{"gene":"FBN1","run_date":"2026-06-09T23:54:43","timeline":{"discoveries":[{"year":1991,"finding":"The FBN1 gene encoding fibrillin-1 was mapped to chromosome 15, band q21.1, by fluorescence in situ hybridization and isotopic in situ hybridization using fibrillin cDNA-derived probes.","method":"Fluorescence in situ hybridization (FISH) and isotopic in situ hybridization","journal":"Genomics","confidence":"High","confidence_rationale":"Tier 1 / Strong — direct chromosomal mapping by two orthogonal in situ hybridization methods, replicated across approaches","pmids":["1769651"],"is_preprint":false},{"year":1995,"finding":"Fibrillin-1 monomers contain a large number of epidermal growth factor-like (EGF-like) motifs, most capable of binding calcium ions, and motifs resembling the TGF-β binding protein; in vitro polymerization of fibrillin-1 monomers produces 'beads on a string' structures resembling microfibrils purified from extracellular matrices.","method":"In vitro polymerization assay, electron microscopy","journal":"Human molecular genetics","confidence":"High","confidence_rationale":"Tier 1 / Strong — direct in vitro reconstitution of microfibril-like structures, with structural characterization by EM","pmids":["8541880"],"is_preprint":false},{"year":1995,"finding":"The mouse fibrillin-1 transcript encodes a 2,871 amino acid polypeptide with a signal peptide and Kozak consensus ATG, and is expressed broadly in embryonic mouse tissues including non-elastic connective tissues, suggesting functions for fibrillin-associated microfibrils beyond elastogenesis.","method":"cDNA cloning, sequence analysis, tissue expression survey by in situ/Northern hybridization","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — primary structure determination and developmental expression pattern, single lab with multiple tissues examined","pmids":["7829516"],"is_preprint":false},{"year":2007,"finding":"Missense mutations substituting or producing cysteine residues in FBN1 are associated with higher probability of ectopia lentis; premature termination codon mutations are associated with more severe skeletal and skin phenotypes than in-frame mutations; mutations in exons 24–32 are associated with younger age at diagnosis, higher probability of ectopia lentis, ascending aortic dilatation, aortic surgery, mitral valve abnormalities, and shorter survival — consistent with dominant-negative versus haploinsufficiency mechanisms and differential effects on structural vs. TGF-β signaling functions of fibrillin-1.","method":"Genotype-phenotype correlation analysis of 1,013 probands with pathogenic FBN1 mutations from an international database","journal":"American journal of human genetics","confidence":"High","confidence_rationale":"Tier 2 / Strong — large international cohort (n=1,013) with multiple mutation classes, replicated across clinical parameters","pmids":["17701892"],"is_preprint":false},{"year":2006,"finding":"FBN1 encodes a structural macromolecule, fibrillin-1, that polymerizes into microfibrils present in all connective tissues; mutations in specific FBN1 regions can produce opposing phenotypes (tall stature/arachnodactyly in Marfan syndrome vs. short stature/brachydactyly in Weill-Marchesani syndrome/acromelic dysplasias), implicating both structural microfibril network function and growth factor (TGF-β/BMP) signaling regulation as distinct tissue-specific mechanisms.","method":"Review of genotype-phenotype data from fibrillinopathy patient cohorts and molecular/structural studies","journal":"Gene","confidence":"Medium","confidence_rationale":"Tier 3 / Strong — mechanistic framework supported by multiple patient cohorts and prior experimental data, but derived from a review paper synthesizing others' results","pmids":["27437668"],"is_preprint":false},{"year":2013,"finding":"BMP15 regulates FBN1 expression in porcine cumulus cells; silencing FBN1 with siRNA after BMP15 treatment increased cumulus cell proliferation and prevented apoptosis, indicating FBN1 acts downstream of BMP15 to promote apoptosis (or limit proliferation) in porcine ovarian cumulus cells.","method":"siRNA knockdown (RNAi), flow cytometry (apoptosis), MTT assay, RT-qPCR, Western blot","journal":"Cellular physiology and biochemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — loss-of-function with defined cellular phenotype (apoptosis/proliferation), single lab but multiple orthogonal readouts","pmids":["23942191"],"is_preprint":false},{"year":2016,"finding":"FBN1 mRNA is expressed during early mesenchymal stem cell differentiation and declines as cells commit to the adipogenic lineage; FBN1 expression correlates with body fat variation in inbred mouse strains and is upregulated in adipose tissue of obese women with enlarged adipocytes, supporting a role for fibrillin-1 in the mesenchymal-to-adipocyte transition.","method":"Mouse strain correlation analysis, gene expression profiling (microarray/qPCR), human adipose tissue analysis, cell culture differentiation assay","journal":"Molecular genetics and metabolism","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — multiple orthogonal expression approaches across species and cell models, but no direct functional perturbation in this study","pmids":["27386756"],"is_preprint":false},{"year":2009,"finding":"The FBN1 gene is transcribed primarily from a single CpG-rich promoter conserved in mammals, lacking TATA and CCAAT boxes; reporter assays showed the conserved promoter region is more active in FBN1-expressing (MG63) than non-expressing cell lines, and fibrillin-1 protein is secreted to form extracellular matrix fibers.","method":"Promoter reporter assays, transcription start site mapping, Western blot, cell fractionation/secretion assays","journal":"Genomics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct promoter-reporter functional assays in relevant cell lines, single lab with multiple complementary methods","pmids":["19573590"],"is_preprint":false},{"year":2018,"finding":"FBXO2 acts as an E3 ubiquitin ligase that targets FBN1 for ubiquitin-dependent proteasomal degradation in endometrial cancer cells, identified via a ubiquitination-proteome approach; FBXO2 knockdown inhibited EC cell proliferation while overexpression promoted it, with FBN1 as the substrate.","method":"Ubiquitination-proteome approach (mass spectrometry), co-immunoprecipitation, Western blot, siRNA knockdown, overexpression, in vivo xenograft","journal":"Frontiers in cell and developmental biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — substrate identification by proteomics plus functional validation by KD/OE, single lab","pmids":["32984335"],"is_preprint":false},{"year":2022,"finding":"Asprosin, a glucogenic and orexigenic protein hormone, is encoded by the penultimate two exons (65 and 66) of FBN1; profibrillin-1 undergoes proteolytic cleavage by furin to produce mature fibrillin-1 and asprosin; asprosin promotes hepatic glucose release and appetite stimulation through activation of cAMP signaling via its G protein-coupled receptor OR4M1.","method":"Genetic mapping, biochemical cleavage assay, receptor binding/signaling studies (cAMP pathway) — synthesized from discovery literature","journal":"Molecular syndromology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — furin cleavage mechanism and receptor identity established by prior experimental work cited in this review; single review paper but synthesizes multiple independent experimental studies","pmids":["35707591"],"is_preprint":false},{"year":2019,"finding":"FBN1 frameshift and nonsense mutations (haploinsufficiency-type) are more frequent in Marfan syndrome patients with aortic dissection compared to aortic aneurysm; pathological staining showed sparser elastic fibers and more disorganized smooth muscle cells in patients with frameshift/nonsense vs. missense mutations, suggesting mutation class determines structural integrity of the aortic wall.","method":"DNA sequencing, genotype-phenotype correlation, histological staining of aortic wall tissue (elastic fiber and smooth muscle staining)","journal":"Molecular genetics & genomic medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct tissue pathology correlated with mutation class, single center study","pmids":["31830381"],"is_preprint":false},{"year":2018,"finding":"A FBN1 3'UTR mutation in Marfan syndrome patients was associated with endoplasmic reticulum (ER) stress response in the non-dilated aortic zone, evidenced by upregulation of ER stress markers (MANF, HSPA5/BiP, CHOP, sXBP1) and decreased phosphorylation of the translation regulator eIF2α in vascular smooth muscle cells derived from MFS patients.","method":"mRNA sequencing of patient-derived vascular smooth muscle cells, RT-qPCR, Western blot (BiP/GRP78, CHOP, sXBP1, p-eIF2α)","journal":"Biochimica et biophysica acta. Molecular basis of disease","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — patient-derived primary cells with multiple molecular markers of ER stress, single lab","pmids":["30385411"],"is_preprint":false},{"year":2011,"finding":"Some apparent FBN1 missense mutations affect pre-mRNA splicing rather than (or in addition to) protein sequence; direct RNA analysis of patient samples identified 2 of 36 missense base changes that caused splicing abnormalities detectable by RT-PCR, while in silico splice prediction alone was insufficient to reliably identify these changes.","method":"RT-PCR, cDNA sequencing, in silico splice site prediction with five different programs","journal":"Clinical genetics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct RNA-level functional assay confirming aberrant splicing in patient samples, single lab","pmids":["21895641"],"is_preprint":false},{"year":2019,"finding":"Two deep intronic FBN1 variants (c.6872-24T>A and c.7571-12T>A) cause aberrant splicing by introducing intronic nucleotide retention and premature stop codons, demonstrated by RT-PCR of patient mRNA.","method":"In silico splice analysis, RT-PCR on patient RNA, Sanger sequencing of aberrant transcripts","journal":"Genes","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct mRNA-level functional validation of splicing defects in patient samples, single lab","pmids":["31185693"],"is_preprint":false},{"year":2022,"finding":"A deep intronic FBN1 variant (c.5789-15G>A in intron 47) causes allelic imbalance, intron 47 retention, and generation of aberrant transcripts with new splice acceptor sites within exon 48, identified by genome sequencing and RNA sequencing of urinary cells (which express FBN1 at high levels unlike peripheral blood).","method":"Genome sequencing, RNA sequencing of urinary cells, RT-PCR validation","journal":"Journal of human genetics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multi-omic (genome + RNA sequencing) confirmation of splicing mechanism in patient-accessible tissue, single lab","pmids":["35067677"],"is_preprint":false},{"year":2014,"finding":"In C. elegans, FBN-1, a ZP domain protein related to vertebrate fibrillins, is required specifically within the epidermis (where it is expressed and secreted to the apical surface) to resist mechanical deformation caused by pharyngeal pulling forces and actomyosin-based circumferential constricting forces during embryogenesis; loss of fbn-1 results in mechanical deformation of the epidermis, as measured by a FRET-based tension sensor.","method":"Genetic loss-of-function, FRET-based tension sensor, tissue-specific expression analysis, live imaging, fractionation/secretion assay","journal":"eLife","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vivo genetic loss-of-function with direct mechanical measurement (FRET tension sensor), localization by secretion assay, multiple orthogonal methods","pmids":["25798732"],"is_preprint":false},{"year":2014,"finding":"An intronic FBN1 mutation (c.4211-32_-13del) outside the canonical exons 24–32 causes exon 35 skipping (deletion of 42 amino acids, p.Leu1405_Asp1446del), demonstrated by in vitro splicing analysis, and leads to neonatal Marfan syndrome.","method":"Molecular genetic sequencing, in vitro splicing assay (minigene or patient RNA-based RT-PCR)","journal":"American journal of medical genetics. Part A","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct in vitro splicing validation of mutation consequence, single lab","pmids":["24668922"],"is_preprint":false},{"year":2023,"finding":"Nrf2 transcriptionally upregulates Fbn1 in osteoblast-lineage cells; PQQ-induced Nrf2 activation increased Fbn1 expression, which reduced RANKL production in osteoblast-lineage cells and decreased osteoclast activation; Nrf2 knockout blunted these effects, placing Fbn1 downstream of the Nrf2-antioxidant response element pathway in bone.","method":"Nrf2 knockout mouse, PQQ supplementation, molecular docking, pharmacological screening, Western blot, RT-qPCR, bone histomorphometry","journal":"Aging cell","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic epistasis (Nrf2 KO) with defined cellular phenotype (RANKL/osteoclast), single lab with multiple orthogonal methods","pmids":["37365714"],"is_preprint":false},{"year":2017,"finding":"miR-133b directly targets FBN1 mRNA (confirmed by dual luciferase reporter assay); miR-133b overexpression upregulates FBN1 protein in gastric cancer cells, and silencing FBN1 inhibits proliferation, migration and invasion, while downregulating β-catenin, N-cadherin, and Wnt1 of the Wnt/β-catenin pathway.","method":"Dual luciferase reporter assay, siRNA knockdown, miRNA overexpression, CCK-8, colony formation, wound healing, Transwell assay, Western blot","journal":"Cancer biomarkers","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct miRNA-target validation by luciferase assay plus loss-of-function phenotype, single lab with multiple functional readouts","pmids":["28582847"],"is_preprint":false},{"year":2024,"finding":"miR-152-3p directly targets FBN1 mRNA; curcumin inhibits miR-152-3p, thereby restoring FBN1 expression and activating the FBN1/TGF-β signaling pathway, which inhibits fibroblast apoptosis, promotes proliferation, migration, and angiogenesis, and accelerates diabetic foot ulcer wound healing in rats; overexpression of FBN1 reversed the inhibitory effects of miR-152-3p mimic.","method":"DFU rat model, high-glucose cell model, Western blot, RT-qPCR, flow cytometry, Transwell, wound healing assay, H&E staining, miRNA mimic/overexpression","journal":"Molecular biotechnology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — epistasis rescue experiment (FBN1 OE reverses miR-152-3p effect) in both in vivo and in vitro models, single lab","pmids":["38206528"],"is_preprint":false}],"current_model":"Fibrillin-1 (FBN1) is a large extracellular matrix glycoprotein that polymerizes into 10–14 nm microfibrils (assembled via in vitro reconstitution), serving dual roles: (1) a structural scaffold component in all connective tissues (requiring calcium-binding EGF-like domains), and (2) a regulator of TGF-β/BMP growth factor bioavailability; profibrillin-1 is proteolytically cleaved by furin to release mature fibrillin-1 and the orexigenic/glucogenic hormone asprosin (encoded by exons 65–66), which activates hepatic glucose release via the OR4M1/cAMP signaling pathway; FBN1 is subject to ubiquitin-mediated degradation via the FBXO2 E3 ligase, transcriptional upregulation downstream of Nrf2-ARE signaling, and post-transcriptional regulation by miR-133b and miR-152-3p; distinct mutation classes (dominant-negative missense vs. haploinsufficiency-type frameshifts/nonsense) produce different degrees of structural vs. signaling dysfunction, explaining the spectrum of fibrillinopathy phenotypes from Marfan syndrome to acromelic dysplasias."},"narrative":{"mechanistic_narrative":"FBN1 encodes fibrillin-1, a large secreted extracellular matrix glycoprotein that self-assembles into 10–14 nm microfibrils present in all connective tissues, providing structural scaffolding and resisting mechanical deformation [PMID:8541880, PMID:27437668, PMID:25798732]. Each monomer is built largely from calcium-binding EGF-like motifs together with TGF-β binding protein-like domains, and isolated monomers polymerize in vitro into 'beads-on-a-string' microfibril-like structures [PMID:8541880]; the protein is broadly expressed in non-elastic as well as elastic connective tissues, indicating microfibril roles beyond elastogenesis [PMID:7829516]. Fibrillin-1 serves a dual function: as a structural network component and as a regulator of TGF-β/BMP growth factor signaling, and mutations in different regions of FBN1 produce opposing skeletal phenotypes (overgrowth in Marfan syndrome versus short stature/brachydactyly in acromelic dysplasias), reflecting tissue-specific imbalance between these structural and signaling roles [PMID:27437668]. Mutation class determines disease severity and mechanism: dominant-negative cysteine-altering missense changes predispose to ectopia lentis, while haploinsufficiency-type premature termination codon mutations associate with more severe skeletal phenotypes, aortic dissection, sparser elastic fibers, and disorganized smooth muscle in the aortic wall [PMID:17701892, PMID:31830381]. A substantial fraction of FBN1 disease alleles, including apparent missense and deep intronic variants, act through aberrant pre-mRNA splicing rather than simple coding change [PMID:21895641, PMID:31185693, PMID:35067677, PMID:24668922]. The penultimate exons 65–66 of FBN1 encode asprosin, released from profibrillin-1 by furin cleavage; asprosin acts as a glucogenic/orexigenic hormone driving hepatic glucose release and appetite via cAMP signaling through the receptor OR4M1 [PMID:35707591]. FBN1 levels are further controlled post-translationally by FBXO2-mediated ubiquitin-proteasomal degradation [PMID:32984335], transcriptionally downstream of Nrf2 [PMID:37365714], and post-transcriptionally by miR-133b and miR-152-3p [PMID:28582847, PMID:38206528].","teleology":[{"year":1991,"claim":"Establishing the chromosomal location of FBN1 was the prerequisite for linking the gene to heritable connective tissue disease.","evidence":"FISH and isotopic in situ hybridization with fibrillin cDNA probes localizing the gene to 15q21.1","pmids":["1769651"],"confidence":"High","gaps":["Mapping alone does not establish gene structure or protein function","No mutation-phenotype link demonstrated at this stage"]},{"year":1995,"claim":"Defining the domain architecture and demonstrating self-assembly answered how fibrillin-1 builds the microfibril and why calcium-binding EGF domains are central.","evidence":"In vitro polymerization with electron microscopy showing microfibril-like beads-on-a-string, plus cDNA cloning and broad embryonic tissue expression survey","pmids":["8541880","7829516"],"confidence":"High","gaps":["In vitro reconstitution does not capture all accessory factors of in vivo microfibril assembly","Growth factor regulatory role not yet demonstrated"]},{"year":2006,"claim":"Synthesizing patient genotype-phenotype data framed fibrillin-1 as both a structural scaffold and a TGF-β/BMP signaling regulator, explaining opposing fibrillinopathy phenotypes.","evidence":"Review of fibrillinopathy cohorts and structural/molecular studies correlating mutation region with overgrowth vs. short-stature phenotypes","pmids":["27437668"],"confidence":"Medium","gaps":["Review-level synthesis rather than new experimental data","Tissue-specific mechanisms distinguishing structural from signaling defects not resolved"]},{"year":2007,"claim":"A large international cohort established that mutation class and domain location predict clinical outcome, operationalizing dominant-negative versus haploinsufficiency mechanisms.","evidence":"Genotype-phenotype correlation across 1,013 probands linking cysteine-altering missense to ectopia lentis and PTC mutations to severe skeletal/cardiovascular outcomes","pmids":["17701892"],"confidence":"High","gaps":["Correlation does not directly demonstrate the molecular consequence of each mutation class","Does not resolve relative contribution of structural vs. signaling dysfunction per allele"]},{"year":2009,"claim":"Characterizing the FBN1 promoter clarified how the gene is transcriptionally controlled in expressing tissues.","evidence":"Promoter-reporter assays and transcription start site mapping in expressing (MG63) vs non-expressing cells, with secretion assays confirming ECM fiber formation","pmids":["19573590"],"confidence":"Medium","gaps":["Upstream transcription factors driving the promoter not identified here","Cell-type specificity of regulation incompletely mapped"]},{"year":2014,"claim":"An invertebrate fibrillin-related ZP-domain protein demonstrated a conserved mechanical role for secreted fibrillins in resisting tissue deformation, and splicing analyses revealed non-coding mechanisms of pathogenicity.","evidence":"C. elegans fbn-1 genetic loss-of-function with FRET tension sensor showing epidermal mechanical failure; in vitro splicing assay showing an intronic variant causes exon 35 skipping in neonatal Marfan syndrome","pmids":["25798732","24668922"],"confidence":"High","gaps":["C. elegans FBN-1 is ZP-domain related, not directly the microfibril-forming vertebrate orthologue","Splicing impact on protein function inferred, not directly measured at protein level"]},{"year":2019,"claim":"Correlating mutation class with aortic wall pathology connected haploinsufficiency-type mutations mechanistically to elastic fiber loss and aortic dissection risk.","evidence":"Sequencing plus histological staining of aortic tissue showing sparser elastic fibers and disorganized smooth muscle in frameshift/nonsense vs missense carriers, with deep intronic variants confirmed to cause aberrant splicing by patient RNA RT-PCR","pmids":["31830381","31185693"],"confidence":"Medium","gaps":["Single-center pathology cohort","Causal chain from elastic fiber loss to dissection not experimentally dissected"]},{"year":2022,"claim":"Identifying asprosin as a furin-cleaved C-terminal fragment of profibrillin-1 revealed an endocrine output of the FBN1 locus distinct from its structural role.","evidence":"Synthesis of genetic mapping, furin cleavage biochemistry, and OR4M1/cAMP receptor signaling studies; plus RNA sequencing of urinary cells localizing a deep intronic splicing variant","pmids":["35707591","35067677"],"confidence":"Medium","gaps":["Asprosin mechanism synthesized from a review rather than newly tested here","How fibrillinopathy mutations affect asprosin output not addressed"]},{"year":2024,"claim":"Multiple post-transcriptional and post-translational regulators were defined, embedding FBN1 in proliferation, signaling, and tissue-repair contexts beyond classical ECM biology.","evidence":"FBXO2 ubiquitination-proteome substrate identification with KD/OE in endometrial cancer; Nrf2 KO epistasis in osteoblasts; dual-luciferase validation of miR-133b and miR-152-3p targeting with rescue experiments in cancer and diabetic wound models; BMP15-FBN1 cumulus cell axis","pmids":["32984335","37365714","28582847","38206528","23942191"],"confidence":"Medium","gaps":["Each regulatory relationship rests on a single lab/model system","Whether these regulatory axes operate in the connective tissues affected by Marfan syndrome is untested"]},{"year":null,"claim":"How distinct FBN1 mutation classes quantitatively partition damage between microfibril structural integrity, TGF-β/BMP signaling, and asprosin endocrine output to produce divergent fibrillinopathy phenotypes remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No unified model linking allele type to structural vs signaling vs endocrine outcome","Tissue-specific regulator contributions not integrated with disease mechanism"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0005198","term_label":"structural molecule activity","supporting_discovery_ids":[1,4,15]}],"localization":[{"term_id":"GO:0031012","term_label":"extracellular matrix","supporting_discovery_ids":[1,4,7]},{"term_id":"GO:0005576","term_label":"extracellular region","supporting_discovery_ids":[7,15]}],"pathway":[{"term_id":"R-HSA-1474244","term_label":"Extracellular matrix organization","supporting_discovery_ids":[1,4,15]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[3,10]}],"complexes":["microfibril"],"partners":["FBXO2","FURIN","OR4M1"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"P35555","full_name":"Fibrillin-1","aliases":[],"length_aa":2871,"mass_kda":312.3,"function":"Structural component of the 10-12 nm diameter microfibrils of the extracellular matrix, which conveys both structural and regulatory properties to load-bearing connective tissues (PubMed:15062093, PubMed:1860873). Fibrillin-1-containing microfibrils provide long-term force bearing structural support (PubMed:27026396). In tissues such as the lung, blood vessels and skin, microfibrils form the periphery of the elastic fiber, acting as a scaffold for the deposition of elastin (PubMed:27026396). In addition, microfibrils can occur as elastin-independent networks in tissues such as the ciliary zonule, tendon, cornea and glomerulus where they provide tensile strength and have anchoring roles (PubMed:27026396). Fibrillin-1 also plays a key role in tissue homeostasis through specific interactions with growth factors, such as the bone morphogenetic proteins (BMPs), growth and differentiation factors (GDFs) and latent transforming growth factor-beta-binding proteins (LTBPs), cell-surface integrins and other extracellular matrix protein and proteoglycan components (PubMed:27026396). Regulates osteoblast maturation by controlling TGF-beta bioavailability and calibrating TGF-beta and BMP levels, respectively (By similarity). Negatively regulates osteoclastogenesis by binding and sequestering an osteoclast differentiation and activation factor TNFSF11 (PubMed:24039232). This leads to disruption of TNFSF11-induced Ca(2+) signaling and impairment of TNFSF11-mediated nuclear translocation and activation of transcription factor NFATC1 which regulates genes important for osteoclast differentiation and function (PubMed:24039232). Mediates cell adhesion via its binding to cell surface receptors integrins ITGAV:ITGB3 and ITGA5:ITGB1 (PubMed:12807887, PubMed:17158881). Binds heparin and this interaction has an important role in the assembly of microfibrils (PubMed:11461921) Adipokine secreted by white adipose tissue that plays an important regulatory role in the glucose metabolism of liver, muscle and pancreas (PubMed:27087445, PubMed:30853600). Hormone that targets the liver in response to fasting to increase plasma glucose levels (PubMed:27087445). Binds the olfactory receptor OR4M1 at the surface of hepatocytes and promotes hepatocyte glucose release by activating the protein kinase A activity in the liver, resulting in rapid glucose release into the circulation (PubMed:27087445, PubMed:31230984). May act as a regulator of adaptive thermogenesis by inhibiting browning and energy consumption, while increasing lipid deposition in white adipose tissue (By similarity). Also acts as an orexigenic hormone that increases appetite: crosses the blood brain barrier and exerts effects on the hypothalamus (By similarity). In the arcuate nucleus of the hypothalamus, asprosin directly activates orexigenic AgRP neurons and indirectly inhibits anorexigenic POMC neurons, resulting in appetite stimulation (By similarity). Activates orexigenic AgRP neurons via binding to the olfactory receptor OR4M1 (By similarity). May also play a role in sperm motility in testis via interaction with OR4M1 receptor (By similarity)","subcellular_location":"Secreted","url":"https://www.uniprot.org/uniprotkb/P35555/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/FBN1","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/FBN1","total_profiled":1310},"omim":[{"mim_id":"621470","title":"ADAMTS-LIKE PROTEIN 5; ADAMTSL5","url":"https://www.omim.org/entry/621470"},{"mim_id":"620528","title":"NEURONOPATHY, DISTAL HEREDITARY MOTOR, AUTOSOMAL DOMINANT 11; HMND11","url":"https://www.omim.org/entry/620528"},{"mim_id":"619939","title":"OLFACTORY RECEPTOR, FAMILY 4, SUBFAMILY M, MEMBER 1; OR4M1","url":"https://www.omim.org/entry/619939"},{"mim_id":"619825","title":"AORTIC ANEURYSM, FAMILIAL THORACIC 12; AAT12","url":"https://www.omim.org/entry/619825"},{"mim_id":"619656","title":"LOEYS-DIETZ SYNDROME 6; LDS6","url":"https://www.omim.org/entry/619656"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Golgi apparatus","reliability":"Approved"},{"location":"Plasma membrane","reliability":"Additional"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"adipose tissue","ntpm":49.5},{"tissue":"placenta","ntpm":61.7}],"url":"https://www.proteinatlas.org/search/FBN1"},"hgnc":{"alias_symbol":["MASS","OCTD","SGS"],"prev_symbol":["FBN","MFS1","WMS"]},"alphafold":{"accession":"P35555","domains":[],"viewer_url":"https://alphafold.ebi.ac.uk/entry/P35555","model_url":"","pae_url":"","plddt_mean":null},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=FBN1","jax_strain_url":"https://www.jax.org/strain/search?query=FBN1"},"sequence":{"accession":"P35555","fasta_url":"https://rest.uniprot.org/uniprotkb/P35555.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/P35555/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/P35555"}},"corpus_meta":[{"pmid":"17701892","id":"PMC_17701892","title":"Effect of mutation type and location on clinical outcome in 1,013 probands with Marfan syndrome or related phenotypes and FBN1 mutations: an international study.","date":"2007","source":"American journal of human genetics","url":"https://pubmed.ncbi.nlm.nih.gov/17701892","citation_count":430,"is_preprint":false},{"pmid":"8541880","id":"PMC_8541880","title":"Mutations in the human gene for fibrillin-1 (FBN1) in the Marfan syndrome and related disorders.","date":"1995","source":"Human molecular genetics","url":"https://pubmed.ncbi.nlm.nih.gov/8541880","citation_count":388,"is_preprint":false},{"pmid":"12928036","id":"PMC_12928036","title":"Molecular mechanisms modulating muscle mass.","date":"2003","source":"Trends in molecular medicine","url":"https://pubmed.ncbi.nlm.nih.gov/12928036","citation_count":319,"is_preprint":false},{"pmid":"20397318","id":"PMC_20397318","title":"Signaling pathways perturbing muscle mass.","date":"2010","source":"Current opinion in clinical nutrition and metabolic care","url":"https://pubmed.ncbi.nlm.nih.gov/20397318","citation_count":286,"is_preprint":false},{"pmid":"15708976","id":"PMC_15708976","title":"Control of seed mass by APETALA2.","date":"2005","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/15708976","citation_count":266,"is_preprint":false},{"pmid":"27437668","id":"PMC_27437668","title":"FBN1: The disease-causing gene for Marfan syndrome and other genetic disorders.","date":"2016","source":"Gene","url":"https://pubmed.ncbi.nlm.nih.gov/27437668","citation_count":263,"is_preprint":false},{"pmid":"10637622","id":"PMC_10637622","title":"Mass spectrometry. 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Molecular basis of disease","url":"https://pubmed.ncbi.nlm.nih.gov/30385411","citation_count":18,"is_preprint":false},{"pmid":"34828442","id":"PMC_34828442","title":"Marfan Syndrome Caused by Disruption of the FBN1 Gene due to A Reciprocal Chromosome Translocation.","date":"2021","source":"Genes","url":"https://pubmed.ncbi.nlm.nih.gov/34828442","citation_count":18,"is_preprint":false},{"pmid":"7869354","id":"PMC_7869354","title":"Detection by PCR and analysis of the distribution of a fibronectin-binding protein gene (fbn) among staphylococcal isolates.","date":"1995","source":"Journal of medical microbiology","url":"https://pubmed.ncbi.nlm.nih.gov/7869354","citation_count":17,"is_preprint":false},{"pmid":"24668922","id":"PMC_24668922","title":"Novel FBN1 gene mutation and maternal germinal mosaicism as the cause of neonatal form of Marfan syndrome.","date":"2014","source":"American journal of medical genetics. Part A","url":"https://pubmed.ncbi.nlm.nih.gov/24668922","citation_count":17,"is_preprint":false},{"pmid":"23176764","id":"PMC_23176764","title":"FBN1 gene mutation characteristics and clinical features for the prediction of mitral valve disease progression.","date":"2012","source":"International journal of cardiology","url":"https://pubmed.ncbi.nlm.nih.gov/23176764","citation_count":17,"is_preprint":false},{"pmid":"31185693","id":"PMC_31185693","title":"Characterization of Two Novel Intronic Variants Affecting Splicing in FBN1-Related Disorders.","date":"2019","source":"Genes","url":"https://pubmed.ncbi.nlm.nih.gov/31185693","citation_count":17,"is_preprint":false},{"pmid":"25812041","id":"PMC_25812041","title":"Difficulties in diagnosing Marfan syndrome using current FBN1 databases.","date":"2015","source":"Genetics in medicine : official journal of the American College of Medical Genetics","url":"https://pubmed.ncbi.nlm.nih.gov/25812041","citation_count":16,"is_preprint":false},{"pmid":"23456714","id":"PMC_23456714","title":"Beginning to understand the role of sugar carriers in Colletotrichum lindemuthianum: the function of the gene mfs1.","date":"2013","source":"Journal of microbiology (Seoul, Korea)","url":"https://pubmed.ncbi.nlm.nih.gov/23456714","citation_count":16,"is_preprint":false},{"pmid":"26272055","id":"PMC_26272055","title":"Wide mutation spectrum and frequent variant Ala27Thr of FBN1 identified in a large cohort of Chinese patients with sporadic TAAD.","date":"2015","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/26272055","citation_count":16,"is_preprint":false},{"pmid":"1695584","id":"PMC_1695584","title":"Noncoordinate expression of Drosophila glue genes: Sgs-4 is expressed at many stages and in two different tissues.","date":"1990","source":"Developmental biology","url":"https://pubmed.ncbi.nlm.nih.gov/1695584","citation_count":15,"is_preprint":false},{"pmid":"33312371","id":"PMC_33312371","title":"FBN1 promotes DLBCL cell migration by activating the Wnt/β-catenin signaling pathway and regulating TIMP1.","date":"2020","source":"American journal of translational research","url":"https://pubmed.ncbi.nlm.nih.gov/33312371","citation_count":15,"is_preprint":false},{"pmid":"35067677","id":"PMC_35067677","title":"Genome sequencing and RNA sequencing of urinary cells reveal an intronic FBN1 variant causing aberrant splicing.","date":"2022","source":"Journal of human genetics","url":"https://pubmed.ncbi.nlm.nih.gov/35067677","citation_count":15,"is_preprint":false},{"pmid":"36411030","id":"PMC_36411030","title":"Conclusion of diagnostic odysseys due to inversions disrupting GLI3 and FBN1.","date":"2022","source":"Journal of medical genetics","url":"https://pubmed.ncbi.nlm.nih.gov/36411030","citation_count":15,"is_preprint":false},{"pmid":"26193948","id":"PMC_26193948","title":"Production and secretion of naphthoquinones is mediated by the MFS transporter MFS1 in the entomopathogenic fungus Ophiocordyceps sp. BCC1869.","date":"2015","source":"World journal of microbiology & biotechnology","url":"https://pubmed.ncbi.nlm.nih.gov/26193948","citation_count":14,"is_preprint":false},{"pmid":"31730815","id":"PMC_31730815","title":"Mutation analysis of the FBN1 gene in a cohort of patients with Marfan Syndrome: A 10-year single center experience.","date":"2019","source":"Clinica chimica acta; international journal of clinical chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/31730815","citation_count":14,"is_preprint":false},{"pmid":"39741318","id":"PMC_39741318","title":"Interpretation and classification of FBN1 variants associated with Marfan syndrome: consensus recommendations from the Clinical Genome Resource's FBN1 variant curation expert panel.","date":"2024","source":"Genome medicine","url":"https://pubmed.ncbi.nlm.nih.gov/39741318","citation_count":13,"is_preprint":false},{"pmid":"25562528","id":"PMC_25562528","title":"Age-related hypertension and salt sensitivity are associated with unique cortico-medullary distribution of D1R, AT1R, and NADPH-oxidase in FBN rats.","date":"2015","source":"Clinical and experimental hypertension (New York, N.Y. : 1993)","url":"https://pubmed.ncbi.nlm.nih.gov/25562528","citation_count":13,"is_preprint":false},{"pmid":"22876116","id":"PMC_22876116","title":"Identification of a novel FBN1 gene mutation in a large Pakistani family with Marfan syndrome.","date":"2012","source":"Molecular vision","url":"https://pubmed.ncbi.nlm.nih.gov/22876116","citation_count":13,"is_preprint":false},{"pmid":"21895641","id":"PMC_21895641","title":"Systematic screening of FBN1 gene unclassified missense variants for splice abnormalities.","date":"2011","source":"Clinical genetics","url":"https://pubmed.ncbi.nlm.nih.gov/21895641","citation_count":13,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":47554,"output_tokens":5007,"usd":0.108883,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":13354,"output_tokens":3595,"usd":0.078323,"stage2_stop_reason":"end_turn"},"total_usd":0.187206,"stage1_batch_id":"msgbatch_01AsR7g8dGTEiEw9U83bJeWn","stage2_batch_id":"msgbatch_01YV5ZyxtFNUZEjxRcpd9jzb","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 1991,\n      \"finding\": \"The FBN1 gene encoding fibrillin-1 was mapped to chromosome 15, band q21.1, by fluorescence in situ hybridization and isotopic in situ hybridization using fibrillin cDNA-derived probes.\",\n      \"method\": \"Fluorescence in situ hybridization (FISH) and isotopic in situ hybridization\",\n      \"journal\": \"Genomics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — direct chromosomal mapping by two orthogonal in situ hybridization methods, replicated across approaches\",\n      \"pmids\": [\"1769651\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1995,\n      \"finding\": \"Fibrillin-1 monomers contain a large number of epidermal growth factor-like (EGF-like) motifs, most capable of binding calcium ions, and motifs resembling the TGF-β binding protein; in vitro polymerization of fibrillin-1 monomers produces 'beads on a string' structures resembling microfibrils purified from extracellular matrices.\",\n      \"method\": \"In vitro polymerization assay, electron microscopy\",\n      \"journal\": \"Human molecular genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — direct in vitro reconstitution of microfibril-like structures, with structural characterization by EM\",\n      \"pmids\": [\"8541880\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1995,\n      \"finding\": \"The mouse fibrillin-1 transcript encodes a 2,871 amino acid polypeptide with a signal peptide and Kozak consensus ATG, and is expressed broadly in embryonic mouse tissues including non-elastic connective tissues, suggesting functions for fibrillin-associated microfibrils beyond elastogenesis.\",\n      \"method\": \"cDNA cloning, sequence analysis, tissue expression survey by in situ/Northern hybridization\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — primary structure determination and developmental expression pattern, single lab with multiple tissues examined\",\n      \"pmids\": [\"7829516\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"Missense mutations substituting or producing cysteine residues in FBN1 are associated with higher probability of ectopia lentis; premature termination codon mutations are associated with more severe skeletal and skin phenotypes than in-frame mutations; mutations in exons 24–32 are associated with younger age at diagnosis, higher probability of ectopia lentis, ascending aortic dilatation, aortic surgery, mitral valve abnormalities, and shorter survival — consistent with dominant-negative versus haploinsufficiency mechanisms and differential effects on structural vs. TGF-β signaling functions of fibrillin-1.\",\n      \"method\": \"Genotype-phenotype correlation analysis of 1,013 probands with pathogenic FBN1 mutations from an international database\",\n      \"journal\": \"American journal of human genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — large international cohort (n=1,013) with multiple mutation classes, replicated across clinical parameters\",\n      \"pmids\": [\"17701892\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"FBN1 encodes a structural macromolecule, fibrillin-1, that polymerizes into microfibrils present in all connective tissues; mutations in specific FBN1 regions can produce opposing phenotypes (tall stature/arachnodactyly in Marfan syndrome vs. short stature/brachydactyly in Weill-Marchesani syndrome/acromelic dysplasias), implicating both structural microfibril network function and growth factor (TGF-β/BMP) signaling regulation as distinct tissue-specific mechanisms.\",\n      \"method\": \"Review of genotype-phenotype data from fibrillinopathy patient cohorts and molecular/structural studies\",\n      \"journal\": \"Gene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Strong — mechanistic framework supported by multiple patient cohorts and prior experimental data, but derived from a review paper synthesizing others' results\",\n      \"pmids\": [\"27437668\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"BMP15 regulates FBN1 expression in porcine cumulus cells; silencing FBN1 with siRNA after BMP15 treatment increased cumulus cell proliferation and prevented apoptosis, indicating FBN1 acts downstream of BMP15 to promote apoptosis (or limit proliferation) in porcine ovarian cumulus cells.\",\n      \"method\": \"siRNA knockdown (RNAi), flow cytometry (apoptosis), MTT assay, RT-qPCR, Western blot\",\n      \"journal\": \"Cellular physiology and biochemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — loss-of-function with defined cellular phenotype (apoptosis/proliferation), single lab but multiple orthogonal readouts\",\n      \"pmids\": [\"23942191\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"FBN1 mRNA is expressed during early mesenchymal stem cell differentiation and declines as cells commit to the adipogenic lineage; FBN1 expression correlates with body fat variation in inbred mouse strains and is upregulated in adipose tissue of obese women with enlarged adipocytes, supporting a role for fibrillin-1 in the mesenchymal-to-adipocyte transition.\",\n      \"method\": \"Mouse strain correlation analysis, gene expression profiling (microarray/qPCR), human adipose tissue analysis, cell culture differentiation assay\",\n      \"journal\": \"Molecular genetics and metabolism\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — multiple orthogonal expression approaches across species and cell models, but no direct functional perturbation in this study\",\n      \"pmids\": [\"27386756\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"The FBN1 gene is transcribed primarily from a single CpG-rich promoter conserved in mammals, lacking TATA and CCAAT boxes; reporter assays showed the conserved promoter region is more active in FBN1-expressing (MG63) than non-expressing cell lines, and fibrillin-1 protein is secreted to form extracellular matrix fibers.\",\n      \"method\": \"Promoter reporter assays, transcription start site mapping, Western blot, cell fractionation/secretion assays\",\n      \"journal\": \"Genomics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct promoter-reporter functional assays in relevant cell lines, single lab with multiple complementary methods\",\n      \"pmids\": [\"19573590\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"FBXO2 acts as an E3 ubiquitin ligase that targets FBN1 for ubiquitin-dependent proteasomal degradation in endometrial cancer cells, identified via a ubiquitination-proteome approach; FBXO2 knockdown inhibited EC cell proliferation while overexpression promoted it, with FBN1 as the substrate.\",\n      \"method\": \"Ubiquitination-proteome approach (mass spectrometry), co-immunoprecipitation, Western blot, siRNA knockdown, overexpression, in vivo xenograft\",\n      \"journal\": \"Frontiers in cell and developmental biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — substrate identification by proteomics plus functional validation by KD/OE, single lab\",\n      \"pmids\": [\"32984335\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Asprosin, a glucogenic and orexigenic protein hormone, is encoded by the penultimate two exons (65 and 66) of FBN1; profibrillin-1 undergoes proteolytic cleavage by furin to produce mature fibrillin-1 and asprosin; asprosin promotes hepatic glucose release and appetite stimulation through activation of cAMP signaling via its G protein-coupled receptor OR4M1.\",\n      \"method\": \"Genetic mapping, biochemical cleavage assay, receptor binding/signaling studies (cAMP pathway) — synthesized from discovery literature\",\n      \"journal\": \"Molecular syndromology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — furin cleavage mechanism and receptor identity established by prior experimental work cited in this review; single review paper but synthesizes multiple independent experimental studies\",\n      \"pmids\": [\"35707591\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"FBN1 frameshift and nonsense mutations (haploinsufficiency-type) are more frequent in Marfan syndrome patients with aortic dissection compared to aortic aneurysm; pathological staining showed sparser elastic fibers and more disorganized smooth muscle cells in patients with frameshift/nonsense vs. missense mutations, suggesting mutation class determines structural integrity of the aortic wall.\",\n      \"method\": \"DNA sequencing, genotype-phenotype correlation, histological staining of aortic wall tissue (elastic fiber and smooth muscle staining)\",\n      \"journal\": \"Molecular genetics & genomic medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct tissue pathology correlated with mutation class, single center study\",\n      \"pmids\": [\"31830381\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"A FBN1 3'UTR mutation in Marfan syndrome patients was associated with endoplasmic reticulum (ER) stress response in the non-dilated aortic zone, evidenced by upregulation of ER stress markers (MANF, HSPA5/BiP, CHOP, sXBP1) and decreased phosphorylation of the translation regulator eIF2α in vascular smooth muscle cells derived from MFS patients.\",\n      \"method\": \"mRNA sequencing of patient-derived vascular smooth muscle cells, RT-qPCR, Western blot (BiP/GRP78, CHOP, sXBP1, p-eIF2α)\",\n      \"journal\": \"Biochimica et biophysica acta. Molecular basis of disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — patient-derived primary cells with multiple molecular markers of ER stress, single lab\",\n      \"pmids\": [\"30385411\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"Some apparent FBN1 missense mutations affect pre-mRNA splicing rather than (or in addition to) protein sequence; direct RNA analysis of patient samples identified 2 of 36 missense base changes that caused splicing abnormalities detectable by RT-PCR, while in silico splice prediction alone was insufficient to reliably identify these changes.\",\n      \"method\": \"RT-PCR, cDNA sequencing, in silico splice site prediction with five different programs\",\n      \"journal\": \"Clinical genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct RNA-level functional assay confirming aberrant splicing in patient samples, single lab\",\n      \"pmids\": [\"21895641\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Two deep intronic FBN1 variants (c.6872-24T>A and c.7571-12T>A) cause aberrant splicing by introducing intronic nucleotide retention and premature stop codons, demonstrated by RT-PCR of patient mRNA.\",\n      \"method\": \"In silico splice analysis, RT-PCR on patient RNA, Sanger sequencing of aberrant transcripts\",\n      \"journal\": \"Genes\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct mRNA-level functional validation of splicing defects in patient samples, single lab\",\n      \"pmids\": [\"31185693\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"A deep intronic FBN1 variant (c.5789-15G>A in intron 47) causes allelic imbalance, intron 47 retention, and generation of aberrant transcripts with new splice acceptor sites within exon 48, identified by genome sequencing and RNA sequencing of urinary cells (which express FBN1 at high levels unlike peripheral blood).\",\n      \"method\": \"Genome sequencing, RNA sequencing of urinary cells, RT-PCR validation\",\n      \"journal\": \"Journal of human genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multi-omic (genome + RNA sequencing) confirmation of splicing mechanism in patient-accessible tissue, single lab\",\n      \"pmids\": [\"35067677\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"In C. elegans, FBN-1, a ZP domain protein related to vertebrate fibrillins, is required specifically within the epidermis (where it is expressed and secreted to the apical surface) to resist mechanical deformation caused by pharyngeal pulling forces and actomyosin-based circumferential constricting forces during embryogenesis; loss of fbn-1 results in mechanical deformation of the epidermis, as measured by a FRET-based tension sensor.\",\n      \"method\": \"Genetic loss-of-function, FRET-based tension sensor, tissue-specific expression analysis, live imaging, fractionation/secretion assay\",\n      \"journal\": \"eLife\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vivo genetic loss-of-function with direct mechanical measurement (FRET tension sensor), localization by secretion assay, multiple orthogonal methods\",\n      \"pmids\": [\"25798732\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"An intronic FBN1 mutation (c.4211-32_-13del) outside the canonical exons 24–32 causes exon 35 skipping (deletion of 42 amino acids, p.Leu1405_Asp1446del), demonstrated by in vitro splicing analysis, and leads to neonatal Marfan syndrome.\",\n      \"method\": \"Molecular genetic sequencing, in vitro splicing assay (minigene or patient RNA-based RT-PCR)\",\n      \"journal\": \"American journal of medical genetics. Part A\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct in vitro splicing validation of mutation consequence, single lab\",\n      \"pmids\": [\"24668922\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Nrf2 transcriptionally upregulates Fbn1 in osteoblast-lineage cells; PQQ-induced Nrf2 activation increased Fbn1 expression, which reduced RANKL production in osteoblast-lineage cells and decreased osteoclast activation; Nrf2 knockout blunted these effects, placing Fbn1 downstream of the Nrf2-antioxidant response element pathway in bone.\",\n      \"method\": \"Nrf2 knockout mouse, PQQ supplementation, molecular docking, pharmacological screening, Western blot, RT-qPCR, bone histomorphometry\",\n      \"journal\": \"Aging cell\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic epistasis (Nrf2 KO) with defined cellular phenotype (RANKL/osteoclast), single lab with multiple orthogonal methods\",\n      \"pmids\": [\"37365714\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"miR-133b directly targets FBN1 mRNA (confirmed by dual luciferase reporter assay); miR-133b overexpression upregulates FBN1 protein in gastric cancer cells, and silencing FBN1 inhibits proliferation, migration and invasion, while downregulating β-catenin, N-cadherin, and Wnt1 of the Wnt/β-catenin pathway.\",\n      \"method\": \"Dual luciferase reporter assay, siRNA knockdown, miRNA overexpression, CCK-8, colony formation, wound healing, Transwell assay, Western blot\",\n      \"journal\": \"Cancer biomarkers\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct miRNA-target validation by luciferase assay plus loss-of-function phenotype, single lab with multiple functional readouts\",\n      \"pmids\": [\"28582847\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"miR-152-3p directly targets FBN1 mRNA; curcumin inhibits miR-152-3p, thereby restoring FBN1 expression and activating the FBN1/TGF-β signaling pathway, which inhibits fibroblast apoptosis, promotes proliferation, migration, and angiogenesis, and accelerates diabetic foot ulcer wound healing in rats; overexpression of FBN1 reversed the inhibitory effects of miR-152-3p mimic.\",\n      \"method\": \"DFU rat model, high-glucose cell model, Western blot, RT-qPCR, flow cytometry, Transwell, wound healing assay, H&E staining, miRNA mimic/overexpression\",\n      \"journal\": \"Molecular biotechnology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — epistasis rescue experiment (FBN1 OE reverses miR-152-3p effect) in both in vivo and in vitro models, single lab\",\n      \"pmids\": [\"38206528\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"Fibrillin-1 (FBN1) is a large extracellular matrix glycoprotein that polymerizes into 10–14 nm microfibrils (assembled via in vitro reconstitution), serving dual roles: (1) a structural scaffold component in all connective tissues (requiring calcium-binding EGF-like domains), and (2) a regulator of TGF-β/BMP growth factor bioavailability; profibrillin-1 is proteolytically cleaved by furin to release mature fibrillin-1 and the orexigenic/glucogenic hormone asprosin (encoded by exons 65–66), which activates hepatic glucose release via the OR4M1/cAMP signaling pathway; FBN1 is subject to ubiquitin-mediated degradation via the FBXO2 E3 ligase, transcriptional upregulation downstream of Nrf2-ARE signaling, and post-transcriptional regulation by miR-133b and miR-152-3p; distinct mutation classes (dominant-negative missense vs. haploinsufficiency-type frameshifts/nonsense) produce different degrees of structural vs. signaling dysfunction, explaining the spectrum of fibrillinopathy phenotypes from Marfan syndrome to acromelic dysplasias.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"FBN1 encodes fibrillin-1, a large secreted extracellular matrix glycoprotein that self-assembles into 10–14 nm microfibrils present in all connective tissues, providing structural scaffolding and resisting mechanical deformation [#1, #4, #15]. Each monomer is built largely from calcium-binding EGF-like motifs together with TGF-β binding protein-like domains, and isolated monomers polymerize in vitro into 'beads-on-a-string' microfibril-like structures [#1]; the protein is broadly expressed in non-elastic as well as elastic connective tissues, indicating microfibril roles beyond elastogenesis [#2]. Fibrillin-1 serves a dual function: as a structural network component and as a regulator of TGF-β/BMP growth factor signaling, and mutations in different regions of FBN1 produce opposing skeletal phenotypes (overgrowth in Marfan syndrome versus short stature/brachydactyly in acromelic dysplasias), reflecting tissue-specific imbalance between these structural and signaling roles [#4]. Mutation class determines disease severity and mechanism: dominant-negative cysteine-altering missense changes predispose to ectopia lentis, while haploinsufficiency-type premature termination codon mutations associate with more severe skeletal phenotypes, aortic dissection, sparser elastic fibers, and disorganized smooth muscle in the aortic wall [#3, #10]. A substantial fraction of FBN1 disease alleles, including apparent missense and deep intronic variants, act through aberrant pre-mRNA splicing rather than simple coding change [#12, #13, #14, #16]. The penultimate exons 65–66 of FBN1 encode asprosin, released from profibrillin-1 by furin cleavage; asprosin acts as a glucogenic/orexigenic hormone driving hepatic glucose release and appetite via cAMP signaling through the receptor OR4M1 [#9]. FBN1 levels are further controlled post-translationally by FBXO2-mediated ubiquitin-proteasomal degradation [#8], transcriptionally downstream of Nrf2 [#17], and post-transcriptionally by miR-133b and miR-152-3p [#18, #19].\",\n  \"teleology\": [\n    {\n      \"year\": 1991,\n      \"claim\": \"Establishing the chromosomal location of FBN1 was the prerequisite for linking the gene to heritable connective tissue disease.\",\n      \"evidence\": \"FISH and isotopic in situ hybridization with fibrillin cDNA probes localizing the gene to 15q21.1\",\n      \"pmids\": [\"1769651\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mapping alone does not establish gene structure or protein function\", \"No mutation-phenotype link demonstrated at this stage\"]\n    },\n    {\n      \"year\": 1995,\n      \"claim\": \"Defining the domain architecture and demonstrating self-assembly answered how fibrillin-1 builds the microfibril and why calcium-binding EGF domains are central.\",\n      \"evidence\": \"In vitro polymerization with electron microscopy showing microfibril-like beads-on-a-string, plus cDNA cloning and broad embryonic tissue expression survey\",\n      \"pmids\": [\"8541880\", \"7829516\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"In vitro reconstitution does not capture all accessory factors of in vivo microfibril assembly\", \"Growth factor regulatory role not yet demonstrated\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Synthesizing patient genotype-phenotype data framed fibrillin-1 as both a structural scaffold and a TGF-β/BMP signaling regulator, explaining opposing fibrillinopathy phenotypes.\",\n      \"evidence\": \"Review of fibrillinopathy cohorts and structural/molecular studies correlating mutation region with overgrowth vs. short-stature phenotypes\",\n      \"pmids\": [\"27437668\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Review-level synthesis rather than new experimental data\", \"Tissue-specific mechanisms distinguishing structural from signaling defects not resolved\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"A large international cohort established that mutation class and domain location predict clinical outcome, operationalizing dominant-negative versus haploinsufficiency mechanisms.\",\n      \"evidence\": \"Genotype-phenotype correlation across 1,013 probands linking cysteine-altering missense to ectopia lentis and PTC mutations to severe skeletal/cardiovascular outcomes\",\n      \"pmids\": [\"17701892\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Correlation does not directly demonstrate the molecular consequence of each mutation class\", \"Does not resolve relative contribution of structural vs. signaling dysfunction per allele\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Characterizing the FBN1 promoter clarified how the gene is transcriptionally controlled in expressing tissues.\",\n      \"evidence\": \"Promoter-reporter assays and transcription start site mapping in expressing (MG63) vs non-expressing cells, with secretion assays confirming ECM fiber formation\",\n      \"pmids\": [\"19573590\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Upstream transcription factors driving the promoter not identified here\", \"Cell-type specificity of regulation incompletely mapped\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"An invertebrate fibrillin-related ZP-domain protein demonstrated a conserved mechanical role for secreted fibrillins in resisting tissue deformation, and splicing analyses revealed non-coding mechanisms of pathogenicity.\",\n      \"evidence\": \"C. elegans fbn-1 genetic loss-of-function with FRET tension sensor showing epidermal mechanical failure; in vitro splicing assay showing an intronic variant causes exon 35 skipping in neonatal Marfan syndrome\",\n      \"pmids\": [\"25798732\", \"24668922\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"C. elegans FBN-1 is ZP-domain related, not directly the microfibril-forming vertebrate orthologue\", \"Splicing impact on protein function inferred, not directly measured at protein level\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Correlating mutation class with aortic wall pathology connected haploinsufficiency-type mutations mechanistically to elastic fiber loss and aortic dissection risk.\",\n      \"evidence\": \"Sequencing plus histological staining of aortic tissue showing sparser elastic fibers and disorganized smooth muscle in frameshift/nonsense vs missense carriers, with deep intronic variants confirmed to cause aberrant splicing by patient RNA RT-PCR\",\n      \"pmids\": [\"31830381\", \"31185693\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single-center pathology cohort\", \"Causal chain from elastic fiber loss to dissection not experimentally dissected\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Identifying asprosin as a furin-cleaved C-terminal fragment of profibrillin-1 revealed an endocrine output of the FBN1 locus distinct from its structural role.\",\n      \"evidence\": \"Synthesis of genetic mapping, furin cleavage biochemistry, and OR4M1/cAMP receptor signaling studies; plus RNA sequencing of urinary cells localizing a deep intronic splicing variant\",\n      \"pmids\": [\"35707591\", \"35067677\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Asprosin mechanism synthesized from a review rather than newly tested here\", \"How fibrillinopathy mutations affect asprosin output not addressed\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Multiple post-transcriptional and post-translational regulators were defined, embedding FBN1 in proliferation, signaling, and tissue-repair contexts beyond classical ECM biology.\",\n      \"evidence\": \"FBXO2 ubiquitination-proteome substrate identification with KD/OE in endometrial cancer; Nrf2 KO epistasis in osteoblasts; dual-luciferase validation of miR-133b and miR-152-3p targeting with rescue experiments in cancer and diabetic wound models; BMP15-FBN1 cumulus cell axis\",\n      \"pmids\": [\"32984335\", \"37365714\", \"28582847\", \"38206528\", \"23942191\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Each regulatory relationship rests on a single lab/model system\", \"Whether these regulatory axes operate in the connective tissues affected by Marfan syndrome is untested\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How distinct FBN1 mutation classes quantitatively partition damage between microfibril structural integrity, TGF-β/BMP signaling, and asprosin endocrine output to produce divergent fibrillinopathy phenotypes remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No unified model linking allele type to structural vs signaling vs endocrine outcome\", \"Tissue-specific regulator contributions not integrated with disease mechanism\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0005198\", \"supporting_discovery_ids\": [1, 4, 15]},\n      {\"term_id\": \"GO:0005509\", \"supporting_discovery_ids\": [1]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0031012\", \"supporting_discovery_ids\": [1, 4, 7]},\n      {\"term_id\": \"GO:0005576\", \"supporting_discovery_ids\": [7, 15]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"GO:0162582\", \"supporting_discovery_ids\": [4]},\n      {\"term_id\": \"R-HSA-1474244\", \"supporting_discovery_ids\": [1, 4, 15]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [3, 10]}\n    ],\n    \"complexes\": [\"microfibril\"],\n    \"partners\": [\"FBXO2\", \"FURIN\", \"OR4M1\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":7,"faith_total":7,"faith_pct":100.0}}