{"gene":"FBN2","run_date":"2026-06-09T23:54:43","timeline":{"discoveries":[{"year":1995,"finding":"Missense mutations in FBN2 causing substitution of cysteine residues in EGF-like domains are responsible for congenital contractural arachnodactyly (CCA), establishing fibrillin-2 as a structural component of extracellular matrix microfibrils whose integrity is required for normal musculoskeletal development.","method":"Mutation identification by direct sequencing in CCA patients; demonstration that FBN2 mutations cause CCA phenotype","journal":"Nature genetics","confidence":"High","confidence_rationale":"Tier 2 / Strong — direct sequencing identifying causative mutations in multiple patients, independently replicated across multiple subsequent studies confirming the same gene-disease relationship","pmids":["7493032"],"is_preprint":false},{"year":1997,"finding":"FBN2 mutations causing exon splicing errors (resulting in deletion of a calcium-binding EGF-like domain) lead to CCA. Analysis of FBN2 transcript levels in dermal fibroblasts showed the mutated allele is expressed at higher levels than the wild-type allele, indicating allele-specific expression differences.","method":"RT-PCR analysis of FBN2 cDNA from dermal fibroblasts; genomic sequencing; transcript level analysis","journal":"American journal of human genetics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct transcript analysis from patient fibroblasts with multiple molecular methods, single lab","pmids":["9106527"],"is_preprint":false},{"year":1998,"finding":"All identified FBN2 mutations in CCA patients cluster in a limited region encoded by exons 24–34, corresponding to the region in FBN1 where neonatal Marfan syndrome mutations cluster, indicating this central domain plays a critical role in human embryogenesis.","method":"FBN2 mRNA screening from patient cell strains; mutation identification and mapping","journal":"American journal of medical genetics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — systematic mutation screening across multiple unrelated patients establishing genotype-phenotype clustering, single lab","pmids":["9714438"],"is_preprint":false},{"year":2002,"finding":"Ten novel FBN2 mutations in CCA patients cluster in exons 23–34 with a 75% detection rate in this limited region. Unlike FBN1 mutations in Marfan syndrome, identified FBN2 mutations do not alter calcium-binding consensus sequences in EGF-like domains, suggesting distinct pathomechanisms for the two fibrillins.","method":"SSCP analysis and direct sequencing of exons 22–36 of FBN2 in 13 CCA patients; clinical correlation","journal":"Human mutation","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — systematic mutation screening with molecular characterization and clinical correlation, single lab","pmids":["11754102"],"is_preprint":false},{"year":2005,"finding":"FBN2 expression is silenced by aberrant promoter methylation in non-small cell lung cancer (NSCLC) cell lines; treatment with the demethylating agent 5-aza-2'-deoxycytidine restored FBN2 expression, establishing promoter methylation as a mechanism of FBN2 silencing in cancer.","method":"RT-PCR for expression analysis; methylation-specific PCR; 5-aza-2'-deoxycytidine demethylation treatment","journal":"Lung cancer (Amsterdam, Netherlands)","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct demonstration of methylation-expression correlation with pharmacological reversal, single lab","pmids":["15951052"],"is_preprint":false},{"year":2013,"finding":"Fbn2-null mice exhibit anterior segment dysgenesis including high incidence of iris coloboma and zonular fiber disorganization; fibrillin-2-rich microfibrils are prominent in the pupillary membrane during development, and loss of Fbn2 causes failed pupillary membrane regression, implicating fibrillin-2 in optic fissure closure and lens fiber cell differentiation.","method":"Confocal microscopy with antibodies against microfibril components in Fbn2(-/-) mice; phenotypic characterization of knockout ocular morphology","journal":"Investigative ophthalmology & visual science","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct localization and loss-of-function phenotype in knockout mice with specific mechanistic readouts, single lab","pmids":["24130178"],"is_preprint":false},{"year":2014,"finding":"FBN2 localizes to Bruch's membrane in the eye; its expression is reduced in aging and AMD eyes. Rare FBN2 variants segregate with autosomal dominant maculopathy, and a common non-synonymous variant (rs154001, p.Val965Ile) is associated with AMD, establishing FBN2 as a component of Bruch's membrane important for blood-retina homeostasis.","method":"Whole exome sequencing in maculopathy family; Sanger sequencing validation; immunolocalization to Bruch's membrane; large-scale association study (10,337 cases/11,174 controls)","journal":"Human molecular genetics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct protein localization combined with genetic segregation and large association study, single lab primary discovery","pmids":["24899048"],"is_preprint":false},{"year":2015,"finding":"Fbn2 null mice are born with reduced muscle mass, abnormal muscle histology, and activated BMP signaling in skeletal muscle. Genetic rescue by deleting a single allele of Bmp7 restored muscle mass and reduced white fat accumulation, demonstrating that fibrillin-2 sequesters BMP complexes (including BMP7) in a latent state in the extracellular matrix and that loss of fibrillin-2 causes abnormally activated BMP signaling leading to myopathy.","method":"Fbn2 null mouse analysis; creatine kinase measurement; in vivo and in vitro BMP signaling assays; genetic epistasis (Fbn2 null × Bmp7 heterozygous rescue); histology and immunofluorescence","journal":"PLoS genetics","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic epistasis rescue experiment combined with multiple in vivo and in vitro assays demonstrating BMP sequestration mechanism, multiple orthogonal methods","pmids":["26114882"],"is_preprint":false},{"year":2014,"finding":"Rare variants in FBN2 (and FBN1) are enriched in severely affected adolescent idiopathic scoliosis (AIS) cases compared to controls, with upregulation of the TGF-beta pathway observed in cases with fibrillin variants, expanding the functional role of FBN2 to include regulation of TGF-beta signaling in spinal development.","method":"Exome sequencing; burden analysis in 852 AIS cases and 669 controls; replication in independent Han Chinese cohort; clinical evaluation with pathway analysis","journal":"Human molecular genetics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — rare variant burden analysis replicated in independent cohort with pathway analysis, but pathway upregulation is observational rather than direct mechanistic demonstration","pmids":["24833718"],"is_preprint":false},{"year":2014,"finding":"5q23 deletions encompassing FBN2 (and PHAX) cause a syndromic form of Pierre Robin sequence with associated digital contractures and crumpled ear helices; haploinsufficiency for FBN2 accounts specifically for the digital and auricular features of this syndrome.","method":"Clinical array-based comparative genome hybridization (aCGH) defining minimum deletion region; expression analysis of orthologous genes in embryonic mice; sequencing of candidate genes","journal":"European journal of medical genetics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — minimal deletion mapping and expression analysis supporting FBN2 haploinsufficiency as mechanism for specific phenotypic features, multiple deletions analyzed","pmids":["25195018"],"is_preprint":false}],"current_model":"Fibrillin-2 (FBN2) is a large extracellular matrix glycoprotein that polymerizes into microfibrils and functions to sequester BMP growth factor complexes (including BMP7) in a latent state; loss of fibrillin-2 causes abnormally activated BMP signaling leading to myopathy, and FBN2 mutations clustering in the central EGF-like domain region (exons 24–34) cause congenital contractural arachnodactyly by disrupting microfibril structure, while FBN2 also localizes to Bruch's membrane and ocular microfibrils where it is required for anterior segment morphogenesis and optic fissure closure."},"narrative":{"mechanistic_narrative":"Fibrillin-2 (FBN2) is a large extracellular matrix glycoprotein that polymerizes into microfibrils and acts as a structural and growth-factor-regulatory scaffold required for normal musculoskeletal, ocular, and craniofacial development [PMID:7493032, PMID:26114882]. Beyond its structural role, fibrillin-2 sequesters BMP growth factor complexes—including BMP7—in a latent state within the matrix; loss of fibrillin-2 in mice releases this restraint, producing abnormally activated BMP signaling, reduced muscle mass, and myopathy that is genetically rescued by lowering Bmp7 gene dosage [PMID:26114882]. Fibrillin variants are also accompanied by upregulated TGF-beta signaling in scoliosis cases, extending its role as a regulator of matrix-sequestered growth factors [PMID:24833718]. Cysteine-substituting missense mutations and splicing errors in FBN2 that disrupt EGF-like domains cause congenital contractural arachnodactyly, with pathogenic mutations clustering tightly in a central domain encoded by exons 23–34 [PMID:7493032, PMID:9106527, PMID:11754102]. Fibrillin-2-rich microfibrils localize to the developing pupillary membrane and to Bruch's membrane, where fibrillin-2 is required for optic fissure closure, anterior segment morphogenesis, and retinal homeostasis, and FBN2 variants are associated with maculopathy [PMID:24130178, PMID:24899048]. Haploinsufficiency for FBN2 also contributes to a syndromic form of Pierre Robin sequence with digital contractures and crumpled ear helices [PMID:25195018].","teleology":[{"year":1995,"claim":"Establishing that FBN2 mutations cause a heritable connective tissue disorder defined fibrillin-2 as a structural microfibril component required for musculoskeletal development.","evidence":"Direct sequencing identifying cysteine-substituting missense mutations in EGF-like domains in congenital contractural arachnodactyly patients","pmids":["7493032"],"confidence":"High","gaps":["Did not define how individual mutations disrupt microfibril assembly at the molecular level","Did not address fibrillin-2 function outside the musculoskeletal system"]},{"year":1997,"claim":"Splicing-error mutations deleting a calcium-binding EGF-like domain extended the mutational spectrum and revealed allele-specific expression differences in patient fibroblasts.","evidence":"RT-PCR and genomic sequencing of FBN2 transcripts from CCA patient dermal fibroblasts","pmids":["9106527"],"confidence":"Medium","gaps":["Functional consequence of the allele-specific expression imbalance not established","No protein-level assay of the mutant fibrillin-2"]},{"year":1998,"claim":"Mapping CCA mutations to a limited central region clarified that one specific domain block is critical for fibrillin-2 function in embryogenesis.","evidence":"FBN2 mRNA screening and mutation mapping across multiple unrelated CCA patient cell strains","pmids":["9714438"],"confidence":"Medium","gaps":["Why this central region is uniquely mutation-sensitive was not mechanistically resolved","Did not test domain function biochemically"]},{"year":2002,"claim":"Systematic screening confirmed mutation clustering in exons 23–34 and distinguished FBN2 pathomechanism from FBN1 by showing mutations spare calcium-binding consensus sequences.","evidence":"SSCP and direct sequencing of exons 22–36 in 13 CCA patients with clinical correlation","pmids":["11754102"],"confidence":"Medium","gaps":["The distinct pathomechanism implied by sparing of calcium-binding sequences not directly demonstrated","No structural model of mutant microfibrils"]},{"year":2005,"claim":"Discovery of promoter methylation silencing of FBN2 implicated the gene as a methylation target in cancer, beyond its developmental role.","evidence":"Methylation-specific PCR and RT-PCR with pharmacological demethylation (5-aza-2'-deoxycytidine) in NSCLC cell lines","pmids":["15951052"],"confidence":"Medium","gaps":["Functional consequence of FBN2 loss for tumor biology not established","No in vivo confirmation"]},{"year":2013,"claim":"Knockout phenotyping revealed a previously unknown ocular developmental role, placing fibrillin-2 microfibrils in optic fissure closure and pupillary membrane regression.","evidence":"Confocal immunolocalization and phenotypic characterization of Fbn2-null mouse eyes","pmids":["24130178"],"confidence":"Medium","gaps":["Molecular signaling pathway linking fibrillin-2 loss to coloboma not defined","Single-lab knockout characterization"]},{"year":2014,"claim":"Localization to Bruch's membrane combined with genetic association linked fibrillin-2 to retinal homeostasis and maculopathy.","evidence":"Exome sequencing in a maculopathy family, immunolocalization to Bruch's membrane, and a large case-control association study","pmids":["24899048"],"confidence":"Medium","gaps":["Causal mechanism by which FBN2 variants impair blood-retina homeostasis not demonstrated","Common-variant association is statistical, not mechanistic"]},{"year":2014,"claim":"Rare-variant burden testing implicated FBN2 in scoliosis and connected fibrillin variants to TGF-beta pathway dysregulation.","evidence":"Exome sequencing and burden analysis in 852 AIS cases vs 669 controls with replication and pathway analysis","pmids":["24833718"],"confidence":"Medium","gaps":["TGF-beta upregulation is observational, not a direct mechanistic demonstration of fibrillin-2 control","Individual variant causality not established"]},{"year":2014,"claim":"Deletion mapping attributed specific digital and auricular features of a Pierre Robin syndrome to FBN2 haploinsufficiency, distinguishing dosage from missense pathology.","evidence":"Array CGH minimal-region mapping with embryonic mouse expression analysis of orthologous genes","pmids":["25195018"],"confidence":"Medium","gaps":["Direct functional proof of haploinsufficiency for these features not provided","Contribution of co-deleted genes not fully excluded"]},{"year":2015,"claim":"Genetic epistasis defined the core mechanism: fibrillin-2 sequesters latent BMP complexes, so its loss derepresses BMP signaling and causes myopathy.","evidence":"Fbn2-null mouse analysis with BMP signaling assays and Bmp7-heterozygous genetic rescue restoring muscle mass","pmids":["26114882"],"confidence":"High","gaps":["Direct binding interface between fibrillin-2 microfibrils and BMP7 complexes not structurally mapped","Whether the same mechanism operates in human CCA muscle not shown"]},{"year":null,"claim":"How specific exon 23–34 mutations and structural disruption of microfibrils mechanistically translate into impaired BMP/TGF-beta sequestration across muscle, eye, and skeleton remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No structural model linking mutant fibrillin-2 to growth-factor release","Tissue-specific contributions of BMP vs TGF-beta dysregulation not disentangled","Human disease mechanism not directly tied to the mouse BMP-sequestration model"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0005198","term_label":"structural molecule activity","supporting_discovery_ids":[0,7]},{"term_id":"GO:0140313","term_label":"molecular sequestering activity","supporting_discovery_ids":[7]}],"localization":[{"term_id":"GO:0031012","term_label":"extracellular matrix","supporting_discovery_ids":[0,5,6]},{"term_id":"GO:0005576","term_label":"extracellular region","supporting_discovery_ids":[6,7]}],"pathway":[{"term_id":"R-HSA-1474244","term_label":"Extracellular matrix organization","supporting_discovery_ids":[0,7]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[7,8]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[5,9]}],"complexes":["microfibril"],"partners":["BMP7"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"P35556","full_name":"Fibrillin-2","aliases":[],"length_aa":2912,"mass_kda":314.8,"function":"Fibrillins are structural components of 10-12 nm extracellular calcium-binding microfibrils, which occur either in association with elastin or in elastin-free bundles. Fibrillin-2-containing microfibrils regulate the early process of elastic fiber assembly. Regulates osteoblast maturation by controlling TGF-beta bioavailability and calibrating TGF-beta and BMP levels, respectively Hormone secreted by trophoblasts that promotes trophoblast invasiveness (PubMed:32329225). Has glucogenic activity: is able to increase plasma glucose levels (By similarity)","subcellular_location":"Secreted","url":"https://www.uniprot.org/uniprotkb/P35556/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/FBN2","classification":"Not Classified","n_dependent_lines":0,"n_total_lines":1208,"dependency_fraction":0.0},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/FBN2","total_profiled":1310},"omim":[{"mim_id":"621470","title":"ADAMTS-LIKE PROTEIN 5; ADAMTSL5","url":"https://www.omim.org/entry/621470"},{"mim_id":"616118","title":"MACULAR DEGENERATION, EARLY-ONSET; EOMD","url":"https://www.omim.org/entry/616118"},{"mim_id":"615582","title":"LOEYS-DIETZ SYNDROME 5; LDS5","url":"https://www.omim.org/entry/615582"},{"mim_id":"612570","title":"FIBRILLIN 2; FBN2","url":"https://www.omim.org/entry/612570"},{"mim_id":"610168","title":"LOEYS-DIETZ SYNDROME 2; LDS2","url":"https://www.omim.org/entry/610168"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Cytosol","reliability":"Approved"},{"location":"Nucleoplasm","reliability":"Additional"},{"location":"Primary cilium","reliability":"Additional"}],"tissue_specificity":"Tissue enriched","tissue_distribution":"Detected in some","driving_tissues":[{"tissue":"placenta","ntpm":63.2}],"url":"https://www.proteinatlas.org/search/FBN2"},"hgnc":{"alias_symbol":["DA9"],"prev_symbol":["CCA"]},"alphafold":{"accession":"P35556","domains":[],"viewer_url":"https://alphafold.ebi.ac.uk/entry/P35556","model_url":"https://alphafold.ebi.ac.uk/files/AF-P35556-2-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-P35556-2-F1-predicted_aligned_error_v6.png","plddt_mean":68.38},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=FBN2","jax_strain_url":"https://www.jax.org/strain/search?query=FBN2"},"sequence":{"accession":"P35556","fasta_url":"https://rest.uniprot.org/uniprotkb/P35556.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/P35556/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/P35556"}},"corpus_meta":[{"pmid":"29360137","id":"PMC_29360137","title":"cHCC-CCA: Consensus terminology for primary liver carcinomas with both hepatocytic and cholangiocytic 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Analysis of FBN2 transcript levels in dermal fibroblasts showed the mutated allele is expressed at higher levels than the wild-type allele, indicating allele-specific expression differences.\",\n      \"method\": \"RT-PCR analysis of FBN2 cDNA from dermal fibroblasts; genomic sequencing; transcript level analysis\",\n      \"journal\": \"American journal of human genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct transcript analysis from patient fibroblasts with multiple molecular methods, single lab\",\n      \"pmids\": [\"9106527\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1998,\n      \"finding\": \"All identified FBN2 mutations in CCA patients cluster in a limited region encoded by exons 24–34, corresponding to the region in FBN1 where neonatal Marfan syndrome mutations cluster, indicating this central domain plays a critical role in human embryogenesis.\",\n      \"method\": \"FBN2 mRNA screening from patient cell strains; mutation identification and mapping\",\n      \"journal\": \"American journal of medical genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — systematic mutation screening across multiple unrelated patients establishing genotype-phenotype clustering, single lab\",\n      \"pmids\": [\"9714438\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"Ten novel FBN2 mutations in CCA patients cluster in exons 23–34 with a 75% detection rate in this limited region. Unlike FBN1 mutations in Marfan syndrome, identified FBN2 mutations do not alter calcium-binding consensus sequences in EGF-like domains, suggesting distinct pathomechanisms for the two fibrillins.\",\n      \"method\": \"SSCP analysis and direct sequencing of exons 22–36 of FBN2 in 13 CCA patients; clinical correlation\",\n      \"journal\": \"Human mutation\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — systematic mutation screening with molecular characterization and clinical correlation, single lab\",\n      \"pmids\": [\"11754102\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"FBN2 expression is silenced by aberrant promoter methylation in non-small cell lung cancer (NSCLC) cell lines; treatment with the demethylating agent 5-aza-2'-deoxycytidine restored FBN2 expression, establishing promoter methylation as a mechanism of FBN2 silencing in cancer.\",\n      \"method\": \"RT-PCR for expression analysis; methylation-specific PCR; 5-aza-2'-deoxycytidine demethylation treatment\",\n      \"journal\": \"Lung cancer (Amsterdam, Netherlands)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct demonstration of methylation-expression correlation with pharmacological reversal, single lab\",\n      \"pmids\": [\"15951052\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Fbn2-null mice exhibit anterior segment dysgenesis including high incidence of iris coloboma and zonular fiber disorganization; fibrillin-2-rich microfibrils are prominent in the pupillary membrane during development, and loss of Fbn2 causes failed pupillary membrane regression, implicating fibrillin-2 in optic fissure closure and lens fiber cell differentiation.\",\n      \"method\": \"Confocal microscopy with antibodies against microfibril components in Fbn2(-/-) mice; phenotypic characterization of knockout ocular morphology\",\n      \"journal\": \"Investigative ophthalmology & visual science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct localization and loss-of-function phenotype in knockout mice with specific mechanistic readouts, single lab\",\n      \"pmids\": [\"24130178\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"FBN2 localizes to Bruch's membrane in the eye; its expression is reduced in aging and AMD eyes. Rare FBN2 variants segregate with autosomal dominant maculopathy, and a common non-synonymous variant (rs154001, p.Val965Ile) is associated with AMD, establishing FBN2 as a component of Bruch's membrane important for blood-retina homeostasis.\",\n      \"method\": \"Whole exome sequencing in maculopathy family; Sanger sequencing validation; immunolocalization to Bruch's membrane; large-scale association study (10,337 cases/11,174 controls)\",\n      \"journal\": \"Human molecular genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct protein localization combined with genetic segregation and large association study, single lab primary discovery\",\n      \"pmids\": [\"24899048\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Fbn2 null mice are born with reduced muscle mass, abnormal muscle histology, and activated BMP signaling in skeletal muscle. Genetic rescue by deleting a single allele of Bmp7 restored muscle mass and reduced white fat accumulation, demonstrating that fibrillin-2 sequesters BMP complexes (including BMP7) in a latent state in the extracellular matrix and that loss of fibrillin-2 causes abnormally activated BMP signaling leading to myopathy.\",\n      \"method\": \"Fbn2 null mouse analysis; creatine kinase measurement; in vivo and in vitro BMP signaling assays; genetic epistasis (Fbn2 null × Bmp7 heterozygous rescue); histology and immunofluorescence\",\n      \"journal\": \"PLoS genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic epistasis rescue experiment combined with multiple in vivo and in vitro assays demonstrating BMP sequestration mechanism, multiple orthogonal methods\",\n      \"pmids\": [\"26114882\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"Rare variants in FBN2 (and FBN1) are enriched in severely affected adolescent idiopathic scoliosis (AIS) cases compared to controls, with upregulation of the TGF-beta pathway observed in cases with fibrillin variants, expanding the functional role of FBN2 to include regulation of TGF-beta signaling in spinal development.\",\n      \"method\": \"Exome sequencing; burden analysis in 852 AIS cases and 669 controls; replication in independent Han Chinese cohort; clinical evaluation with pathway analysis\",\n      \"journal\": \"Human molecular genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — rare variant burden analysis replicated in independent cohort with pathway analysis, but pathway upregulation is observational rather than direct mechanistic demonstration\",\n      \"pmids\": [\"24833718\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"5q23 deletions encompassing FBN2 (and PHAX) cause a syndromic form of Pierre Robin sequence with associated digital contractures and crumpled ear helices; haploinsufficiency for FBN2 accounts specifically for the digital and auricular features of this syndrome.\",\n      \"method\": \"Clinical array-based comparative genome hybridization (aCGH) defining minimum deletion region; expression analysis of orthologous genes in embryonic mice; sequencing of candidate genes\",\n      \"journal\": \"European journal of medical genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — minimal deletion mapping and expression analysis supporting FBN2 haploinsufficiency as mechanism for specific phenotypic features, multiple deletions analyzed\",\n      \"pmids\": [\"25195018\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"Fibrillin-2 (FBN2) is a large extracellular matrix glycoprotein that polymerizes into microfibrils and functions to sequester BMP growth factor complexes (including BMP7) in a latent state; loss of fibrillin-2 causes abnormally activated BMP signaling leading to myopathy, and FBN2 mutations clustering in the central EGF-like domain region (exons 24–34) cause congenital contractural arachnodactyly by disrupting microfibril structure, while FBN2 also localizes to Bruch's membrane and ocular microfibrils where it is required for anterior segment morphogenesis and optic fissure closure.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"Fibrillin-2 (FBN2) is a large extracellular matrix glycoprotein that polymerizes into microfibrils and acts as a structural and growth-factor-regulatory scaffold required for normal musculoskeletal, ocular, and craniofacial development [#0, #7]. Beyond its structural role, fibrillin-2 sequesters BMP growth factor complexes—including BMP7—in a latent state within the matrix; loss of fibrillin-2 in mice releases this restraint, producing abnormally activated BMP signaling, reduced muscle mass, and myopathy that is genetically rescued by lowering Bmp7 gene dosage [#7]. Fibrillin variants are also accompanied by upregulated TGF-beta signaling in scoliosis cases, extending its role as a regulator of matrix-sequestered growth factors [#8]. Cysteine-substituting missense mutations and splicing errors in FBN2 that disrupt EGF-like domains cause congenital contractural arachnodactyly, with pathogenic mutations clustering tightly in a central domain encoded by exons 23–34 [#0, #1, #3]. Fibrillin-2-rich microfibrils localize to the developing pupillary membrane and to Bruch's membrane, where fibrillin-2 is required for optic fissure closure, anterior segment morphogenesis, and retinal homeostasis, and FBN2 variants are associated with maculopathy [#5, #6]. Haploinsufficiency for FBN2 also contributes to a syndromic form of Pierre Robin sequence with digital contractures and crumpled ear helices [#9].\",\n  \"teleology\": [\n    {\n      \"year\": 1995,\n      \"claim\": \"Establishing that FBN2 mutations cause a heritable connective tissue disorder defined fibrillin-2 as a structural microfibril component required for musculoskeletal development.\",\n      \"evidence\": \"Direct sequencing identifying cysteine-substituting missense mutations in EGF-like domains in congenital contractural arachnodactyly patients\",\n      \"pmids\": [\"7493032\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not define how individual mutations disrupt microfibril assembly at the molecular level\", \"Did not address fibrillin-2 function outside the musculoskeletal system\"]\n    },\n    {\n      \"year\": 1997,\n      \"claim\": \"Splicing-error mutations deleting a calcium-binding EGF-like domain extended the mutational spectrum and revealed allele-specific expression differences in patient fibroblasts.\",\n      \"evidence\": \"RT-PCR and genomic sequencing of FBN2 transcripts from CCA patient dermal fibroblasts\",\n      \"pmids\": [\"9106527\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Functional consequence of the allele-specific expression imbalance not established\", \"No protein-level assay of the mutant fibrillin-2\"]\n    },\n    {\n      \"year\": 1998,\n      \"claim\": \"Mapping CCA mutations to a limited central region clarified that one specific domain block is critical for fibrillin-2 function in embryogenesis.\",\n      \"evidence\": \"FBN2 mRNA screening and mutation mapping across multiple unrelated CCA patient cell strains\",\n      \"pmids\": [\"9714438\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Why this central region is uniquely mutation-sensitive was not mechanistically resolved\", \"Did not test domain function biochemically\"]\n    },\n    {\n      \"year\": 2002,\n      \"claim\": \"Systematic screening confirmed mutation clustering in exons 23–34 and distinguished FBN2 pathomechanism from FBN1 by showing mutations spare calcium-binding consensus sequences.\",\n      \"evidence\": \"SSCP and direct sequencing of exons 22–36 in 13 CCA patients with clinical correlation\",\n      \"pmids\": [\"11754102\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"The distinct pathomechanism implied by sparing of calcium-binding sequences not directly demonstrated\", \"No structural model of mutant microfibrils\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Discovery of promoter methylation silencing of FBN2 implicated the gene as a methylation target in cancer, beyond its developmental role.\",\n      \"evidence\": \"Methylation-specific PCR and RT-PCR with pharmacological demethylation (5-aza-2'-deoxycytidine) in NSCLC cell lines\",\n      \"pmids\": [\"15951052\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Functional consequence of FBN2 loss for tumor biology not established\", \"No in vivo confirmation\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Knockout phenotyping revealed a previously unknown ocular developmental role, placing fibrillin-2 microfibrils in optic fissure closure and pupillary membrane regression.\",\n      \"evidence\": \"Confocal immunolocalization and phenotypic characterization of Fbn2-null mouse eyes\",\n      \"pmids\": [\"24130178\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Molecular signaling pathway linking fibrillin-2 loss to coloboma not defined\", \"Single-lab knockout characterization\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Localization to Bruch's membrane combined with genetic association linked fibrillin-2 to retinal homeostasis and maculopathy.\",\n      \"evidence\": \"Exome sequencing in a maculopathy family, immunolocalization to Bruch's membrane, and a large case-control association study\",\n      \"pmids\": [\"24899048\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Causal mechanism by which FBN2 variants impair blood-retina homeostasis not demonstrated\", \"Common-variant association is statistical, not mechanistic\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Rare-variant burden testing implicated FBN2 in scoliosis and connected fibrillin variants to TGF-beta pathway dysregulation.\",\n      \"evidence\": \"Exome sequencing and burden analysis in 852 AIS cases vs 669 controls with replication and pathway analysis\",\n      \"pmids\": [\"24833718\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"TGF-beta upregulation is observational, not a direct mechanistic demonstration of fibrillin-2 control\", \"Individual variant causality not established\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Deletion mapping attributed specific digital and auricular features of a Pierre Robin syndrome to FBN2 haploinsufficiency, distinguishing dosage from missense pathology.\",\n      \"evidence\": \"Array CGH minimal-region mapping with embryonic mouse expression analysis of orthologous genes\",\n      \"pmids\": [\"25195018\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct functional proof of haploinsufficiency for these features not provided\", \"Contribution of co-deleted genes not fully excluded\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Genetic epistasis defined the core mechanism: fibrillin-2 sequesters latent BMP complexes, so its loss derepresses BMP signaling and causes myopathy.\",\n      \"evidence\": \"Fbn2-null mouse analysis with BMP signaling assays and Bmp7-heterozygous genetic rescue restoring muscle mass\",\n      \"pmids\": [\"26114882\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct binding interface between fibrillin-2 microfibrils and BMP7 complexes not structurally mapped\", \"Whether the same mechanism operates in human CCA muscle not shown\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How specific exon 23–34 mutations and structural disruption of microfibrils mechanistically translate into impaired BMP/TGF-beta sequestration across muscle, eye, and skeleton remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No structural model linking mutant fibrillin-2 to growth-factor release\", \"Tissue-specific contributions of BMP vs TGF-beta dysregulation not disentangled\", \"Human disease mechanism not directly tied to the mouse BMP-sequestration model\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0005198\", \"supporting_discovery_ids\": [0, 7]},\n      {\"term_id\": \"GO:0140313\", \"supporting_discovery_ids\": [7]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0031012\", \"supporting_discovery_ids\": [0, 5, 6]},\n      {\"term_id\": \"GO:0005576\", \"supporting_discovery_ids\": [6, 7]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1474244\", \"supporting_discovery_ids\": [0, 7]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [7, 8]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [5, 9]}\n    ],\n    \"complexes\": [\"microfibril\"],\n    \"partners\": [\"BMP7\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":6,"faith_total":6,"faith_pct":100.0}}