","pmids":["37003352"],"is_preprint":false},{"year":2025,"finding":"MTMR7 interacts with FLNB (identified by mass spectrometry and co-immunoprecipitation) and is required for FLNB ubiquitination and subsequent proteasomal degradation. MTMR7-mediated FLNB degradation suppresses β-catenin signaling, thereby inhibiting human spermatogonial stem cell proliferation and migration.","method":"Mass spectrometry; co-immunoprecipitation; MTMR7 knockdown/overexpression; ubiquitination assay; immunofluorescence; β-catenin signaling analysis","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — MS identification confirmed by Co-IP, ubiquitination assay, and functional rescue, single lab with multiple orthogonal methods","pmids":["40638605"],"is_preprint":false},{"year":2026,"finding":"FLNB and TTC26 cooperate to regulate Sonic hedgehog (Shh)-GLI2 signaling in intervertebral disc nucleus pulposus cells. TTC26 localizes PRMT7 to the primary cilium where it methylates GLI2; FLNB then binds methylated GLI2 to promote its nuclear import. Double heterozygous Flnb/Ttc26 mice develop progressive spinal curvature during puberty with reduced collagen II and aggrecan production due to suppressed Shh signaling.","method":"Double heterozygous Flnb/Ttc26 mouse model; transcriptomic analysis; protein binding assays; cilium localization studies; Shh pathway rescue in vivo","journal":"Genome biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic epistasis in mouse plus mechanistic binding studies (FLNB binds methylated GLI2), in vivo rescue, single lab","pmids":["42178579"],"is_preprint":false},{"year":2026,"finding":"Biallelic FLNB pathogenic variants cause pediatric steroid-resistant nephrotic syndrome through podocyte cytoskeletal dysfunction. FLNB variants p.L117P and p.M1803L reduce protein expression; p.R470L and p.K2586R induce perinuclear FLNB aggregation with F-actin rearrangement. FLNB silencing in human podocytes downregulates Nephrin and Synaptopodin, disrupts cytoskeletal organization, and impairs cell migration. Zebrafish flnb knockdown causes pericardial edema, defective nephron development, and abnormal podocyte foot processes.","method":"shRNA knockdown in immortalized human podocytes; western blot; immunofluorescence of F-actin and FLNB; zebrafish flnb knockdown; patient variant transfection in HEK293T and podocytes","journal":"Journal of medical genetics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — KD with defined cellular phenotype plus zebrafish model plus patient variant characterization, single lab with multiple orthogonal methods","pmids":["42209213"],"is_preprint":false},{"year":2025,"finding":"FLNB disruption in Xenopus (CRISPR/Cas9 screen) causes congenital heart defects and impaired motile cilia function recapitulating heterotaxy phenotypes. Rescue with human FLNB confirmed functional conservation. This implicates FLNB in ciliogenesis and left-right patterning through actin cytoskeletal disruption.","method":"High-throughput CRISPR/Cas9 screen in Xenopus; cardiac development assay; motile cilia function assay; human FLNB rescue experiments","journal":"HGG advances","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — CRISPR screen plus rescue with human FLNB in Xenopus, single lab","pmids":["41674076"],"is_preprint":false},{"year":2025,"finding":"FLNB knockdown in human keratinocytes produces a morphoeic phenotype in vitro. FLNB expression is reduced ~4-fold in morphoeic basal cell carcinoma compared to normal eyelids, and a mutational cluster was identified in FLNB filamin domain 24, suggesting FLNB acts as a tumor suppressor in this context.","method":"FLNB knockdown in keratinocytes; phenotypic assessment; whole-exome sequencing; RNA sequencing; immunostaining","journal":"International journal of molecular sciences","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single KD experiment with phenotype, limited mechanistic pathway placement, single lab","pmids":["41373535"],"is_preprint":false},{"year":2000,"finding":"FLNB consists of 45 exons spanning ~80 kb of genomic DNA, mapped to chromosome 3p14. Comparative analysis of FLNB, FLNA, and FLNC revealed a highly conserved exon-intron structure with significant differences in the hinge I region encoded by exon 32, establishing the genomic organization of the three filamin paralogues.","method":"Genomic sequencing; exon-intron mapping; comparative genomic analysis; chromosomal mapping by genetic markers","journal":"Human genetics","confidence":"Low","confidence_rationale":"Tier 3 / Weak — structural/genomic mapping only, no direct functional biochemical assay","pmids":["11153914"],"is_preprint":false}],"current_model":"Filamin B (FLNB) is a large actin-binding cytoskeletal protein that crosslinks actin filaments; it is required for skeletal joint maintenance, palate formation, and ciliogenesis, operates antagonistically to FlnA in regulating RhoA activity and β1-integrin expression in chondrocytes, undergoes MTMR7-mediated ubiquitination and degradation to control β-catenin signaling, cooperates with TTC26 to shuttle methylated GLI2 into the nucleus for Shh pathway activation in intervertebral disc cells, and regulates EMT through QKI/RBFOX1-dependent alternative splicing of exon 30 that releases the FOXC1 transcription factor; disease-causing mutations cluster in the CH2 actin-binding domain and filamin repeats 14–15, with dominant mutations causing gain-of-function skeletal dysplasias and recessive loss-of-function mutations causing spondylocarpotarsal synostosis, nephrotic syndrome, and scoliosis."},"narrative":{"mechanistic_narrative":"Filamin B (FLNB) is an actin-binding cytoskeletal protein essential for skeletal joint maintenance, palate formation, and ciliated-tissue development, with its cellular activity centered on organizing the actin cytoskeleton and coupling it to signaling [PMID:17635842, PMID:28175289, PMID:37003352]. In chondrocytes FLNB acts antagonistically to filamin A: the two physically interact, and whereas FlnA promotes RhoA activation, FlnB indirectly inhibits the RhoA pathway and restrains actin stress fiber formation and β1-integrin expression [PMID:28175289]. FLNB feeds into multiple downstream signaling programs—it modulates β-catenin and MAP kinase signaling through interaction with the MAP3K1/RAC1 complex and SOX9 [PMID:29095481], its abundance is controlled by MTMR7-mediated ubiquitination and proteasomal degradation that in turn tunes β-catenin signaling [PMID:40638605], and it cooperates with TTC26 to bind methylated GLI2 and promote its nuclear import for Sonic hedgehog pathway activation in intervertebral disc cells [PMID:42178579]. FLNB also operates upstream of HOX gene transcription during skeletal segmentation [PMID:38463381] and is required for motile cilia function and left-right patterning [PMID:41674076]. Beyond its cytoskeletal scaffolding role, an alternative splicing switch of FLNB exon 30—controlled by QKI and RBFOX1—governs epithelial–mesenchymal transition by releasing the FOXC1 transcription factor [PMID:30059005]. Disease-causing mutations partition by mechanism: dominant missense/in-frame substitutions clustering in the CH2 actin-binding domain and filamin repeats 13–17 cause gain-of-function skeletal dysplasias (boomerang dysplasia, atelosteogenesis, Larsen syndrome) [PMID:15994868, PMID:16752402, PMID:16801345, PMID:29887954], while recessive loss-of-function alleles cause spondylocarpotarsal synostosis [PMID:17635842], steroid-resistant nephrotic syndrome via podocyte cytoskeletal dysfunction [PMID:42209213], and contribute to scoliosis [PMID:32381728].","teleology":[{"year":2000,"claim":"Established the genomic architecture of FLNB and its relationship to the filamin paralogues, providing the structural framework later used to map disease mutations.","evidence":"genomic sequencing and comparative exon-intron mapping of FLNB, FLNA, FLNC","pmids":["11153914"],"confidence":"Low","gaps":["structural mapping only, no functional assay","no protein-level function established"]},{"year":2005,"claim":"Showed that skeletal dysplasia mutations target the CH2 actin-binding domain, implicating the actin-binding function of FLNB in skeletogenesis.","evidence":"molecular genetic analysis of boomerang dysplasia patients identifying CH2 substitutions L171R, S235P","pmids":["15994868"],"confidence":"Medium","gaps":["no direct biochemical assay of altered actin binding","mechanism of dominance not addressed"]},{"year":2006,"claim":"Defined two functional mutation hotspots—the CH2 domain and filamin repeats 13–17—and established that dominant heterozygous missense alleles act via gain-of-function/dominant-negative mechanisms.","evidence":"sequencing and domain mapping across atelosteogenesis and Larsen syndrome probands","pmids":["16752402","16801345"],"confidence":"Medium","gaps":["no in vitro biochemical functional assay","distinction between gain-of-function and dominant-negative unresolved"]},{"year":2007,"claim":"Demonstrated by knockout mouse and patient protein analysis that complete FLNB loss causes spondylocarpotarsal synostosis, establishing FLNB as required for maintenance of intervertebral, carpal and sternal joints.","evidence":"Flnb knockout mouse phenocopy, western blot of SCT patient extracts, skeletal histology/micro-CT","pmids":["17635842"],"confidence":"High","gaps":["molecular basis of joint maintenance not defined","no link to downstream signaling at this stage"]},{"year":2017,"claim":"Defined the antagonistic relationship between FlnA and FlnB in regulating RhoA activity, actin stress fibers and β1-integrin, and linked FLNB to β-catenin/MAPK signaling through MAP3K1/RAC1 in gonadal dysgenesis.","evidence":"reciprocal Co-IP, RhoA activation assays, integrin-substrate spreading, plus WES and TOPFLASH reporter assays in disease variants","pmids":["28175289","29095481"],"confidence":"Medium","gaps":["single-lab functional assays","direct biochemical mechanism of RhoA inhibition not resolved"]},{"year":2018,"claim":"Revealed FLNB as a node in EMT control via QKI/RBFOX1-regulated exon 30 splicing that releases FOXC1, and showed distinct cellular consequences of dysplasia mutations (aggregation/apoptosis vs. impaired migration).","evidence":"RNA-seq, eCLIP, gain/loss-of-function for QKI/RBFOX1; ATDC5 chondrogenic cell mutation comparison","pmids":["30059005","29887954"],"confidence":"High","gaps":["how the splice variants differ functionally at the protein level not defined","mutation cellular phenotypes are correlative with clinical severity"]},{"year":2020,"claim":"Connected FLNB to primary cilia biology by linking AIS-associated variants to altered conformation, localization, and interaction with TTC26 and OFD1.","evidence":"AIS exome sequencing, burden test, Co-IP and localization studies","pmids":["32381728"],"confidence":"Medium","gaps":["functional consequence of TTC26/OFD1 interaction not yet mechanistic","single-lab Co-IP"]},{"year":2024,"claim":"Placed FLNB upstream of HOX gene transcription during skeletal segmentation, showing a Larsen mutation downregulates HOXD10 and HOXB2 leading to tarsal fusions.","evidence":"CRISPR-Cas9 G1586R knock-in mouse with micro-CT and HOX in situ hybridization","pmids":["38463381"],"confidence":"Medium","gaps":["mechanism linking FLNB to HOX transcription unknown","single-lab model"]},{"year":2025,"claim":"Established FLNB as required for palate development and motile cilia/left-right patterning, and identified MTMR7 as the E3-pathway adaptor controlling FLNB ubiquitination and β-catenin signaling.","evidence":"Flnb-null mouse palate analysis with cell-stretch variant assays; Xenopus CRISPR screen with human FLNB rescue; MS/Co-IP/ubiquitination assays for MTMR7","pmids":["37003352","41674076","40638605"],"confidence":"Medium","gaps":["specific ubiquitin ligase mediating MTMR7-dependent degradation not identified","single-lab studies across distinct contexts"]},{"year":2026,"claim":"Defined a ciliary FLNB–TTC26 mechanism shuttling methylated GLI2 into the nucleus for Shh activation, and established biallelic FLNB loss as a cause of steroid-resistant nephrotic syndrome via podocyte cytoskeletal dysfunction.","evidence":"double heterozygous Flnb/Ttc26 mouse with binding and cilium localization assays; podocyte shRNA knockdown, zebrafish knockdown, patient variant transfection","pmids":["42178579","42209213"],"confidence":"Medium","gaps":["structural basis of FLNB binding to methylated GLI2 not resolved","single-lab models for each disease context"]},{"year":null,"claim":"How FLNB's distinct molecular activities—actin crosslinking, signaling scaffolding (RhoA/β-catenin/MAPK), ciliary GLI2 transport, and splice-isoform-dependent EMT control—are coordinated within a single tissue context remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["no unified structural/mechanistic model integrating cytoskeletal and signaling roles","tissue-specific determinants of which FLNB function dominates are unknown"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0008092","term_label":"cytoskeletal protein binding","supporting_discovery_ids":[2,10,13]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[2,6,12]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[2,11]}],"localization":[{"term_id":"GO:0005856","term_label":"cytoskeleton","supporting_discovery_ids":[2,13]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[2]},{"term_id":"GO:0005929","term_label":"cilium","supporting_discovery_ids":[12,14]}],"pathway":[{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[0,9,10]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[2,6,12]},{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[1,9]}],"complexes":[],"partners":["FLNA","MTMR7","TTC26","OFD1","GLI2","MAP3K1","RAC1","RHOA"],"other_free_text":[]}},"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":"22014577","id":"PMC_22014577","title":"Renal 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applied microbiology","url":"https://pubmed.ncbi.nlm.nih.gov/12483618","citation_count":14,"is_preprint":false},{"pmid":"33858092","id":"PMC_33858092","title":"Zn2+-dependent enhancement of Atrazine biodegradation by Klebsiella variicola FH-1.","date":"2021","source":"Journal of hazardous materials","url":"https://pubmed.ncbi.nlm.nih.gov/33858092","citation_count":13,"is_preprint":false},{"pmid":"19727905","id":"PMC_19727905","title":"Common variants in FLNB/CRTAP, not ARHGEF3 at 3p, are associated with osteoporosis in southern Chinese women.","date":"2009","source":"Osteoporosis international : a journal established as result of cooperation between the European Foundation for Osteoporosis and the National Osteoporosis Foundation of the USA","url":"https://pubmed.ncbi.nlm.nih.gov/19727905","citation_count":11,"is_preprint":false},{"pmid":"3910024","id":"PMC_3910024","title":"Linkage of loci encoding a kidney endothelial antigen and fumarate hydratase (Fh-1) in the rat.","date":"1985","source":"Biochemical genetics","url":"https://pubmed.ncbi.nlm.nih.gov/3910024","citation_count":11,"is_preprint":false},{"pmid":"29887954","id":"PMC_29887954","title":"Comparative analysis of the two extremes of FLNB-mutated autosomal dominant disease spectrum: from clinical phenotypes to cellular and molecular findings.","date":"2018","source":"American journal of translational research","url":"https://pubmed.ncbi.nlm.nih.gov/29887954","citation_count":10,"is_preprint":false},{"pmid":"36819060","id":"PMC_36819060","title":"Immobilization of bacterial mixture of Klebsiella variicola FH-1 and Arthrobacter sp. NJ-1 enhances the bioremediation of atrazine-polluted soil environments.","date":"2023","source":"Frontiers in microbiology","url":"https://pubmed.ncbi.nlm.nih.gov/36819060","citation_count":10,"is_preprint":false},{"pmid":"31841891","id":"PMC_31841891","title":"Synergistic effect of Klebsiella sp. FH-1 and Arthrobacter sp. NJ-1 on the growth of the microbiota in the black soil of Northeast China.","date":"2019","source":"Ecotoxicology and environmental safety","url":"https://pubmed.ncbi.nlm.nih.gov/31841891","citation_count":9,"is_preprint":false},{"pmid":"10415346","id":"PMC_10415346","title":"The forkhead gene FH1 is involved in evolutionary modification of the ascidian tadpole larva.","date":"1999","source":"Mechanisms of development","url":"https://pubmed.ncbi.nlm.nih.gov/10415346","citation_count":8,"is_preprint":false},{"pmid":"29095481","id":"PMC_29095481","title":"Biallelic mutations in FLNB cause a skeletal dysplasia with 46,XY gonadal dysgenesis by activating β-catenin.","date":"2017","source":"Clinical genetics","url":"https://pubmed.ncbi.nlm.nih.gov/29095481","citation_count":8,"is_preprint":false},{"pmid":"33649519","id":"PMC_33649519","title":"The variants at FLNA and FLNB contribute to the susceptibility of hypertension and stroke with differentially expressed mRNA.","date":"2021","source":"The pharmacogenomics journal","url":"https://pubmed.ncbi.nlm.nih.gov/33649519","citation_count":7,"is_preprint":false},{"pmid":"24861497","id":"PMC_24861497","title":"A cooperative jack model of random coil-to-elongation transition of the FH1 domain by profilin binding explains formin motor behavior in actin polymerization.","date":"2014","source":"FEBS letters","url":"https://pubmed.ncbi.nlm.nih.gov/24861497","citation_count":7,"is_preprint":false},{"pmid":"24624349","id":"PMC_24624349","title":"Identification of a de novo heterozygous missense FLNB mutation in lethal atelosteogenesis type I by exome sequencing.","date":"2014","source":"Annals of laboratory medicine","url":"https://pubmed.ncbi.nlm.nih.gov/24624349","citation_count":7,"is_preprint":false},{"pmid":"34422999","id":"PMC_34422999","title":"Functional hit 1 (FH1)-based rapid and efficient generation of functional hepatocytes from human mesenchymal stem cells: a novel strategy for hepatic differentiation.","date":"2021","source":"Annals of translational medicine","url":"https://pubmed.ncbi.nlm.nih.gov/34422999","citation_count":6,"is_preprint":false},{"pmid":"34491919","id":"PMC_34491919","title":"Whole Exome Sequencing in Individuals with Idiopathic Clubfoot Reveals a Recurrent Filamin B (FLNB) Deletion.","date":"2022","source":"Clinical orthopaedics and related research","url":"https://pubmed.ncbi.nlm.nih.gov/34491919","citation_count":6,"is_preprint":false},{"pmid":"24176111","id":"PMC_24176111","title":"Conditional testing of multiple variants associated with bone mineral density in the FLNB gene region suggests that they represent a single association signal.","date":"2013","source":"BMC genetics","url":"https://pubmed.ncbi.nlm.nih.gov/24176111","citation_count":6,"is_preprint":false},{"pmid":"29797497","id":"PMC_29797497","title":"Piepkorn type of osteochondrodysplasia: Defining the severe end of FLNB-related skeletal disorders in three fetuses and a 106-year-old exhibit.","date":"2018","source":"American journal of medical genetics. Part A","url":"https://pubmed.ncbi.nlm.nih.gov/29797497","citation_count":6,"is_preprint":false},{"pmid":"37003352","id":"PMC_37003352","title":"Rare loss-of-function variants in FLNB cause non-syndromic orofacial clefts.","date":"2023","source":"Journal of genetics and genomics = Yi chuan xue bao","url":"https://pubmed.ncbi.nlm.nih.gov/37003352","citation_count":5,"is_preprint":false},{"pmid":"38188541","id":"PMC_38188541","title":"Probing the ligand binding specificity of FNBP4 WW domains and interaction with FH1 domain of FMN1.","date":"2023","source":"Current research in structural biology","url":"https://pubmed.ncbi.nlm.nih.gov/38188541","citation_count":4,"is_preprint":false},{"pmid":"38803542","id":"PMC_38803542","title":"MYLK*FLNB and DOCK1*LAMA2 gene-gene interactions associated with rheumatoid arthritis in the focal adhesion pathway.","date":"2024","source":"Frontiers in genetics","url":"https://pubmed.ncbi.nlm.nih.gov/38803542","citation_count":3,"is_preprint":false},{"pmid":"30511670","id":"PMC_30511670","title":"X-ray crystallographic analysis of the catalytic domain of α-1,3-glucanase FH1 from Paenibacillus glycanilyticus overexpressed in Brevibacillus choshinensis.","date":"2018","source":"Acta crystallographica. Section F, Structural biology communications","url":"https://pubmed.ncbi.nlm.nih.gov/30511670","citation_count":3,"is_preprint":false},{"pmid":"40986231","id":"PMC_40986231","title":"Fumarate Signaling in Cardiovascular Disease: Therapeutic Potential and Pathologic Pitfalls of DMF/MMF and FH1 Deficiency.","date":"2025","source":"Journal of cardiovascular translational research","url":"https://pubmed.ncbi.nlm.nih.gov/40986231","citation_count":2,"is_preprint":false},{"pmid":"39086440","id":"PMC_39086440","title":"Novel FLNB Variants in Seven Argentinian Cases with Spondylocarpotarsal Synostosis Syndrome.","date":"2022","source":"Journal of pediatric genetics","url":"https://pubmed.ncbi.nlm.nih.gov/39086440","citation_count":2,"is_preprint":false},{"pmid":"40346964","id":"PMC_40346964","title":"The Potential Hepatocyte Differentiation Targets and MSC Proliferation by FH1.","date":"2025","source":"Journal of cellular and molecular medicine","url":"https://pubmed.ncbi.nlm.nih.gov/40346964","citation_count":2,"is_preprint":false},{"pmid":"40150866","id":"PMC_40150866","title":"The Quorum Sensing Regulated sRNA Lrs1 Is Involved in the Adaptation to Low Iron in Pseudomonas aeruginosa.","date":"2025","source":"Environmental microbiology reports","url":"https://pubmed.ncbi.nlm.nih.gov/40150866","citation_count":2,"is_preprint":false},{"pmid":"40638605","id":"PMC_40638605","title":"MTMR7 regulates human spermatogonial stem cells proliferation and migration via targeting FLNB.","date":"2025","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/40638605","citation_count":1,"is_preprint":false},{"pmid":"38455418","id":"PMC_38455418","title":"FLNB overexpression promotes tumor progression and associates with immune suppression, evasion and stemness in pancreatic cancer.","date":"2024","source":"American journal of cancer research","url":"https://pubmed.ncbi.nlm.nih.gov/38455418","citation_count":1,"is_preprint":false},{"pmid":"38463381","id":"PMC_38463381","title":"Disruption of FLNB leads to skeletal malformation by interfering with skeletal segmentation through the HOX gene.","date":"2024","source":"Bone reports","url":"https://pubmed.ncbi.nlm.nih.gov/38463381","citation_count":1,"is_preprint":false},{"pmid":"38743867","id":"PMC_38743867","title":"A novel variant in the FLNB gene associated with spondylocarpotarsal synostosis syndrome.","date":"2024","source":"Journal of basic and clinical physiology and pharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/38743867","citation_count":1,"is_preprint":false},{"pmid":"41279393","id":"PMC_41279393","title":"Patient-informed CRISPR Screen Identifies FLNB as a Novel Congenital Heart Disease and Ciliopathy Gene.","date":"2025","source":"bioRxiv : the preprint server for biology","url":"https://pubmed.ncbi.nlm.nih.gov/41279393","citation_count":1,"is_preprint":false},{"pmid":"31836586","id":"PMC_31836586","title":"Novel in-frame FLNB deletion causes Larsen syndrome in a three-generation pedigree.","date":"2019","source":"Cold Spring Harbor molecular case studies","url":"https://pubmed.ncbi.nlm.nih.gov/31836586","citation_count":1,"is_preprint":false},{"pmid":"41373535","id":"PMC_41373535","title":"GLI2 and FLNB Define Periocular Morphoeic Basal Cell Carcinoma.","date":"2025","source":"International journal of molecular sciences","url":"https://pubmed.ncbi.nlm.nih.gov/41373535","citation_count":0,"is_preprint":false},{"pmid":"37781000","id":"PMC_37781000","title":"A Stop-gain Variant c.220C>T (p.(Gln74*)) in FLNB Segregates with Spondylocarpotarsal Synostosis Syndrome in a Consanguineous Family.","date":"2023","source":"The Yale journal of biology and medicine","url":"https://pubmed.ncbi.nlm.nih.gov/37781000","citation_count":0,"is_preprint":false},{"pmid":"41674076","id":"PMC_41674076","title":"Patient-informed CRISPR screen identifies FLNB as a congenital heart disease and ciliopathy gene.","date":"2026","source":"HGG advances","url":"https://pubmed.ncbi.nlm.nih.gov/41674076","citation_count":0,"is_preprint":false},{"pmid":"38453218","id":"PMC_38453218","title":"Severe skeletal dysplasia caused by a novel FLNB gene mutation.","date":"2024","source":"BMJ case reports","url":"https://pubmed.ncbi.nlm.nih.gov/38453218","citation_count":0,"is_preprint":false},{"pmid":"42178579","id":"PMC_42178579","title":"FLNB and TTC26 regulate ciliary Hedgehog signaling to maintain intervertebral disc matrix homeostasis in adolescent idiopathic scoliosis.","date":"2026","source":"Genome biology","url":"https://pubmed.ncbi.nlm.nih.gov/42178579","citation_count":0,"is_preprint":false},{"pmid":"42209213","id":"PMC_42209213","title":"Biallelic pathogenic variants in FLNB are associated with paediatric steroid-resistant nephrotic syndrome via podocyte cytoskeletal dysfunction.","date":"2026","source":"Journal of medical genetics","url":"https://pubmed.ncbi.nlm.nih.gov/42209213","citation_count":0,"is_preprint":false},{"pmid":"41062856","id":"PMC_41062856","title":"Severe Osteoporosis in Larsen Syndrome-A Case Report of Bone Morphology and A Novel Filamin B (FLNB) Variant.","date":"2025","source":"Calcified tissue international","url":"https://pubmed.ncbi.nlm.nih.gov/41062856","citation_count":0,"is_preprint":false},{"pmid":null,"id":"bio_10.1101_2025.05.09.653129","title":"Mechanism of formin-mediated filament nucleation from profilin-actin","date":"2025-05-14","source":"bioRxiv","url":"https://doi.org/10.1101/2025.05.09.653129","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2025.11.21.689827","title":"Impact of N-terminal dimerization on formin homology 1 domain polymer dynamics and actin assembly","date":"2025-11-23","source":"bioRxiv","url":"https://doi.org/10.1101/2025.11.21.689827","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2024.12.07.627365","title":"Mechanistic Insights into FNBP4-Mediated Regulation of non-diaphanous formin FMN1 in Actin Cytoskeleton Dynamics","date":"2024-12-08","source":"bioRxiv","url":"https://doi.org/10.1101/2024.12.07.627365","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":32592,"output_tokens":4668,"usd":0.083898,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":12449,"output_tokens":3645,"usd":0.076685,"stage2_stop_reason":"end_turn"},"total_usd":0.160583,"stage1_batch_id":"msgbatch_01AsR7g8dGTEiEw9U83bJeWn","stage2_batch_id":"msgbatch_01YV5ZyxtFNUZEjxRcpd9jzb","note":"batch pricing = 50% of standard"},"stage1_raw":"Looking through the corpus, I need to identify papers about the canonical FLNB protein (filamin B, an actin-binding cytoskeletal protein). I'll exclude:\n- Papers about fumarate hydratase (FH1 as fumarate hydratase - papers 1, 3, 20, 45, 28)\n- Papers about formin FH1/FH2 domains of other proteins (papers 2, 4, 8, 9, 11, 13, 15, 35, 62, 63 - these are about formins, not filamin B)\n- Bacterial/microbial papers (25, 26, 30, 31, 44)\n- Ascidian FH1 forkhead gene (32)\n- TFH1 immune cells (7)\n- Papers about FNBP4/FMN1 (42, 64) - different proteins\n- Pseudomonas sRNA (48)\n- Dictyostelium formins (15) - different protein\n\nNow extracting from FLNB-relevant papers:\n\n```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2007,\n      \"finding\": \"Flnb-knockout mice phenocopy spondylocarpotarsal synostosis syndrome (SCT), exhibiting progressive vertebral fusions, carpal and sternal joint fusions. Protein extracts from SCT patients with nonsense FLNB mutations lacked filamin B, demonstrating SCT results from complete absence of the protein. The skeletal fusions begin antenatally and are progressive, indicating filamin B is required for maintenance (not initial formation) of intervertebral, carpal and sternal joints.\",\n      \"method\": \"Flnb knockout mouse model; western blot of patient cell extracts; skeletal histology and micro-CT\",\n      \"journal\": \"Human molecular genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — clean KO mouse with defined skeletal phenotype plus patient protein-level validation, replicated across multiple skeletal sites\",\n      \"pmids\": [\"17635842\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"The RNA-binding proteins QKI and RBFOX1 coordinately regulate alternative splicing of FLNB exon 30; skipping of exon 30 promotes EMT by releasing the FOXC1 transcription factor. This splicing switch is necessary and sufficient to induce an intermediate mesenchymal cell state and increased tumorigenicity in breast cancer cells.\",\n      \"method\": \"RNA-seq, eCLIP analysis, gain/loss-of-function experiments with QKI and RBFOX1, genome-scale expression screen for EMT inducers\",\n      \"journal\": \"eLife\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (RNA-seq, eCLIP, functional rescue), necessity and sufficiency demonstrated, mechanistic pathway defined\",\n      \"pmids\": [\"30059005\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"FlnA and FlnB physically interact in the cytoplasm of chondrocytes. FlnB loss promotes actin stress fiber formation and enhanced cell spreading on integrin-activating substrates, whereas FlnA inhibition decreases actin formation. FlnA more strongly binds RhoA and promotes RhoA activation, while FlnB indirectly inhibits the RhoA pathway. FlnB loss promotes β1-integrin expression, while FlnA loss diminishes it. FlnA and FlnB have antagonistic roles in regulating RhoA activity and actin stress fiber remodeling.\",\n      \"method\": \"Co-immunoprecipitation of FlnA/FlnB; RhoA activation assays; loss-of-function with integrin substrates; immunofluorescence of actin and RhoA\",\n      \"journal\": \"Human molecular genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP plus functional assays (RhoA activation, cell spreading), single lab with multiple orthogonal methods\",\n      \"pmids\": [\"28175289\"],\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, defining the actin-binding domain as critical for FLNB function in skeletogenesis.\",\n      \"method\": \"Molecular genetic analysis; sequencing; identification of mutation clustering in CH2 actin-binding domain\",\n      \"journal\": \"Journal of medical genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Strong — mutation clustering in functional domain across multiple independent cases, convergent genetic evidence, but no direct biochemical assay\",\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 FLNB: the CH2 domain of the actin-binding region (exons 2–3) and filamin repeats 14–15 (exons 28–29). This non-random mutation distribution identifies these two structural domains as functionally critical for FLNB's role in skeletogenesis.\",\n      \"method\": \"Sequencing of 15 unrelated AOI/AOIII patients; mapping of mutations to FLNB protein domains\",\n      \"journal\": \"Human mutation\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Strong — convergent mutation mapping across multiple independent patients and labs defines functional domains, but no direct in vitro biochemical assay\",\n      \"pmids\": [\"16752402\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"Larsen syndrome-causing FLNB mutations cluster in the actin-binding domain (CH2 region) and filamin repeats 13–17, defining these as functional hotspots. All affected individuals are heterozygous for missense or small in-frame deletions, consistent with a dominant gain-of-function or dominant-negative mechanism.\",\n      \"method\": \"DHPLC, direct sequencing, restriction endonuclease digestion across 20 Larsen syndrome probands\",\n      \"journal\": \"Journal of medical genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Strong — convergent mutation analysis across multiple labs and patients, but no direct biochemical functional assay\",\n      \"pmids\": [\"16801345\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Novel biallelic FLNB mutations (p.F964L, p.A1577V) increase binding of FLNB protein to the MAP3K1 and RAC1 signal transduction complex, activate β-catenin signaling, and affect phosphorylation of MAP kinase pathway intermediates and SOX9 expression, causing 46,XY gonadal dysgenesis alongside skeletal dysplasia.\",\n      \"method\": \"Whole exome sequencing; qPCR; flow variant assays; TOPFLASH reporter assay for β-catenin activity; protein interaction assays\",\n      \"journal\": \"Clinical genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — TOPFLASH reporter plus binding assays plus phosphorylation analysis, single lab with multiple complementary methods\",\n      \"pmids\": [\"29095481\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"BD-associated FLNB mutation L171R causes globular protein aggregation and increased cellular apoptosis in ATDC5 chondrogenic cells, while LS-associated FLNB G1586R causes evenly distributed protein but decreased cellular migration. Both mutations increase Runx2 expression. These differing cellular phenotypes correlate with clinical severity differences between boomerang dysplasia and Larsen syndrome.\",\n      \"method\": \"ATDC5 chondrogenic cell transfection model; immunofluorescence of FLNB localization; apoptosis assay; cell migration assay; Runx2 expression analysis\",\n      \"journal\": \"American journal of translational research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — direct comparison of mutant protein behaviors in relevant chondrogenic cell line with multiple readouts, single lab\",\n      \"pmids\": [\"29887954\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"AIS-associated FLNB variants alter protein conformation, subcellular localization, and interaction with TTC26 and OFD1 (proteins involved in primary cilia and AIS). FLNB was identified as the top signal in a gene-based burden test for adolescent idiopathic scoliosis.\",\n      \"method\": \"Exome sequencing of AIS trios; gene-based burden test; functional studies of protein conformation, subcellular localization, and co-immunoprecipitation with TTC26 and OFD1\",\n      \"journal\": \"Journal of medical genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — Co-IP plus localization studies in disease context, single lab, moderate mechanistic follow-up\",\n      \"pmids\": [\"32381728\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"FLNB disruption by a Larsen syndrome-associated point mutation (G1586R, generated by CRISPR-Cas9) causes downregulation of HOXD10 in the carpal region and HOXB2 in the cervical spine region at E12.5, leading to tarsal bone fusions. This places FLNB upstream of HOX gene transcription during skeletal segmentation.\",\n      \"method\": \"CRISPR-Cas9 knock-in mouse model; micro-CT; HE staining; whole skeletal preparation; in situ hybridization for HOX genes in embryos\",\n      \"journal\": \"Bone reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — CRISPR knock-in mouse with defined phenotype and in situ hybridization pathway placement, single lab\",\n      \"pmids\": [\"38463381\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Loss-of-function FLNB variants (p.P441T, p.G565R) are less potent than wild-type FLNB in inducing cell stretches in mammalian cells. Flnb-null embryos display cleft palates, demonstrating FLNB is required for palate development.\",\n      \"method\": \"Mammalian cell transfection with WT and variant FLNB; cell morphology assay; Flnb knockout mouse embryo analysis; immunohistochemistry of palatal tissues\",\n      \"journal\": \"Journal of genetics and genomics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — loss-of-function in cells plus mouse KO with specific palate phenotype, single lab\",\n      \"pmids\": [\"37003352\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"MTMR7 interacts with FLNB (identified by mass spectrometry and co-immunoprecipitation) and is required for FLNB ubiquitination and subsequent proteasomal degradation. MTMR7-mediated FLNB degradation suppresses β-catenin signaling, thereby inhibiting human spermatogonial stem cell proliferation and migration.\",\n      \"method\": \"Mass spectrometry; co-immunoprecipitation; MTMR7 knockdown/overexpression; ubiquitination assay; immunofluorescence; β-catenin signaling analysis\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — MS identification confirmed by Co-IP, ubiquitination assay, and functional rescue, single lab with multiple orthogonal methods\",\n      \"pmids\": [\"40638605\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"FLNB and TTC26 cooperate to regulate Sonic hedgehog (Shh)-GLI2 signaling in intervertebral disc nucleus pulposus cells. TTC26 localizes PRMT7 to the primary cilium where it methylates GLI2; FLNB then binds methylated GLI2 to promote its nuclear import. Double heterozygous Flnb/Ttc26 mice develop progressive spinal curvature during puberty with reduced collagen II and aggrecan production due to suppressed Shh signaling.\",\n      \"method\": \"Double heterozygous Flnb/Ttc26 mouse model; transcriptomic analysis; protein binding assays; cilium localization studies; Shh pathway rescue in vivo\",\n      \"journal\": \"Genome biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic epistasis in mouse plus mechanistic binding studies (FLNB binds methylated GLI2), in vivo rescue, single lab\",\n      \"pmids\": [\"42178579\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"Biallelic FLNB pathogenic variants cause pediatric steroid-resistant nephrotic syndrome through podocyte cytoskeletal dysfunction. FLNB variants p.L117P and p.M1803L reduce protein expression; p.R470L and p.K2586R induce perinuclear FLNB aggregation with F-actin rearrangement. FLNB silencing in human podocytes downregulates Nephrin and Synaptopodin, disrupts cytoskeletal organization, and impairs cell migration. Zebrafish flnb knockdown causes pericardial edema, defective nephron development, and abnormal podocyte foot processes.\",\n      \"method\": \"shRNA knockdown in immortalized human podocytes; western blot; immunofluorescence of F-actin and FLNB; zebrafish flnb knockdown; patient variant transfection in HEK293T and podocytes\",\n      \"journal\": \"Journal of medical genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — KD with defined cellular phenotype plus zebrafish model plus patient variant characterization, single lab with multiple orthogonal methods\",\n      \"pmids\": [\"42209213\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"FLNB disruption in Xenopus (CRISPR/Cas9 screen) causes congenital heart defects and impaired motile cilia function recapitulating heterotaxy phenotypes. Rescue with human FLNB confirmed functional conservation. This implicates FLNB in ciliogenesis and left-right patterning through actin cytoskeletal disruption.\",\n      \"method\": \"High-throughput CRISPR/Cas9 screen in Xenopus; cardiac development assay; motile cilia function assay; human FLNB rescue experiments\",\n      \"journal\": \"HGG advances\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — CRISPR screen plus rescue with human FLNB in Xenopus, single lab\",\n      \"pmids\": [\"41674076\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"FLNB knockdown in human keratinocytes produces a morphoeic phenotype in vitro. FLNB expression is reduced ~4-fold in morphoeic basal cell carcinoma compared to normal eyelids, and a mutational cluster was identified in FLNB filamin domain 24, suggesting FLNB acts as a tumor suppressor in this context.\",\n      \"method\": \"FLNB knockdown in keratinocytes; phenotypic assessment; whole-exome sequencing; RNA sequencing; immunostaining\",\n      \"journal\": \"International journal of molecular sciences\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single KD experiment with phenotype, limited mechanistic pathway placement, single lab\",\n      \"pmids\": [\"41373535\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"FLNB consists of 45 exons spanning ~80 kb of genomic DNA, mapped to chromosome 3p14. Comparative analysis of FLNB, FLNA, and FLNC revealed a highly conserved exon-intron structure with significant differences in the hinge I region encoded by exon 32, establishing the genomic organization of the three filamin paralogues.\",\n      \"method\": \"Genomic sequencing; exon-intron mapping; comparative genomic analysis; chromosomal mapping by genetic markers\",\n      \"journal\": \"Human genetics\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — structural/genomic mapping only, no direct functional biochemical assay\",\n      \"pmids\": [\"11153914\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"Filamin B (FLNB) is a large actin-binding cytoskeletal protein that crosslinks actin filaments; it is required for skeletal joint maintenance, palate formation, and ciliogenesis, operates antagonistically to FlnA in regulating RhoA activity and β1-integrin expression in chondrocytes, undergoes MTMR7-mediated ubiquitination and degradation to control β-catenin signaling, cooperates with TTC26 to shuttle methylated GLI2 into the nucleus for Shh pathway activation in intervertebral disc cells, and regulates EMT through QKI/RBFOX1-dependent alternative splicing of exon 30 that releases the FOXC1 transcription factor; disease-causing mutations cluster in the CH2 actin-binding domain and filamin repeats 14–15, with dominant mutations causing gain-of-function skeletal dysplasias and recessive loss-of-function mutations causing spondylocarpotarsal synostosis, nephrotic syndrome, and scoliosis.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"Filamin B (FLNB) is an actin-binding cytoskeletal protein essential for skeletal joint maintenance, palate formation, and ciliated-tissue development, with its cellular activity centered on organizing the actin cytoskeleton and coupling it to signaling [#0, #2, #10]. In chondrocytes FLNB acts antagonistically to filamin A: the two physically interact, and whereas FlnA promotes RhoA activation, FlnB indirectly inhibits the RhoA pathway and restrains actin stress fiber formation and β1-integrin expression [#2]. FLNB feeds into multiple downstream signaling programs—it modulates β-catenin and MAP kinase signaling through interaction with the MAP3K1/RAC1 complex and SOX9 [#6], its abundance is controlled by MTMR7-mediated ubiquitination and proteasomal degradation that in turn tunes β-catenin signaling [#11], and it cooperates with TTC26 to bind methylated GLI2 and promote its nuclear import for Sonic hedgehog pathway activation in intervertebral disc cells [#12]. FLNB also operates upstream of HOX gene transcription during skeletal segmentation [#9] and is required for motile cilia function and left-right patterning [#14]. Beyond its cytoskeletal scaffolding role, an alternative splicing switch of FLNB exon 30—controlled by QKI and RBFOX1—governs epithelial–mesenchymal transition by releasing the FOXC1 transcription factor [#1]. Disease-causing mutations partition by mechanism: dominant missense/in-frame substitutions clustering in the CH2 actin-binding domain and filamin repeats 13–17 cause gain-of-function skeletal dysplasias (boomerang dysplasia, atelosteogenesis, Larsen syndrome) [#3, #4, #5, #7], while recessive loss-of-function alleles cause spondylocarpotarsal synostosis [#0], steroid-resistant nephrotic syndrome via podocyte cytoskeletal dysfunction [#13], and contribute to scoliosis [#8].\",\n  \"teleology\": [\n    {\n      \"year\": 2000,\n      \"claim\": \"Established the genomic architecture of FLNB and its relationship to the filamin paralogues, providing the structural framework later used to map disease mutations.\",\n      \"evidence\": \"genomic sequencing and comparative exon-intron mapping of FLNB, FLNA, FLNC\",\n      \"pmids\": [\"11153914\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"structural mapping only, no functional assay\", \"no protein-level function established\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Showed that skeletal dysplasia mutations target the CH2 actin-binding domain, implicating the actin-binding function of FLNB in skeletogenesis.\",\n      \"evidence\": \"molecular genetic analysis of boomerang dysplasia patients identifying CH2 substitutions L171R, S235P\",\n      \"pmids\": [\"15994868\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"no direct biochemical assay of altered actin binding\", \"mechanism of dominance not addressed\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Defined two functional mutation hotspots—the CH2 domain and filamin repeats 13–17—and established that dominant heterozygous missense alleles act via gain-of-function/dominant-negative mechanisms.\",\n      \"evidence\": \"sequencing and domain mapping across atelosteogenesis and Larsen syndrome probands\",\n      \"pmids\": [\"16752402\", \"16801345\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"no in vitro biochemical functional assay\", \"distinction between gain-of-function and dominant-negative unresolved\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Demonstrated by knockout mouse and patient protein analysis that complete FLNB loss causes spondylocarpotarsal synostosis, establishing FLNB as required for maintenance of intervertebral, carpal and sternal joints.\",\n      \"evidence\": \"Flnb knockout mouse phenocopy, western blot of SCT patient extracts, skeletal histology/micro-CT\",\n      \"pmids\": [\"17635842\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"molecular basis of joint maintenance not defined\", \"no link to downstream signaling at this stage\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Defined the antagonistic relationship between FlnA and FlnB in regulating RhoA activity, actin stress fibers and β1-integrin, and linked FLNB to β-catenin/MAPK signaling through MAP3K1/RAC1 in gonadal dysgenesis.\",\n      \"evidence\": \"reciprocal Co-IP, RhoA activation assays, integrin-substrate spreading, plus WES and TOPFLASH reporter assays in disease variants\",\n      \"pmids\": [\"28175289\", \"29095481\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"single-lab functional assays\", \"direct biochemical mechanism of RhoA inhibition not resolved\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Revealed FLNB as a node in EMT control via QKI/RBFOX1-regulated exon 30 splicing that releases FOXC1, and showed distinct cellular consequences of dysplasia mutations (aggregation/apoptosis vs. impaired migration).\",\n      \"evidence\": \"RNA-seq, eCLIP, gain/loss-of-function for QKI/RBFOX1; ATDC5 chondrogenic cell mutation comparison\",\n      \"pmids\": [\"30059005\", \"29887954\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"how the splice variants differ functionally at the protein level not defined\", \"mutation cellular phenotypes are correlative with clinical severity\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Connected FLNB to primary cilia biology by linking AIS-associated variants to altered conformation, localization, and interaction with TTC26 and OFD1.\",\n      \"evidence\": \"AIS exome sequencing, burden test, Co-IP and localization studies\",\n      \"pmids\": [\"32381728\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"functional consequence of TTC26/OFD1 interaction not yet mechanistic\", \"single-lab Co-IP\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Placed FLNB upstream of HOX gene transcription during skeletal segmentation, showing a Larsen mutation downregulates HOXD10 and HOXB2 leading to tarsal fusions.\",\n      \"evidence\": \"CRISPR-Cas9 G1586R knock-in mouse with micro-CT and HOX in situ hybridization\",\n      \"pmids\": [\"38463381\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"mechanism linking FLNB to HOX transcription unknown\", \"single-lab model\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Established FLNB as required for palate development and motile cilia/left-right patterning, and identified MTMR7 as the E3-pathway adaptor controlling FLNB ubiquitination and β-catenin signaling.\",\n      \"evidence\": \"Flnb-null mouse palate analysis with cell-stretch variant assays; Xenopus CRISPR screen with human FLNB rescue; MS/Co-IP/ubiquitination assays for MTMR7\",\n      \"pmids\": [\"37003352\", \"41674076\", \"40638605\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"specific ubiquitin ligase mediating MTMR7-dependent degradation not identified\", \"single-lab studies across distinct contexts\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Defined a ciliary FLNB–TTC26 mechanism shuttling methylated GLI2 into the nucleus for Shh activation, and established biallelic FLNB loss as a cause of steroid-resistant nephrotic syndrome via podocyte cytoskeletal dysfunction.\",\n      \"evidence\": \"double heterozygous Flnb/Ttc26 mouse with binding and cilium localization assays; podocyte shRNA knockdown, zebrafish knockdown, patient variant transfection\",\n      \"pmids\": [\"42178579\", \"42209213\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"structural basis of FLNB binding to methylated GLI2 not resolved\", \"single-lab models for each disease context\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How FLNB's distinct molecular activities—actin crosslinking, signaling scaffolding (RhoA/β-catenin/MAPK), ciliary GLI2 transport, and splice-isoform-dependent EMT control—are coordinated within a single tissue context remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"no unified structural/mechanistic model integrating cytoskeletal and signaling roles\", \"tissue-specific determinants of which FLNB function dominates are unknown\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0008092\", \"supporting_discovery_ids\": [2, 10, 13]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [2, 6, 12]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [2, 11]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005856\", \"supporting_discovery_ids\": [2, 13]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [2]},\n      {\"term_id\": \"GO:0005929\", \"supporting_discovery_ids\": [12, 14]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [0, 9, 10]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [2, 6, 12]},\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [1, 9]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"FLNA\", \"MTMR7\", \"TTC26\", \"OFD1\", \"GLI2\", \"MAP3K1\", \"RAC1\", \"RhoA\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":6,"faith_total":6,"faith_pct":100.0}}