{"gene":"FBN2","run_date":"2026-04-28T17:46:03","timeline":{"discoveries":[{"year":1995,"finding":"Missense mutations in FBN2 that substitute cysteine residues in EGF-like (epidermal growth-factor-like) repeats cause congenital contractural arachnodactyly (CCA), establishing that fibrillin-2 is a structural component of extracellular matrix microfibrils and that its EGF-like domains are critical for function.","method":"Identification of FBN2 missense mutations in CCA patients by sequencing; functional inference from domain architecture","journal":"Nature genetics","confidence":"High","confidence_rationale":"Tier 2 — direct mutation identification in patients linked to structural domain, replicated across multiple subsequent studies","pmids":["7493032"],"is_preprint":false},{"year":1998,"finding":"CCA-causing FBN2 mutations cluster specifically in the region encoded by exons 24–34, mirroring the neonatal severe-MFS mutation cluster in FBN1, indicating this central fibrillin-2 domain plays a critical role in human embryogenesis and musculoskeletal development.","method":"RT-PCR mutation screening of FBN2 mRNA from CCA patient cell lines; genotype-phenotype correlation","journal":"American journal of medical genetics","confidence":"Medium","confidence_rationale":"Tier 2 — systematic mutation mapping across multiple patient lines, consistent with mechanistic domain assignment","pmids":["9714438"],"is_preprint":false},{"year":2002,"finding":"Ten novel FBN2 mutations causing CCA cluster between exons 23 and 34, and notably none alter the calcium-binding consensus sequence in EGF-like domains (in contrast to FBN1 mutations), indicating distinct mechanisms of fibrillin-1 vs fibrillin-2 pathogenesis and revealing that the calcium-binding EGF module is not the primary functional target in fibrillin-2.","method":"SSCP analysis and direct sequencing of exons 22–36 of FBN2 in CCA patients; genotype-phenotype analysis","journal":"Human mutation","confidence":"Medium","confidence_rationale":"Tier 2 — systematic mutation mapping with functional domain inference, single study","pmids":["11754102"],"is_preprint":false},{"year":2013,"finding":"Fibrillin-2 is the dominant fibrillin isoform expressed during mouse eye development; Fbn2-null mice display anterior segment dysgenesis including iris coloboma, ciliary body hypoplasia, and disorganized zonular fibers, demonstrating an indispensable role for fibrillin-2 in ocular morphogenesis and optic fissure closure. Loss of Fbn2 is partially compensated by increased fibrillin-1 expression, but resulting microfibrils are disorganized.","method":"Confocal microscopy with antibodies against microfibril components in Fbn2−/− mice; histological analysis","journal":"Investigative ophthalmology & visual science","confidence":"High","confidence_rationale":"Tier 2 — clean KO with defined ocular phenotype and mechanistic insight into compensation by FBN1, direct imaging","pmids":["24130178"],"is_preprint":false},{"year":2015,"finding":"Loss of fibrillin-2 in Fbn2 null mice causes reduced muscle mass, abnormal muscle histology, and abnormally activated BMP signaling in skeletal muscle; genetic rescue by deletion of a single Bmp7 allele rescues reduced muscle mass and white fat accumulation, demonstrating that fibrillin-2 sequesters BMP complexes in a latent state in the extracellular matrix to regulate BMP signaling during postnatal muscle development.","method":"Fbn2 null mouse phenotyping (creatine kinase assays, histology, myosin isoform analysis); genetic epistasis by Bmp7 heterozygous deletion; in vitro BMP signaling assays","journal":"PLoS genetics","confidence":"High","confidence_rationale":"Tier 1–2 — genetic epistasis rescue combined with in vivo and in vitro evidence; multiple orthogonal methods in single study","pmids":["26114882"],"is_preprint":false},{"year":2014,"finding":"FBN2 localizes to Bruch's membrane in the human eye, and its expression is reduced in aging and AMD eyes; rare variants in FBN2 (including p.Glu1144Lys) segregate with autosomal dominant maculopathy, implicating fibrillin-2 in maintenance of blood-retina homeostasis through the elastin microfibril ECM of Bruch's membrane.","method":"Whole exome sequencing and Sanger validation in family; immunolocalization of FBN2 in human eye sections; genetic association in 10,337 AMD cases and 11,174 controls","journal":"Human molecular genetics","confidence":"Medium","confidence_rationale":"Tier 2–3 — direct immunolocalization data combined with segregation analysis; functional mechanism inferred from localization","pmids":["24899048"],"is_preprint":false},{"year":2014,"finding":"Rare variants in FBN2 are enriched in severely affected adolescent idiopathic scoliosis (AIS) cases and are associated with upregulation of the TGF-β pathway, extending the biological role of fibrillin-2 to spinal curvature regulation through TGF-β signaling control.","method":"Exome sequencing and sequencing of FBN2 in 852 AIS cases and 669 controls; TGF-β pathway activation analysis; replication in Han Chinese cohort","journal":"Human molecular genetics","confidence":"Medium","confidence_rationale":"Tier 2 — rare variant burden analysis with pathway activation data and independent replication","pmids":["24833718"],"is_preprint":false},{"year":2005,"finding":"FBN2 promoter methylation leads to silencing of FBN2 expression in non-small cell lung cancer cells; treatment with the demethylating agent 5-aza-2'-deoxycytidine restores FBN2 expression, establishing that FBN2 is epigenetically silenced by DNA methylation in NSCLC.","method":"RT-PCR, methylation-specific PCR, and 5-aza-2'-deoxycytidine demethylation treatment of NSCLC cell lines and primary tumors","journal":"Lung cancer (Amsterdam, Netherlands)","confidence":"Medium","confidence_rationale":"Tier 2 — direct experimental link between methylation and gene silencing with pharmacological rescue","pmids":["15951052"],"is_preprint":false},{"year":2014,"finding":"Haploinsufficiency for FBN2 in 5q23 deletions accounts for the digital (finger contractures) and auricular features (crumpled ear helices) in a syndromic form of Pierre Robin sequence, establishing a developmental role for fibrillin-2 in digit and ear morphogenesis.","method":"Clinical array-based comparative genome hybridisation (aCGH) in patients with 5q22–5q31 deletions; expression analysis of orthologous genes in embryonic mice","journal":"European journal of medical genetics","confidence":"Medium","confidence_rationale":"Tier 2 — deletion mapping with expression analysis linking FBN2 haploinsufficiency to specific phenotypic features","pmids":["25195018"],"is_preprint":false}],"current_model":"Fibrillin-2 (FBN2) is a large extracellular matrix glycoprotein that polymerizes into microfibrils and acts as a structural scaffold that sequesters BMP ligands (including BMP7) in a latent state to regulate BMP signaling during musculoskeletal development; mutations in its central EGF-like domain region (exons 23–34) cause congenital contractural arachnodactyly, loss of FBN2 leads to abnormally activated BMP signaling, myopathy, and ocular dysgenesis in mice, and epigenetic silencing of FBN2 via promoter methylation occurs in multiple human cancers."},"narrative":{"teleology":[{"year":1995,"claim":"Identifying FBN2 as the disease gene for congenital contractural arachnodactyly established that fibrillin-2 is a functional component of extracellular microfibrils whose EGF-like domains are essential for musculoskeletal development.","evidence":"Sequencing of FBN2 in CCA patients identified cysteine-disrupting missense mutations in EGF-like repeats","pmids":["7493032"],"confidence":"High","gaps":["No biochemical demonstration of how cysteine substitutions disrupt microfibril assembly","Signaling consequences of FBN2 mutations were unknown","Functional redundancy with FBN1 not addressed"]},{"year":2002,"claim":"Systematic mutation mapping revealed that CCA mutations cluster in exons 23–34 and, unlike FBN1 mutations, do not target calcium-binding consensus sequences, indicating distinct pathogenic mechanisms for the two fibrillins.","evidence":"SSCP analysis and direct sequencing of exons 22–36 in CCA patients across two studies identified a concentrated mutation hotspot","pmids":["9714438","11754102"],"confidence":"Medium","gaps":["No structural or biophysical explanation for why non-calcium-binding residues are preferentially affected","Functional significance of the exon 23–34 region beyond genotype–phenotype correlation not tested"]},{"year":2005,"claim":"Demonstrating promoter methylation-mediated silencing of FBN2 in lung cancer revealed that loss of this ECM component is an epigenetically regulated event in tumorigenesis, extending FBN2's relevance beyond connective tissue disorders.","evidence":"Methylation-specific PCR and 5-aza-2'-deoxycytidine rescue of FBN2 expression in NSCLC cell lines and primary tumors","pmids":["15951052"],"confidence":"Medium","gaps":["Whether restored FBN2 expression suppresses tumor growth was not tested","Mechanism by which FBN2 silencing promotes tumorigenesis unknown"]},{"year":2013,"claim":"Analysis of Fbn2-null mice demonstrated that fibrillin-2 is the dominant fibrillin during eye development and is indispensable for optic fissure closure and zonular fiber organization, with only partial compensation by upregulated fibrillin-1.","evidence":"Confocal immunofluorescence and histology of Fbn2−/− mouse eyes showing iris coloboma, ciliary body hypoplasia, and disorganized microfibrils","pmids":["24130178"],"confidence":"High","gaps":["Whether BMP or TGF-β signaling is dysregulated in the Fbn2-null eye was not examined","Relevance to human ocular disease beyond CCA not established at this point"]},{"year":2014,"claim":"Multiple genetic studies extended fibrillin-2's developmental roles: FBN2 haploinsufficiency in 5q23 deletions explained digit and ear anomalies, rare FBN2 variants localized to Bruch's membrane were linked to macular degeneration, and rare FBN2 variants in scoliosis patients were associated with TGF-β pathway upregulation.","evidence":"Array CGH in deletion patients with expression analysis (digit/ear phenotype); exome sequencing with immunolocalization in human eye sections (maculopathy); exome sequencing with TGF-β pathway analysis in AIS cohorts","pmids":["25195018","24899048","24833718"],"confidence":"Medium","gaps":["Functional validation of specific FBN2 variants (e.g., p.Glu1144Lys) has not been performed","Direct measurement of TGF-β or BMP sequestration by fibrillin-2 in these tissue contexts is lacking","Mechanisms connecting FBN2 loss to scoliosis pathogenesis remain correlative"]},{"year":2015,"claim":"Genetic epistasis in Fbn2-null mice proved that fibrillin-2 sequesters BMP7 in a latent ECM complex to regulate postnatal muscle development, directly linking microfibril function to growth factor bioavailability.","evidence":"Fbn2-null mice showed reduced muscle mass with activated BMP signaling; Bmp7 heterozygous deletion rescued muscle mass and fat phenotypes; in vitro BMP signaling assays","pmids":["26114882"],"confidence":"High","gaps":["Direct biochemical interaction between fibrillin-2 and BMP7 propeptide complexes not reconstituted","Whether fibrillin-2 also sequesters other BMP family members in muscle ECM is unknown","Structural basis for fibrillin-2 preferentially sequestering BMPs versus TGF-β ligands not resolved"]},{"year":null,"claim":"The structural basis for fibrillin-2's selective sequestration of BMP versus TGF-β ligands, the molecular mechanism by which exon 23–34 mutations dominantly disrupt microfibril function, and whether FBN2 silencing functionally contributes to cancer progression remain unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No reconstituted fibrillin-2–BMP complex structure exists","Dominant-negative versus haploinsufficiency mechanisms for CCA mutations not distinguished","Tumor-suppressive role of FBN2 not functionally validated"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[4,6]},{"term_id":"GO:0005198","term_label":"structural molecule activity","supporting_discovery_ids":[0,3]}],"localization":[{"term_id":"GO:0031012","term_label":"extracellular matrix","supporting_discovery_ids":[0,3,4,5]},{"term_id":"GO:0005576","term_label":"extracellular region","supporting_discovery_ids":[0,4]}],"pathway":[{"term_id":"R-HSA-1474244","term_label":"Extracellular matrix organization","supporting_discovery_ids":[0,3,5]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[4,6]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[3,8]}],"complexes":["microfibrils"],"partners":["FBN1","BMP7"],"other_free_text":[]},"mechanistic_narrative":"Fibrillin-2 is a large extracellular matrix glycoprotein that polymerizes into microfibrils and functions as a critical scaffold for sequestering BMP and TGF-β ligands in a latent state, thereby regulating growth factor signaling during embryonic and postnatal development. In Fbn2-null mice, loss of fibrillin-2 leads to abnormally activated BMP signaling in skeletal muscle—a phenotype rescued by Bmp7 haploinsufficiency—and causes anterior segment dysgenesis in the eye including iris coloboma and disorganized zonular fibers [PMID:26114882, PMID:24130178]. Missense mutations disrupting cysteine residues within EGF-like repeats encoded by exons 23–34 of FBN2 cause congenital contractural arachnodactyly, and FBN2 haploinsufficiency contributes to digit contractures and auricular anomalies in 5q23 deletion syndromes [PMID:7493032, PMID:11754102, PMID:25195018]. Epigenetic silencing of FBN2 by promoter DNA methylation occurs in non-small cell lung cancer, where demethylation restores expression [PMID:15951052]."},"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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\"method\": \"Identification of FBN2 missense mutations in CCA patients by sequencing; functional inference from domain architecture\",\n      \"journal\": \"Nature genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — direct mutation identification in patients linked to structural domain, replicated across multiple subsequent studies\",\n      \"pmids\": [\"7493032\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1998,\n      \"finding\": \"CCA-causing FBN2 mutations cluster specifically in the region encoded by exons 24–34, mirroring the neonatal severe-MFS mutation cluster in FBN1, indicating this central fibrillin-2 domain plays a critical role in human embryogenesis and musculoskeletal development.\",\n      \"method\": \"RT-PCR mutation screening of FBN2 mRNA from CCA patient cell lines; genotype-phenotype correlation\",\n      \"journal\": \"American journal of medical genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — systematic mutation mapping across multiple patient lines, consistent with mechanistic domain assignment\",\n      \"pmids\": [\"9714438\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"Ten novel FBN2 mutations causing CCA cluster between exons 23 and 34, and notably none alter the calcium-binding consensus sequence in EGF-like domains (in contrast to FBN1 mutations), indicating distinct mechanisms of fibrillin-1 vs fibrillin-2 pathogenesis and revealing that the calcium-binding EGF module is not the primary functional target in fibrillin-2.\",\n      \"method\": \"SSCP analysis and direct sequencing of exons 22–36 of FBN2 in CCA patients; genotype-phenotype analysis\",\n      \"journal\": \"Human mutation\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — systematic mutation mapping with functional domain inference, single study\",\n      \"pmids\": [\"11754102\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Fibrillin-2 is the dominant fibrillin isoform expressed during mouse eye development; Fbn2-null mice display anterior segment dysgenesis including iris coloboma, ciliary body hypoplasia, and disorganized zonular fibers, demonstrating an indispensable role for fibrillin-2 in ocular morphogenesis and optic fissure closure. Loss of Fbn2 is partially compensated by increased fibrillin-1 expression, but resulting microfibrils are disorganized.\",\n      \"method\": \"Confocal microscopy with antibodies against microfibril components in Fbn2−/− mice; histological analysis\",\n      \"journal\": \"Investigative ophthalmology & visual science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — clean KO with defined ocular phenotype and mechanistic insight into compensation by FBN1, direct imaging\",\n      \"pmids\": [\"24130178\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Loss of fibrillin-2 in Fbn2 null mice causes reduced muscle mass, abnormal muscle histology, and abnormally activated BMP signaling in skeletal muscle; genetic rescue by deletion of a single Bmp7 allele rescues reduced muscle mass and white fat accumulation, demonstrating that fibrillin-2 sequesters BMP complexes in a latent state in the extracellular matrix to regulate BMP signaling during postnatal muscle development.\",\n      \"method\": \"Fbn2 null mouse phenotyping (creatine kinase assays, histology, myosin isoform analysis); genetic epistasis by Bmp7 heterozygous deletion; in vitro BMP signaling assays\",\n      \"journal\": \"PLoS genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — genetic epistasis rescue combined with in vivo and in vitro evidence; multiple orthogonal methods in single study\",\n      \"pmids\": [\"26114882\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"FBN2 localizes to Bruch's membrane in the human eye, and its expression is reduced in aging and AMD eyes; rare variants in FBN2 (including p.Glu1144Lys) segregate with autosomal dominant maculopathy, implicating fibrillin-2 in maintenance of blood-retina homeostasis through the elastin microfibril ECM of Bruch's membrane.\",\n      \"method\": \"Whole exome sequencing and Sanger validation in family; immunolocalization of FBN2 in human eye sections; genetic association in 10,337 AMD cases and 11,174 controls\",\n      \"journal\": \"Human molecular genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 — direct immunolocalization data combined with segregation analysis; functional mechanism inferred from localization\",\n      \"pmids\": [\"24899048\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"Rare variants in FBN2 are enriched in severely affected adolescent idiopathic scoliosis (AIS) cases and are associated with upregulation of the TGF-β pathway, extending the biological role of fibrillin-2 to spinal curvature regulation through TGF-β signaling control.\",\n      \"method\": \"Exome sequencing and sequencing of FBN2 in 852 AIS cases and 669 controls; TGF-β pathway activation analysis; replication in Han Chinese cohort\",\n      \"journal\": \"Human molecular genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — rare variant burden analysis with pathway activation data and independent replication\",\n      \"pmids\": [\"24833718\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"FBN2 promoter methylation leads to silencing of FBN2 expression in non-small cell lung cancer cells; treatment with the demethylating agent 5-aza-2'-deoxycytidine restores FBN2 expression, establishing that FBN2 is epigenetically silenced by DNA methylation in NSCLC.\",\n      \"method\": \"RT-PCR, methylation-specific PCR, and 5-aza-2'-deoxycytidine demethylation treatment of NSCLC cell lines and primary tumors\",\n      \"journal\": \"Lung cancer (Amsterdam, Netherlands)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — direct experimental link between methylation and gene silencing with pharmacological rescue\",\n      \"pmids\": [\"15951052\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"Haploinsufficiency for FBN2 in 5q23 deletions accounts for the digital (finger contractures) and auricular features (crumpled ear helices) in a syndromic form of Pierre Robin sequence, establishing a developmental role for fibrillin-2 in digit and ear morphogenesis.\",\n      \"method\": \"Clinical array-based comparative genome hybridisation (aCGH) in patients with 5q22–5q31 deletions; expression analysis of orthologous genes in embryonic mice\",\n      \"journal\": \"European journal of medical genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — deletion mapping with expression analysis linking FBN2 haploinsufficiency to specific phenotypic features\",\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 acts as a structural scaffold that sequesters BMP ligands (including BMP7) in a latent state to regulate BMP signaling during musculoskeletal development; mutations in its central EGF-like domain region (exons 23–34) cause congenital contractural arachnodactyly, loss of FBN2 leads to abnormally activated BMP signaling, myopathy, and ocular dysgenesis in mice, and epigenetic silencing of FBN2 via promoter methylation occurs in multiple human cancers.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"Fibrillin-2 is a large extracellular matrix glycoprotein that polymerizes into microfibrils and functions as a critical scaffold for sequestering BMP and TGF-β ligands in a latent state, thereby regulating growth factor signaling during embryonic and postnatal development. In Fbn2-null mice, loss of fibrillin-2 leads to abnormally activated BMP signaling in skeletal muscle—a phenotype rescued by Bmp7 haploinsufficiency—and causes anterior segment dysgenesis in the eye including iris coloboma and disorganized zonular fibers [PMID:26114882, PMID:24130178]. Missense mutations disrupting cysteine residues within EGF-like repeats encoded by exons 23–34 of FBN2 cause congenital contractural arachnodactyly, and FBN2 haploinsufficiency contributes to digit contractures and auricular anomalies in 5q23 deletion syndromes [PMID:7493032, PMID:11754102, PMID:25195018]. Epigenetic silencing of FBN2 by promoter DNA methylation occurs in non-small cell lung cancer, where demethylation restores expression [PMID:15951052].\",\n  \"teleology\": [\n    {\n      \"year\": 1995,\n      \"claim\": \"Identifying FBN2 as the disease gene for congenital contractural arachnodactyly established that fibrillin-2 is a functional component of extracellular microfibrils whose EGF-like domains are essential for musculoskeletal development.\",\n      \"evidence\": \"Sequencing of FBN2 in CCA patients identified cysteine-disrupting missense mutations in EGF-like repeats\",\n      \"pmids\": [\"7493032\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"No biochemical demonstration of how cysteine substitutions disrupt microfibril assembly\",\n        \"Signaling consequences of FBN2 mutations were unknown\",\n        \"Functional redundancy with FBN1 not addressed\"\n      ]\n    },\n    {\n      \"year\": 2002,\n      \"claim\": \"Systematic mutation mapping revealed that CCA mutations cluster in exons 23–34 and, unlike FBN1 mutations, do not target calcium-binding consensus sequences, indicating distinct pathogenic mechanisms for the two fibrillins.\",\n      \"evidence\": \"SSCP analysis and direct sequencing of exons 22–36 in CCA patients across two studies identified a concentrated mutation hotspot\",\n      \"pmids\": [\"9714438\", \"11754102\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"No structural or biophysical explanation for why non-calcium-binding residues are preferentially affected\",\n        \"Functional significance of the exon 23–34 region beyond genotype–phenotype correlation not tested\"\n      ]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Demonstrating promoter methylation-mediated silencing of FBN2 in lung cancer revealed that loss of this ECM component is an epigenetically regulated event in tumorigenesis, extending FBN2's relevance beyond connective tissue disorders.\",\n      \"evidence\": \"Methylation-specific PCR and 5-aza-2'-deoxycytidine rescue of FBN2 expression in NSCLC cell lines and primary tumors\",\n      \"pmids\": [\"15951052\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Whether restored FBN2 expression suppresses tumor growth was not tested\",\n        \"Mechanism by which FBN2 silencing promotes tumorigenesis unknown\"\n      ]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Analysis of Fbn2-null mice demonstrated that fibrillin-2 is the dominant fibrillin during eye development and is indispensable for optic fissure closure and zonular fiber organization, with only partial compensation by upregulated fibrillin-1.\",\n      \"evidence\": \"Confocal immunofluorescence and histology of Fbn2−/− mouse eyes showing iris coloboma, ciliary body hypoplasia, and disorganized microfibrils\",\n      \"pmids\": [\"24130178\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Whether BMP or TGF-β signaling is dysregulated in the Fbn2-null eye was not examined\",\n        \"Relevance to human ocular disease beyond CCA not established at this point\"\n      ]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Multiple genetic studies extended fibrillin-2's developmental roles: FBN2 haploinsufficiency in 5q23 deletions explained digit and ear anomalies, rare FBN2 variants localized to Bruch's membrane were linked to macular degeneration, and rare FBN2 variants in scoliosis patients were associated with TGF-β pathway upregulation.\",\n      \"evidence\": \"Array CGH in deletion patients with expression analysis (digit/ear phenotype); exome sequencing with immunolocalization in human eye sections (maculopathy); exome sequencing with TGF-β pathway analysis in AIS cohorts\",\n      \"pmids\": [\"25195018\", \"24899048\", \"24833718\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Functional validation of specific FBN2 variants (e.g., p.Glu1144Lys) has not been performed\",\n        \"Direct measurement of TGF-β or BMP sequestration by fibrillin-2 in these tissue contexts is lacking\",\n        \"Mechanisms connecting FBN2 loss to scoliosis pathogenesis remain correlative\"\n      ]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Genetic epistasis in Fbn2-null mice proved that fibrillin-2 sequesters BMP7 in a latent ECM complex to regulate postnatal muscle development, directly linking microfibril function to growth factor bioavailability.\",\n      \"evidence\": \"Fbn2-null mice showed reduced muscle mass with activated BMP signaling; Bmp7 heterozygous deletion rescued muscle mass and fat phenotypes; in vitro BMP signaling assays\",\n      \"pmids\": [\"26114882\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Direct biochemical interaction between fibrillin-2 and BMP7 propeptide complexes not reconstituted\",\n        \"Whether fibrillin-2 also sequesters other BMP family members in muscle ECM is unknown\",\n        \"Structural basis for fibrillin-2 preferentially sequestering BMPs versus TGF-β ligands not resolved\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The structural basis for fibrillin-2's selective sequestration of BMP versus TGF-β ligands, the molecular mechanism by which exon 23–34 mutations dominantly disrupt microfibril function, and whether FBN2 silencing functionally contributes to cancer progression remain unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"No reconstituted fibrillin-2–BMP complex structure exists\",\n        \"Dominant-negative versus haploinsufficiency mechanisms for CCA mutations not distinguished\",\n        \"Tumor-suppressive role of FBN2 not functionally validated\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [4, 6]},\n      {\"term_id\": \"GO:0005198\", \"supporting_discovery_ids\": [0, 3]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0031012\", \"supporting_discovery_ids\": [0, 3, 4, 5]},\n      {\"term_id\": \"GO:0005576\", \"supporting_discovery_ids\": [0, 4]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1474244\", \"supporting_discovery_ids\": [0, 3, 5]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [4, 6]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [3, 8]}\n    ],\n    \"complexes\": [\n      \"microfibrils\"\n    ],\n    \"partners\": [\n      \"FBN1\",\n      \"BMP7\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}