{"gene":"FBN1","run_date":"2026-04-28T17:46:03","timeline":{"discoveries":[{"year":1995,"finding":"FBN1 encodes fibrillin-1, a large extracellular matrix glycoprotein that polymerizes into 10–14 nm microfibrils; in vitro polymerization of fibrillin monomers produces 'beads on a string' structures resembling native microfibrils, and the protein contains calcium-binding EGF-like motifs and TGF-β binding protein-like motifs.","method":"In vitro polymerization assay, electron microscopy, domain analysis of cDNA","journal":"Human molecular genetics","confidence":"High","confidence_rationale":"Tier 1 — in vitro reconstitution of microfibril assembly with structural validation by EM; foundational paper replicated across labs","pmids":["8541880"],"is_preprint":false},{"year":1995,"finding":"A heterozygous FBN1 missense mutation (R2726W) adjacent to a consensus protease cleavage site disrupts proteolytic processing of profibrillin to fibrillin outside the cell, with only half of secreted profibrillin converted to mature fibrillin and deposited in the extracellular matrix.","method":"Pulse-chase metabolic labeling, fibroblast culture, electron microscopy of rotary-shadowed microfibrils, FBN1 gene sequencing","journal":"The Journal of clinical investigation","confidence":"High","confidence_rationale":"Tier 1 — direct biochemical assay of fibrillin processing in patient-derived fibroblasts with mutation identification and EM validation","pmids":["7738200"],"is_preprint":false},{"year":1991,"finding":"The FBN1 gene localizes to human chromosome 15q21.1, establishing its chromosomal position.","method":"Fluorescence in situ hybridization (FISH) and isotopic in situ hybridization","journal":"Genomics","confidence":"High","confidence_rationale":"Tier 2 — direct cytogenetic mapping confirmed by two independent hybridization methods","pmids":["1769651"],"is_preprint":false},{"year":1994,"finding":"Three of five Marfan syndrome patients produce less than 5% of normal FBN1 transcript levels from one allele (null-allele phenotype), demonstrating that allelic haploinsufficiency is a molecular mechanism in Marfan syndrome.","method":"Allele-specific mRNA quantification using RsaI restriction-site dimorphism in FBN1 3′ UTR in fibroblast cultures","journal":"American journal of human genetics","confidence":"Medium","confidence_rationale":"Tier 2 — direct allele-specific expression measurement in patient fibroblasts; single lab","pmids":["7915876"],"is_preprint":false},{"year":2001,"finding":"Multi-exon in-frame deletions of FBN1 (exons 42–43 or 44–46) produce stable mutant mRNA but significantly reduce fibrillin synthesis and extracellular matrix deposition, with the exon 44–46 deletion causing normal protein synthesis but strikingly reduced matrix deposition, indicating a dominant-negative interference with microfibril assembly.","method":"Long-range RT-PCR, allele-specific transcript analysis, pulse-chase studies in cultured fibroblasts, Southern blot","journal":"BMC medical genetics","confidence":"High","confidence_rationale":"Tier 1 — quantitative pulse-chase biochemistry with multiple orthogonal methods in patient fibroblasts","pmids":["11710961"],"is_preprint":false},{"year":2007,"finding":"FBN1 mutations in exons 24–32 are associated with the most severe phenotype (younger diagnosis, higher probability of ectopia lentis, aortic dilatation, aortic surgery, mitral valve abnormalities, scoliosis, shorter survival), while cysteine-substituting or cysteine-producing missense mutations are associated with higher probability of ectopia lentis, and premature termination codons produce more severe skeletal and skin phenotypes than in-frame mutations — implicating distinct mechanisms (dominant-negative vs. haploinsufficiency) and the dual structural/TGF-β signaling functions of fibrillin-1.","method":"Genotype-phenotype correlation study of 1,013 probands with pathogenic FBN1 mutations using international UMD-FBN1 database","journal":"American journal of human genetics","confidence":"High","confidence_rationale":"Tier 2 — large-scale multi-center study with quantitative clinical parameters; strong preponderance of evidence from 1,013 probands","pmids":["17701892"],"is_preprint":false},{"year":2016,"finding":"Fibrillin-1 is expressed during early mesenchymal differentiation and declines as human mesenchymal stem cells differentiate to adipocytes; FBN1 mRNA and protein decrease during adipogenesis, suggesting fibrillin-1 functions in maintaining the undifferentiated mesenchymal state and its loss permits adipogenic commitment.","method":"Differentiation of human mesenchymal stem cells in culture, gene expression analysis (FBN1 mRNA), FANTOM5 expression profiling, mouse inbred strain variation analysis","journal":"Molecular genetics and metabolism","confidence":"Medium","confidence_rationale":"Tier 2 — direct cell-culture differentiation experiment with expression analysis; single lab","pmids":["27386756"],"is_preprint":false},{"year":2016,"finding":"Mutations in specific regions of FBN1 (TB/8-cysteine domains associated with acromelic dysplasias) alter fibrillin microfibril network architecture in a way that perturbs growth factor (e.g., BMP) bioavailability and signaling in tissue-specific contexts, producing phenotypes opposite to Marfan syndrome (short stature/brachydactyly vs. tall stature/arachnodactyly).","method":"Review integrating structural domain analysis of fibrillin-1, mutational spectrum analysis, and tissue-specific microfibril microenvironment data","journal":"Gene","confidence":"Medium","confidence_rationale":"Tier 3 — mechanistic framework based on domain-mutation mapping; supported by preponderance of fibrillinopathy literature","pmids":["27437668"],"is_preprint":false},{"year":2018,"finding":"A FBN1 3′UTR mutation in Marfan syndrome patients is associated with endoplasmic reticulum (ER) stress response in vascular smooth muscle cells from the non-dilated aortic zone, evidenced by increased transcription of ER stress markers (MANF, HSPA5/BiP, SEL1L, DDIT3/CHOP, CRELD2) and elevated protein levels of BiP/GRP78, CHOP, and sXBP1, along with decreased phosphorylation of eIF2α.","method":"mRNA sequencing and RT-PCR of vascular smooth muscle cells from MFS patients and controls, western blot for ER stress proteins","journal":"Biochimica et biophysica acta. Molecular basis of disease","confidence":"Medium","confidence_rationale":"Tier 2 — transcriptomic and proteomic characterization in patient-derived primary cells with multiple orthogonal methods; single lab","pmids":["30385411"],"is_preprint":false},{"year":2022,"finding":"Asprosin, a C-terminal cleavage product of profibrillin-1 encoded by FBN1 exons 65–66, is produced by furin-mediated proteolytic cleavage of profibrillin-1 and acts as a glucogenic/orexigenic hormone that promotes hepatic glucose release and appetite stimulation through the G protein-coupled receptor OR4M1 via cAMP signaling.","method":"Genetic studies in neonatal progeroid syndrome patients, proteolytic processing analysis, receptor binding studies (OR4M1), cAMP signaling assays","journal":"Molecular syndromology","confidence":"Medium","confidence_rationale":"Tier 2 — mechanism established through genetic patient data and signaling assays; supported by multiple studies","pmids":["35419902","35707591"],"is_preprint":false},{"year":2009,"finding":"FBN1 transcription initiates primarily from a single CpG-rich, evolutionarily conserved promoter containing binding sites for mesenchyme-differentiation transcription factors; the osteosarcoma cell line MG63 (high FBN1 expression) secretes fibrillin-1 to form extracellular matrix fibres, while non-mesenchymal cell lines (HEK293, MCF7, MDA-MB-231) have ~1000-fold lower FBN1 mRNA and negligible fibrillin-1 protein.","method":"Transcription start site mapping in mouse and human tissues, reporter assay in cell lines with differential FBN1 expression, western blot for fibrillin-1 protein","journal":"Genomics","confidence":"Medium","confidence_rationale":"Tier 2 — direct promoter reporter assay and protein secretion analysis across multiple cell lines; single lab","pmids":["19573590"],"is_preprint":false},{"year":2011,"finding":"Apparent FBN1 missense mutations can alter pre-mRNA splicing; direct RNA analysis of patient samples identified 2 out of 36 different missense base changes that caused splicing abnormalities, demonstrating that some FBN1 mutations act at the RNA level rather than solely through amino acid substitution.","method":"RT-PCR, cDNA amplification and sequencing from patient blood RNA, in silico splice site prediction","journal":"Clinical genetics","confidence":"Medium","confidence_rationale":"Tier 2 — direct RNA analysis from patient material confirming splice defects; single lab","pmids":["21895641"],"is_preprint":false},{"year":2019,"finding":"Deep intronic FBN1 variants (c.6872-24T>A and c.7571-12T>A) cause aberrant splicing through retention of intronic nucleotides, leading to premature stop codons, demonstrating that non-exonic FBN1 mutations can be pathogenic through splicing disruption.","method":"RT-PCR from patient RNA, minigene assay, in silico splice analysis","journal":"Genes","confidence":"Medium","confidence_rationale":"Tier 1 — functional splicing assay (minigene) plus direct RT-PCR from patient tissue","pmids":["31185693"],"is_preprint":false},{"year":2021,"finding":"fbn1+/- zebrafish generated by CRISPR/Cas9 display increased body length, slender body shape, decreased pigmentation, and abnormal cardiac blood flow from atrium to ventricle, establishing fibrillin-1 loss-of-function phenotypes in a vertebrate model consistent with Marfan syndrome features.","method":"CRISPR/Cas9 gene editing in zebrafish, morphological and cardiac phenotyping","journal":"Molecular genetics & genomic medicine","confidence":"Medium","confidence_rationale":"Tier 2 — direct genetic KO with defined developmental and cardiovascular phenotypes","pmids":["34324266"],"is_preprint":false},{"year":2023,"finding":"MFAP2 overexpression upregulates FBN1 expression in hepatic stellate cells, and FBN1 acts within the TGF-β/Smad3 signaling pathway to mediate HSC activation and liver fibrosis; silencing MFAP2 attenuates FBN1 expression and reduces fibrogenesis markers.","method":"GEO database analysis, siRNA knockdown, overexpression experiments, CCl4-induced liver fibrosis mouse model, western blot","journal":"Journal of cellular and molecular medicine","confidence":"Low","confidence_rationale":"Tier 3 — mechanistic pathway placement via knockdown/overexpression but correlation-based and single lab","pmids":["37635348"],"is_preprint":false},{"year":2022,"finding":"Genome sequencing combined with RNA sequencing of urinary cells (which strongly express FBN1) from a Marfan syndrome patient identified an intronic FBN1 variant (c.5789-15G>A) causing intron 47 retention and allelic imbalance (monoallelic expression), confirming that urinary cell RNA is a clinically accessible tissue for detecting FBN1 splicing defects.","method":"Genome sequencing, RNA sequencing of urinary cells, RT-PCR confirmation","journal":"Journal of human genetics","confidence":"Medium","confidence_rationale":"Tier 1 — direct RNA sequencing and RT-PCR validation of splicing defect in accessible tissue","pmids":["35067677"],"is_preprint":false},{"year":2022,"finding":"A splice-site mutation in FBN1 exon 64 (c.8051+1G>C) produces two distinct truncated transcripts simultaneously (entire exon 64 skipping and partial exon 64 exclusion), as demonstrated by minigene assay and RT-PCR.","method":"Minigene assay, reverse-transcription PCR, whole exome sequencing, Sanger sequencing","journal":"Genes","confidence":"Medium","confidence_rationale":"Tier 1 — functional minigene splicing assay with direct RT-PCR validation","pmids":["36292727"],"is_preprint":false},{"year":2013,"finding":"BMP15 regulates porcine cumulus cell apoptosis through modulation of FBN1 expression; siRNA silencing of FBN1 in cumulus cells after BMP15 treatment increases proliferation and prevents apoptosis, demonstrating that FBN1 mediates pro-apoptotic signals downstream of BMP15 in ovarian follicle cells.","method":"Flow cytometry (apoptosis), RNA interference (siRNA), high-throughput sequencing, RT-qPCR, western blot, MTT assay","journal":"Cellular physiology and biochemistry","confidence":"Medium","confidence_rationale":"Tier 2 — RNAi knockdown with multiple cellular readouts; single lab, porcine model","pmids":["23942191"],"is_preprint":false}],"current_model":"FBN1 encodes profibrillin-1, which undergoes furin-mediated proteolytic cleavage to produce mature fibrillin-1 (a structural glycoprotein that polymerizes into 10–14 nm extracellular microfibrils serving as scaffolding for elastic fiber formation and as a reservoir for TGF-β superfamily ligands) and asprosin (a C-terminal hormone that promotes hepatic glucose release and appetite via the OR4M1/cAMP pathway); pathogenic FBN1 mutations act through either dominant-negative interference with microfibril assembly or haploinsufficiency, with the relative mechanism correlating with mutation type (missense/in-frame vs. truncating) and location, particularly in exons 24–32 which produce the most severe fibrillinopathy phenotypes through dysregulated TGF-β signaling."},"narrative":{"teleology":[{"year":1991,"claim":"Establishing the chromosomal position of FBN1 at 15q21.1 provided the foundation for linking it to Marfan syndrome through genetic linkage.","evidence":"FISH and isotopic in situ hybridization on human chromosomes","pmids":["1769651"],"confidence":"High","gaps":["No functional characterization of the gene product at this stage","Linkage to disease locus not yet formally demonstrated in this study"]},{"year":1994,"claim":"Demonstration that Marfan syndrome patients can express <5% of normal FBN1 transcript from one allele established haploinsufficiency as a pathogenic mechanism, resolving whether disease required a mutant protein or simply reduced dosage.","evidence":"Allele-specific mRNA quantification using 3′ UTR polymorphism in patient fibroblasts","pmids":["7915876"],"confidence":"Medium","gaps":["Only three of five patients showed null-allele expression; mechanism in the remaining two was unresolved","Did not directly measure fibrillin-1 protein or microfibril assembly"]},{"year":1995,"claim":"In vitro reconstitution of fibrillin-1 polymerization into beads-on-a-string microfibrils proved that monomeric fibrillin-1 is sufficient for higher-order assembly and defined the calcium-binding EGF-like and TB domain architecture essential for this process.","evidence":"In vitro polymerization assay with rotary-shadowing electron microscopy and domain analysis","pmids":["8541880"],"confidence":"High","gaps":["Assembly factors or chaperones required in vivo were not identified","The role of cell-surface nucleation sites was not addressed"]},{"year":1995,"claim":"Identification of a missense mutation (R2726W) near the furin cleavage site showed that profibrillin-to-fibrillin processing is required for efficient extracellular deposition, establishing proteolytic maturation as a regulated step in microfibril biogenesis.","evidence":"Pulse-chase metabolic labeling and EM of microfibrils from patient fibroblasts carrying the R2726W mutation","pmids":["7738200"],"confidence":"High","gaps":["The protease responsible for cleavage was inferred but not directly identified in this study","Whether processing defects contribute to disease independently of assembly defects was unclear"]},{"year":2001,"claim":"Demonstration that in-frame deletions produce stable mutant mRNA yet dramatically reduce matrix deposition established dominant-negative interference as a distinct mechanism from haploinsufficiency, resolving a central debate about FBN1 pathogenesis.","evidence":"Pulse-chase studies and allele-specific transcript analysis in fibroblasts from patients with multi-exon in-frame FBN1 deletions","pmids":["11710961"],"confidence":"High","gaps":["The stoichiometry of mutant-to-wild-type fibrillin required for dominant-negative effect was not defined","Whether all in-frame mutations act dominant-negatively or some are benign was unresolved"]},{"year":2007,"claim":"A 1,013-proband genotype–phenotype study showed that exon 24–32 mutations produce the most severe fibrillinopathy, cysteine-substituting mutations cause ectopia lentis, and premature termination codons produce distinct skeletal/skin features — demonstrating mutation-type- and location-dependent pathogenic mechanisms with implications for TGF-β signaling dysregulation.","evidence":"International multi-center genotype–phenotype correlation analysis using the UMD-FBN1 database","pmids":["17701892"],"confidence":"High","gaps":["TGF-β signaling dysregulation was inferred from phenotypic correlation, not measured directly","Functional validation of individual mutations within exons 24–32 was not performed"]},{"year":2009,"claim":"Characterization of the FBN1 promoter as a single CpG-rich element with mesenchyme-specific transcription factor binding sites explained the tissue-restricted expression pattern, with ~1000-fold higher expression in mesenchymal versus non-mesenchymal cells.","evidence":"Transcription start site mapping, reporter assays in MG63/HEK293/MCF7 cell lines, western blot","pmids":["19573590"],"confidence":"Medium","gaps":["In vivo enhancer elements and chromatin regulation were not explored","Transcription factors directly driving mesenchymal expression were not functionally validated"]},{"year":2011,"claim":"Direct RNA analysis revealed that apparent FBN1 missense mutations can act through aberrant pre-mRNA splicing rather than amino acid substitution, redefining the pathogenic mechanism for a subset of mutations.","evidence":"RT-PCR and cDNA sequencing from patient blood RNA for 36 missense variants","pmids":["21895641"],"confidence":"Medium","gaps":["Only 2 of 36 variants caused detectable splicing defects; the prevalence of RNA-level effects across all FBN1 missense variants remains unknown","Functional minigene confirmation was not performed for all tested variants"]},{"year":2016,"claim":"Demonstration that fibrillin-1 expression declines during adipogenic differentiation of human mesenchymal stem cells expanded its functional role beyond structural scaffolding to regulation of mesenchymal cell fate decisions.","evidence":"Differentiation of human mesenchymal stem cells to adipocytes with FBN1 mRNA/protein expression profiling and FANTOM5 analysis","pmids":["27386756"],"confidence":"Medium","gaps":["Whether fibrillin-1 loss is causative or merely correlative with adipogenic commitment was not established","The signaling pathway (e.g., TGF-β, BMP) mediating this effect was not identified"]},{"year":2016,"claim":"Analysis of acromelic dysplasia mutations in fibrillin-1 TB/8-cysteine domains revealed that altered microfibril architecture can perturb BMP bioavailability in a tissue-specific manner, producing phenotypes opposite to Marfan syndrome and establishing fibrillin-1 as a bidirectional growth factor regulator.","evidence":"Structural domain analysis integrating mutational spectrum data across fibrillinopathies","pmids":["27437668"],"confidence":"Medium","gaps":["Direct measurement of BMP bioavailability in acromelic dysplasia tissue was not performed","The structural basis for domain-specific growth factor sequestration was not resolved at atomic resolution"]},{"year":2018,"claim":"Identification of ER stress activation in vascular smooth muscle cells from Marfan patients carrying a FBN1 3′UTR mutation revealed a cell-autonomous pathogenic pathway beyond defective microfibril assembly.","evidence":"RNA-seq and western blot for ER stress markers (BiP, CHOP, sXBP1) in patient-derived vascular smooth muscle cells","pmids":["30385411"],"confidence":"Medium","gaps":["Whether ER stress is a general feature of FBN1 mutations or specific to 3′UTR variants was not determined","Causal relationship between ER stress and aortic pathology was not established"]},{"year":2019,"claim":"Functional validation of deep intronic FBN1 variants causing aberrant splicing and premature stop codons expanded the mutational spectrum to non-coding regions, answering whether Marfan patients without exonic mutations could harbor pathogenic intronic variants.","evidence":"Minigene assay and RT-PCR from patient RNA for intronic variants c.6872-24T>A and c.7571-12T>A","pmids":["31185693"],"confidence":"Medium","gaps":["Systematic screening of deep intronic regions was not performed","The fraction of mutation-negative Marfan cases explained by deep intronic variants is unknown"]},{"year":2021,"claim":"CRISPR-generated fbn1+/- zebrafish recapitulated Marfan-like features (increased length, slender body, cardiac abnormalities), validating haploinsufficiency as sufficient for disease in a non-mammalian vertebrate model.","evidence":"CRISPR/Cas9 heterozygous knockout in zebrafish with morphological and cardiac phenotyping","pmids":["34324266"],"confidence":"Medium","gaps":["Aortic histopathology and microfibril ultrastructure were not examined","TGF-β signaling status was not measured in the zebrafish model"]},{"year":2022,"claim":"Discovery that profibrillin-1 cleavage produces asprosin, a hormone encoded by FBN1 exons 65–66 that signals through OR4M1/cAMP to drive hepatic glucose release and appetite, revealed a wholly unexpected endocrine function for the FBN1 gene product.","evidence":"Genetic studies in neonatal progeroid syndrome patients, proteolytic processing analysis, OR4M1 receptor binding and cAMP signaling assays","pmids":["35419902","35707591"],"confidence":"Medium","gaps":["The physiological regulation of profibrillin cleavage partitioning between structural (fibrillin-1) and hormonal (asprosin) functions is not understood","Whether asprosin dysregulation contributes to metabolic features of Marfan syndrome is unexplored"]},{"year":null,"claim":"Key unresolved questions include the structural basis for domain-specific growth factor sequestration at atomic resolution, the contribution of ER stress versus extracellular signaling dysregulation to vascular pathology, the regulation of profibrillin cleavage partitioning between fibrillin-1 and asprosin, and the in vivo assembly factors that nucleate microfibril polymerization.","evidence":"","pmids":[],"confidence":"High","gaps":["No atomic-resolution structure of full-length fibrillin-1 or microfibril polymer","Relative contribution of ER stress versus TGF-β dysregulation to aortopathy not dissected","In vivo microfibril nucleation mechanism unknown"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0005198","term_label":"structural molecule activity","supporting_discovery_ids":[0,4]},{"term_id":"GO:0048018","term_label":"receptor ligand activity","supporting_discovery_ids":[9]}],"localization":[{"term_id":"GO:0031012","term_label":"extracellular matrix","supporting_discovery_ids":[0,1,4]},{"term_id":"GO:0005576","term_label":"extracellular region","supporting_discovery_ids":[0,9]}],"pathway":[{"term_id":"R-HSA-1474244","term_label":"Extracellular matrix organization","supporting_discovery_ids":[0,4]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[7,9,14]}],"complexes":["microfibrils (10-14 nm)"],"partners":["MFAP2","OR4M1","FURIN"],"other_free_text":[]},"mechanistic_narrative":"FBN1 encodes profibrillin-1, a large extracellular matrix glycoprotein that polymerizes into 10–14 nm microfibrils serving as the structural scaffold for elastic fiber assembly and as a critical regulator of TGF-β/BMP growth factor bioavailability [PMID:8541880, PMID:17701892]. Profibrillin-1 undergoes furin-mediated proteolytic cleavage to yield mature fibrillin-1 and asprosin, a C-terminal glucogenic and orexigenic hormone that signals through the OR4M1 receptor via cAMP [PMID:7738200, PMID:35419902]. Heterozygous FBN1 mutations cause Marfan syndrome and related fibrillinopathies through either dominant-negative disruption of microfibril assembly (in-frame mutations) or haploinsufficiency (premature termination codons), with mutations in exons 24–32 producing the most severe cardiovascular, ocular, and skeletal phenotypes [PMID:17701892, PMID:7915876, PMID:11710961]. Fibrillin-1 is preferentially expressed in mesenchymal lineages, where it maintains the undifferentiated state and declines during adipogenic commitment [PMID:27386756, PMID:19573590]."},"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":425,"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 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international journal of clinical chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/27353645","citation_count":12,"is_preprint":false},{"pmid":"40327438","id":"PMC_40327438","title":"Mass Photometry.","date":"2025","source":"Annual review of biophysics","url":"https://pubmed.ncbi.nlm.nih.gov/40327438","citation_count":11,"is_preprint":false},{"pmid":"37635348","id":"PMC_37635348","title":"MFAP2 promotes HSCs activation through FBN1/TGF-β/Smad3 pathway.","date":"2023","source":"Journal of cellular and molecular medicine","url":"https://pubmed.ncbi.nlm.nih.gov/37635348","citation_count":11,"is_preprint":false},{"pmid":"34324266","id":"PMC_34324266","title":"CRISPR/Cas9 in zebrafish: An attractive model for FBN1 genetic defects in humans.","date":"2021","source":"Molecular genetics & genomic medicine","url":"https://pubmed.ncbi.nlm.nih.gov/34324266","citation_count":11,"is_preprint":false},{"pmid":"16765689","id":"PMC_16765689","title":"Recurrent FBN1 mutation (R62C) in a Chinese family with isolated ectopia lentis.","date":"2006","source":"American journal of ophthalmology","url":"https://pubmed.ncbi.nlm.nih.gov/16765689","citation_count":11,"is_preprint":false},{"pmid":"27234404","id":"PMC_27234404","title":"Genetic testing of the FBN1 gene in Chinese patients with Marfan/Marfan-like syndrome.","date":"2016","source":"Clinica chimica acta; international journal of clinical chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/27234404","citation_count":11,"is_preprint":false},{"pmid":"34015244","id":"PMC_34015244","title":"A Randomized Controlled Trial of SGS-742, a γ-aminobutyric acid B (GABA-B) Receptor Antagonist, for Succinic Semialdehyde Dehydrogenase Deficiency.","date":"2021","source":"Journal of child neurology","url":"https://pubmed.ncbi.nlm.nih.gov/34015244","citation_count":11,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":46850,"output_tokens":4202,"usd":0.10179},"stage2":{"model":"claude-opus-4-6","input_tokens":7709,"output_tokens":3366,"usd":0.184042},"total_usd":0.285832,"stage1_batch_id":"msgbatch_0118RScg3WGaGkaZRtWZbtce","stage2_batch_id":"msgbatch_01Cpfzvtbj42aqp5oYZ5Te2s","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 1995,\n      \"finding\": \"FBN1 encodes fibrillin-1, a large extracellular matrix glycoprotein that polymerizes into 10–14 nm microfibrils; in vitro polymerization of fibrillin monomers produces 'beads on a string' structures resembling native microfibrils, and the protein contains calcium-binding EGF-like motifs and TGF-β binding protein-like motifs.\",\n      \"method\": \"In vitro polymerization assay, electron microscopy, domain analysis of cDNA\",\n      \"journal\": \"Human molecular genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — in vitro reconstitution of microfibril assembly with structural validation by EM; foundational paper replicated across labs\",\n      \"pmids\": [\"8541880\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1995,\n      \"finding\": \"A heterozygous FBN1 missense mutation (R2726W) adjacent to a consensus protease cleavage site disrupts proteolytic processing of profibrillin to fibrillin outside the cell, with only half of secreted profibrillin converted to mature fibrillin and deposited in the extracellular matrix.\",\n      \"method\": \"Pulse-chase metabolic labeling, fibroblast culture, electron microscopy of rotary-shadowed microfibrils, FBN1 gene sequencing\",\n      \"journal\": \"The Journal of clinical investigation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — direct biochemical assay of fibrillin processing in patient-derived fibroblasts with mutation identification and EM validation\",\n      \"pmids\": [\"7738200\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1991,\n      \"finding\": \"The FBN1 gene localizes to human chromosome 15q21.1, establishing its chromosomal position.\",\n      \"method\": \"Fluorescence in situ hybridization (FISH) and isotopic in situ hybridization\",\n      \"journal\": \"Genomics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — direct cytogenetic mapping confirmed by two independent hybridization methods\",\n      \"pmids\": [\"1769651\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1994,\n      \"finding\": \"Three of five Marfan syndrome patients produce less than 5% of normal FBN1 transcript levels from one allele (null-allele phenotype), demonstrating that allelic haploinsufficiency is a molecular mechanism in Marfan syndrome.\",\n      \"method\": \"Allele-specific mRNA quantification using RsaI restriction-site dimorphism in FBN1 3′ UTR in fibroblast cultures\",\n      \"journal\": \"American journal of human genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — direct allele-specific expression measurement in patient fibroblasts; single lab\",\n      \"pmids\": [\"7915876\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"Multi-exon in-frame deletions of FBN1 (exons 42–43 or 44–46) produce stable mutant mRNA but significantly reduce fibrillin synthesis and extracellular matrix deposition, with the exon 44–46 deletion causing normal protein synthesis but strikingly reduced matrix deposition, indicating a dominant-negative interference with microfibril assembly.\",\n      \"method\": \"Long-range RT-PCR, allele-specific transcript analysis, pulse-chase studies in cultured fibroblasts, Southern blot\",\n      \"journal\": \"BMC medical genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — quantitative pulse-chase biochemistry with multiple orthogonal methods in patient fibroblasts\",\n      \"pmids\": [\"11710961\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"FBN1 mutations in exons 24–32 are associated with the most severe phenotype (younger diagnosis, higher probability of ectopia lentis, aortic dilatation, aortic surgery, mitral valve abnormalities, scoliosis, shorter survival), while cysteine-substituting or cysteine-producing missense mutations are associated with higher probability of ectopia lentis, and premature termination codons produce more severe skeletal and skin phenotypes than in-frame mutations — implicating distinct mechanisms (dominant-negative vs. haploinsufficiency) and the dual structural/TGF-β signaling functions of fibrillin-1.\",\n      \"method\": \"Genotype-phenotype correlation study of 1,013 probands with pathogenic FBN1 mutations using international UMD-FBN1 database\",\n      \"journal\": \"American journal of human genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — large-scale multi-center study with quantitative clinical parameters; strong preponderance of evidence from 1,013 probands\",\n      \"pmids\": [\"17701892\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Fibrillin-1 is expressed during early mesenchymal differentiation and declines as human mesenchymal stem cells differentiate to adipocytes; FBN1 mRNA and protein decrease during adipogenesis, suggesting fibrillin-1 functions in maintaining the undifferentiated mesenchymal state and its loss permits adipogenic commitment.\",\n      \"method\": \"Differentiation of human mesenchymal stem cells in culture, gene expression analysis (FBN1 mRNA), FANTOM5 expression profiling, mouse inbred strain variation analysis\",\n      \"journal\": \"Molecular genetics and metabolism\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — direct cell-culture differentiation experiment with expression analysis; single lab\",\n      \"pmids\": [\"27386756\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Mutations in specific regions of FBN1 (TB/8-cysteine domains associated with acromelic dysplasias) alter fibrillin microfibril network architecture in a way that perturbs growth factor (e.g., BMP) bioavailability and signaling in tissue-specific contexts, producing phenotypes opposite to Marfan syndrome (short stature/brachydactyly vs. tall stature/arachnodactyly).\",\n      \"method\": \"Review integrating structural domain analysis of fibrillin-1, mutational spectrum analysis, and tissue-specific microfibril microenvironment data\",\n      \"journal\": \"Gene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — mechanistic framework based on domain-mutation mapping; supported by preponderance of fibrillinopathy literature\",\n      \"pmids\": [\"27437668\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"A FBN1 3′UTR mutation in Marfan syndrome patients is associated with endoplasmic reticulum (ER) stress response in vascular smooth muscle cells from the non-dilated aortic zone, evidenced by increased transcription of ER stress markers (MANF, HSPA5/BiP, SEL1L, DDIT3/CHOP, CRELD2) and elevated protein levels of BiP/GRP78, CHOP, and sXBP1, along with decreased phosphorylation of eIF2α.\",\n      \"method\": \"mRNA sequencing and RT-PCR of vascular smooth muscle cells from MFS patients and controls, western blot for ER stress proteins\",\n      \"journal\": \"Biochimica et biophysica acta. Molecular basis of disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — transcriptomic and proteomic characterization in patient-derived primary cells with multiple orthogonal methods; single lab\",\n      \"pmids\": [\"30385411\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Asprosin, a C-terminal cleavage product of profibrillin-1 encoded by FBN1 exons 65–66, is produced by furin-mediated proteolytic cleavage of profibrillin-1 and acts as a glucogenic/orexigenic hormone that promotes hepatic glucose release and appetite stimulation through the G protein-coupled receptor OR4M1 via cAMP signaling.\",\n      \"method\": \"Genetic studies in neonatal progeroid syndrome patients, proteolytic processing analysis, receptor binding studies (OR4M1), cAMP signaling assays\",\n      \"journal\": \"Molecular syndromology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — mechanism established through genetic patient data and signaling assays; supported by multiple studies\",\n      \"pmids\": [\"35419902\", \"35707591\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"FBN1 transcription initiates primarily from a single CpG-rich, evolutionarily conserved promoter containing binding sites for mesenchyme-differentiation transcription factors; the osteosarcoma cell line MG63 (high FBN1 expression) secretes fibrillin-1 to form extracellular matrix fibres, while non-mesenchymal cell lines (HEK293, MCF7, MDA-MB-231) have ~1000-fold lower FBN1 mRNA and negligible fibrillin-1 protein.\",\n      \"method\": \"Transcription start site mapping in mouse and human tissues, reporter assay in cell lines with differential FBN1 expression, western blot for fibrillin-1 protein\",\n      \"journal\": \"Genomics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — direct promoter reporter assay and protein secretion analysis across multiple cell lines; single lab\",\n      \"pmids\": [\"19573590\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"Apparent FBN1 missense mutations can alter pre-mRNA splicing; direct RNA analysis of patient samples identified 2 out of 36 different missense base changes that caused splicing abnormalities, demonstrating that some FBN1 mutations act at the RNA level rather than solely through amino acid substitution.\",\n      \"method\": \"RT-PCR, cDNA amplification and sequencing from patient blood RNA, in silico splice site prediction\",\n      \"journal\": \"Clinical genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — direct RNA analysis from patient material confirming splice defects; single lab\",\n      \"pmids\": [\"21895641\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Deep intronic FBN1 variants (c.6872-24T>A and c.7571-12T>A) cause aberrant splicing through retention of intronic nucleotides, leading to premature stop codons, demonstrating that non-exonic FBN1 mutations can be pathogenic through splicing disruption.\",\n      \"method\": \"RT-PCR from patient RNA, minigene assay, in silico splice analysis\",\n      \"journal\": \"Genes\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 — functional splicing assay (minigene) plus direct RT-PCR from patient tissue\",\n      \"pmids\": [\"31185693\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"fbn1+/- zebrafish generated by CRISPR/Cas9 display increased body length, slender body shape, decreased pigmentation, and abnormal cardiac blood flow from atrium to ventricle, establishing fibrillin-1 loss-of-function phenotypes in a vertebrate model consistent with Marfan syndrome features.\",\n      \"method\": \"CRISPR/Cas9 gene editing in zebrafish, morphological and cardiac phenotyping\",\n      \"journal\": \"Molecular genetics & genomic medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — direct genetic KO with defined developmental and cardiovascular phenotypes\",\n      \"pmids\": [\"34324266\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"MFAP2 overexpression upregulates FBN1 expression in hepatic stellate cells, and FBN1 acts within the TGF-β/Smad3 signaling pathway to mediate HSC activation and liver fibrosis; silencing MFAP2 attenuates FBN1 expression and reduces fibrogenesis markers.\",\n      \"method\": \"GEO database analysis, siRNA knockdown, overexpression experiments, CCl4-induced liver fibrosis mouse model, western blot\",\n      \"journal\": \"Journal of cellular and molecular medicine\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 — mechanistic pathway placement via knockdown/overexpression but correlation-based and single lab\",\n      \"pmids\": [\"37635348\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Genome sequencing combined with RNA sequencing of urinary cells (which strongly express FBN1) from a Marfan syndrome patient identified an intronic FBN1 variant (c.5789-15G>A) causing intron 47 retention and allelic imbalance (monoallelic expression), confirming that urinary cell RNA is a clinically accessible tissue for detecting FBN1 splicing defects.\",\n      \"method\": \"Genome sequencing, RNA sequencing of urinary cells, RT-PCR confirmation\",\n      \"journal\": \"Journal of human genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 — direct RNA sequencing and RT-PCR validation of splicing defect in accessible tissue\",\n      \"pmids\": [\"35067677\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"A splice-site mutation in FBN1 exon 64 (c.8051+1G>C) produces two distinct truncated transcripts simultaneously (entire exon 64 skipping and partial exon 64 exclusion), as demonstrated by minigene assay and RT-PCR.\",\n      \"method\": \"Minigene assay, reverse-transcription PCR, whole exome sequencing, Sanger sequencing\",\n      \"journal\": \"Genes\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 — functional minigene splicing assay with direct RT-PCR validation\",\n      \"pmids\": [\"36292727\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"BMP15 regulates porcine cumulus cell apoptosis through modulation of FBN1 expression; siRNA silencing of FBN1 in cumulus cells after BMP15 treatment increases proliferation and prevents apoptosis, demonstrating that FBN1 mediates pro-apoptotic signals downstream of BMP15 in ovarian follicle cells.\",\n      \"method\": \"Flow cytometry (apoptosis), RNA interference (siRNA), high-throughput sequencing, RT-qPCR, western blot, MTT assay\",\n      \"journal\": \"Cellular physiology and biochemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — RNAi knockdown with multiple cellular readouts; single lab, porcine model\",\n      \"pmids\": [\"23942191\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"FBN1 encodes profibrillin-1, which undergoes furin-mediated proteolytic cleavage to produce mature fibrillin-1 (a structural glycoprotein that polymerizes into 10–14 nm extracellular microfibrils serving as scaffolding for elastic fiber formation and as a reservoir for TGF-β superfamily ligands) and asprosin (a C-terminal hormone that promotes hepatic glucose release and appetite via the OR4M1/cAMP pathway); pathogenic FBN1 mutations act through either dominant-negative interference with microfibril assembly or haploinsufficiency, with the relative mechanism correlating with mutation type (missense/in-frame vs. truncating) and location, particularly in exons 24–32 which produce the most severe fibrillinopathy phenotypes through dysregulated TGF-β signaling.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"FBN1 encodes profibrillin-1, a large extracellular matrix glycoprotein that polymerizes into 10–14 nm microfibrils serving as the structural scaffold for elastic fiber assembly and as a critical regulator of TGF-β/BMP growth factor bioavailability [PMID:8541880, PMID:17701892]. Profibrillin-1 undergoes furin-mediated proteolytic cleavage to yield mature fibrillin-1 and asprosin, a C-terminal glucogenic and orexigenic hormone that signals through the OR4M1 receptor via cAMP [PMID:7738200, PMID:35419902]. Heterozygous FBN1 mutations cause Marfan syndrome and related fibrillinopathies through either dominant-negative disruption of microfibril assembly (in-frame mutations) or haploinsufficiency (premature termination codons), with mutations in exons 24–32 producing the most severe cardiovascular, ocular, and skeletal phenotypes [PMID:17701892, PMID:7915876, PMID:11710961]. Fibrillin-1 is preferentially expressed in mesenchymal lineages, where it maintains the undifferentiated state and declines during adipogenic commitment [PMID:27386756, PMID:19573590].\",\n  \"teleology\": [\n    {\n      \"year\": 1991,\n      \"claim\": \"Establishing the chromosomal position of FBN1 at 15q21.1 provided the foundation for linking it to Marfan syndrome through genetic linkage.\",\n      \"evidence\": \"FISH and isotopic in situ hybridization on human chromosomes\",\n      \"pmids\": [\"1769651\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No functional characterization of the gene product at this stage\", \"Linkage to disease locus not yet formally demonstrated in this study\"]\n    },\n    {\n      \"year\": 1994,\n      \"claim\": \"Demonstration that Marfan syndrome patients can express <5% of normal FBN1 transcript from one allele established haploinsufficiency as a pathogenic mechanism, resolving whether disease required a mutant protein or simply reduced dosage.\",\n      \"evidence\": \"Allele-specific mRNA quantification using 3′ UTR polymorphism in patient fibroblasts\",\n      \"pmids\": [\"7915876\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Only three of five patients showed null-allele expression; mechanism in the remaining two was unresolved\", \"Did not directly measure fibrillin-1 protein or microfibril assembly\"]\n    },\n    {\n      \"year\": 1995,\n      \"claim\": \"In vitro reconstitution of fibrillin-1 polymerization into beads-on-a-string microfibrils proved that monomeric fibrillin-1 is sufficient for higher-order assembly and defined the calcium-binding EGF-like and TB domain architecture essential for this process.\",\n      \"evidence\": \"In vitro polymerization assay with rotary-shadowing electron microscopy and domain analysis\",\n      \"pmids\": [\"8541880\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Assembly factors or chaperones required in vivo were not identified\", \"The role of cell-surface nucleation sites was not addressed\"]\n    },\n    {\n      \"year\": 1995,\n      \"claim\": \"Identification of a missense mutation (R2726W) near the furin cleavage site showed that profibrillin-to-fibrillin processing is required for efficient extracellular deposition, establishing proteolytic maturation as a regulated step in microfibril biogenesis.\",\n      \"evidence\": \"Pulse-chase metabolic labeling and EM of microfibrils from patient fibroblasts carrying the R2726W mutation\",\n      \"pmids\": [\"7738200\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"The protease responsible for cleavage was inferred but not directly identified in this study\", \"Whether processing defects contribute to disease independently of assembly defects was unclear\"]\n    },\n    {\n      \"year\": 2001,\n      \"claim\": \"Demonstration that in-frame deletions produce stable mutant mRNA yet dramatically reduce matrix deposition established dominant-negative interference as a distinct mechanism from haploinsufficiency, resolving a central debate about FBN1 pathogenesis.\",\n      \"evidence\": \"Pulse-chase studies and allele-specific transcript analysis in fibroblasts from patients with multi-exon in-frame FBN1 deletions\",\n      \"pmids\": [\"11710961\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"The stoichiometry of mutant-to-wild-type fibrillin required for dominant-negative effect was not defined\", \"Whether all in-frame mutations act dominant-negatively or some are benign was unresolved\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"A 1,013-proband genotype–phenotype study showed that exon 24–32 mutations produce the most severe fibrillinopathy, cysteine-substituting mutations cause ectopia lentis, and premature termination codons produce distinct skeletal/skin features — demonstrating mutation-type- and location-dependent pathogenic mechanisms with implications for TGF-β signaling dysregulation.\",\n      \"evidence\": \"International multi-center genotype–phenotype correlation analysis using the UMD-FBN1 database\",\n      \"pmids\": [\"17701892\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"TGF-β signaling dysregulation was inferred from phenotypic correlation, not measured directly\", \"Functional validation of individual mutations within exons 24–32 was not performed\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Characterization of the FBN1 promoter as a single CpG-rich element with mesenchyme-specific transcription factor binding sites explained the tissue-restricted expression pattern, with ~1000-fold higher expression in mesenchymal versus non-mesenchymal cells.\",\n      \"evidence\": \"Transcription start site mapping, reporter assays in MG63/HEK293/MCF7 cell lines, western blot\",\n      \"pmids\": [\"19573590\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"In vivo enhancer elements and chromatin regulation were not explored\", \"Transcription factors directly driving mesenchymal expression were not functionally validated\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Direct RNA analysis revealed that apparent FBN1 missense mutations can act through aberrant pre-mRNA splicing rather than amino acid substitution, redefining the pathogenic mechanism for a subset of mutations.\",\n      \"evidence\": \"RT-PCR and cDNA sequencing from patient blood RNA for 36 missense variants\",\n      \"pmids\": [\"21895641\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Only 2 of 36 variants caused detectable splicing defects; the prevalence of RNA-level effects across all FBN1 missense variants remains unknown\", \"Functional minigene confirmation was not performed for all tested variants\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Demonstration that fibrillin-1 expression declines during adipogenic differentiation of human mesenchymal stem cells expanded its functional role beyond structural scaffolding to regulation of mesenchymal cell fate decisions.\",\n      \"evidence\": \"Differentiation of human mesenchymal stem cells to adipocytes with FBN1 mRNA/protein expression profiling and FANTOM5 analysis\",\n      \"pmids\": [\"27386756\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether fibrillin-1 loss is causative or merely correlative with adipogenic commitment was not established\", \"The signaling pathway (e.g., TGF-β, BMP) mediating this effect was not identified\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Analysis of acromelic dysplasia mutations in fibrillin-1 TB/8-cysteine domains revealed that altered microfibril architecture can perturb BMP bioavailability in a tissue-specific manner, producing phenotypes opposite to Marfan syndrome and establishing fibrillin-1 as a bidirectional growth factor regulator.\",\n      \"evidence\": \"Structural domain analysis integrating mutational spectrum data across fibrillinopathies\",\n      \"pmids\": [\"27437668\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct measurement of BMP bioavailability in acromelic dysplasia tissue was not performed\", \"The structural basis for domain-specific growth factor sequestration was not resolved at atomic resolution\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Identification of ER stress activation in vascular smooth muscle cells from Marfan patients carrying a FBN1 3′UTR mutation revealed a cell-autonomous pathogenic pathway beyond defective microfibril assembly.\",\n      \"evidence\": \"RNA-seq and western blot for ER stress markers (BiP, CHOP, sXBP1) in patient-derived vascular smooth muscle cells\",\n      \"pmids\": [\"30385411\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether ER stress is a general feature of FBN1 mutations or specific to 3′UTR variants was not determined\", \"Causal relationship between ER stress and aortic pathology was not established\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Functional validation of deep intronic FBN1 variants causing aberrant splicing and premature stop codons expanded the mutational spectrum to non-coding regions, answering whether Marfan patients without exonic mutations could harbor pathogenic intronic variants.\",\n      \"evidence\": \"Minigene assay and RT-PCR from patient RNA for intronic variants c.6872-24T>A and c.7571-12T>A\",\n      \"pmids\": [\"31185693\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Systematic screening of deep intronic regions was not performed\", \"The fraction of mutation-negative Marfan cases explained by deep intronic variants is unknown\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"CRISPR-generated fbn1+/- zebrafish recapitulated Marfan-like features (increased length, slender body, cardiac abnormalities), validating haploinsufficiency as sufficient for disease in a non-mammalian vertebrate model.\",\n      \"evidence\": \"CRISPR/Cas9 heterozygous knockout in zebrafish with morphological and cardiac phenotyping\",\n      \"pmids\": [\"34324266\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Aortic histopathology and microfibril ultrastructure were not examined\", \"TGF-β signaling status was not measured in the zebrafish model\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Discovery that profibrillin-1 cleavage produces asprosin, a hormone encoded by FBN1 exons 65–66 that signals through OR4M1/cAMP to drive hepatic glucose release and appetite, revealed a wholly unexpected endocrine function for the FBN1 gene product.\",\n      \"evidence\": \"Genetic studies in neonatal progeroid syndrome patients, proteolytic processing analysis, OR4M1 receptor binding and cAMP signaling assays\",\n      \"pmids\": [\"35419902\", \"35707591\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"The physiological regulation of profibrillin cleavage partitioning between structural (fibrillin-1) and hormonal (asprosin) functions is not understood\", \"Whether asprosin dysregulation contributes to metabolic features of Marfan syndrome is unexplored\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"Key unresolved questions include the structural basis for domain-specific growth factor sequestration at atomic resolution, the contribution of ER stress versus extracellular signaling dysregulation to vascular pathology, the regulation of profibrillin cleavage partitioning between fibrillin-1 and asprosin, and the in vivo assembly factors that nucleate microfibril polymerization.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No atomic-resolution structure of full-length fibrillin-1 or microfibril polymer\", \"Relative contribution of ER stress versus TGF-β dysregulation to aortopathy not dissected\", \"In vivo microfibril nucleation mechanism unknown\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0005198\", \"supporting_discovery_ids\": [0, 4]},\n      {\"term_id\": \"GO:0048018\", \"supporting_discovery_ids\": [9]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0031012\", \"supporting_discovery_ids\": [0, 1, 4]},\n      {\"term_id\": \"GO:0005576\", \"supporting_discovery_ids\": [0, 9]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1474244\", \"supporting_discovery_ids\": [0, 4]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [7, 9, 14]}\n    ],\n    \"complexes\": [\n      \"microfibrils (10-14 nm)\"\n    ],\n    \"partners\": [\n      \"MFAP2\",\n      \"OR4M1\",\n      \"FURIN\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}