{"gene":"ADAMTSL2","run_date":"2026-04-28T17:12:37","timeline":{"discoveries":[{"year":2008,"finding":"ADAMTSL2 interacts with latent TGF-β-binding protein 1 (LTBP1), as identified by yeast two-hybrid screen; loss-of-function mutations in ADAMTSL2 lead to increased total and active TGF-β in culture medium and nuclear localization of phosphorylated SMAD2 in patient fibroblasts, demonstrating ADAMTSL2 as a regulator of TGF-β bioavailability.","method":"Yeast two-hybrid screen; functional studies in HEK293 cells; phospho-SMAD2 nuclear localization in patient fibroblasts","journal":"Nature genetics","confidence":"High","confidence_rationale":"Tier 2 — reciprocal interaction identified by Y2H, functional TGF-β signaling readout in patient cells, replicated across labs in subsequent studies","pmids":["18677313"],"is_preprint":false},{"year":2007,"finding":"ADAMTSL2 is a secreted glycoprotein that binds to the cell surface and extracellular matrix; it contains 7 thrombospondin type-1 repeats and an unusually long spacer module with six N-glycosylation sites, with N-linked carbohydrate constituting ~20% of its mass; expression is regulated during skeletal myogenesis downstream of MyoD.","method":"Protein expression in HEK293F and COS-1 cells; northern blotting; in situ hybridization; immunohistochemistry; in vitro myogenic differentiation assay","journal":"Matrix biology","confidence":"Medium","confidence_rationale":"Tier 2 — direct localization and biochemical characterization in multiple cell systems, functional link to myogenesis via MyoD activation","pmids":["17509843"],"is_preprint":false},{"year":2010,"finding":"The Musladin-Lueke Syndrome (MLS) founder mutation p.R221C in ADAMTSL2 causes formation of anomalous disulfide-bonded dimers when expressed in COS-1, HEK293F and CHO cells, and results in reduced secretion of the mutant protein into the medium.","method":"Transient expression in COS-1, HEK293F, CHO cells; SDS-PAGE under reducing/non-reducing conditions; medium protein quantification","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 — direct biochemical demonstration of aberrant disulfide bonding in multiple cell lines","pmids":["20862248"],"is_preprint":false},{"year":2015,"finding":"ADAMTSL2 binds directly to fibrillin-2 (FBN2) with an affinity comparable to fibrillin-1 (FBN1); loss of Adamtsl2 in mice leads to accumulation of fibrillin microfibrils, increased FBN2 and MAGP1 staining, increased LTBP1 in bronchial epithelium, and increased bronchial epithelial TGFβ signaling, revealing a role for ADAMTSL2 in modulating microfibril formation.","method":"Direct binding assay (solid-phase binding); immunostaining of Adamtsl2−/− mouse tissue; TGFβ-neutralizing antibody treatment; lacZ reporter expression analysis","journal":"Disease models & mechanisms","confidence":"High","confidence_rationale":"Tier 1-2 — direct binding assay for FBN2, knockout mouse model with multiple orthogonal readouts including signaling and matrix staining","pmids":["25762570"],"is_preprint":false},{"year":2018,"finding":"Adamtsl2 deletion in chondrocytes impairs growth plate formation, disrupts chondrocyte differentiation and proliferation, impairs TGF-β signaling in limbs, and prevents establishment of a microfibrillar network composed of fibrillin-1 and LTBP1 fibrils in chondrocytes.","method":"Total and chondrocyte-specific Adamtsl2 knockout mice; histology of growth plates; immunostaining for fibrillin-1, LTBP1; TGF-β signaling assays","journal":"FASEB journal","confidence":"High","confidence_rationale":"Tier 2 — conditional and total KO mice with multiple orthogonal mechanistic readouts","pmids":["30303737"],"is_preprint":false},{"year":2019,"finding":"ADAMTSL2 is strongly expressed in limb tendons and regulates microfibril assembly therein; conditional deletion using Prx1-Cre causes tendon anomalies and distal limb shortening; recombinant ADAMTSL2 colocalizes with fibrillin microfibrils in vitro; enhanced fibrillin-1 microfibril staining is observed in Prx1-Cre Adamtsl2 tendons, suggesting ADAMTSL2 limits fibrillin microfibril assembly.","method":"Intragenic lacZ reporter expression analysis; conditional KO with Prx1-Cre and Scx-Cre; in vitro colocalization assay with recombinant ADAMTSL2; immunostaining","journal":"Matrix biology","confidence":"High","confidence_rationale":"Tier 2 — conditional KO with two independent Cre lines, in vitro colocalization, immunostaining, multiple orthogonal approaches","pmids":["30738849"],"is_preprint":false},{"year":2020,"finding":"ADAMTSL2 thrombospondin type-1 repeats (TSRs) are modified by O-fucosylation via POFUT2 and subsequently elongated to a Glcβ1-3Fuc disaccharide by B3GLCT; O-fucosylation is required for ADAMTSL2 secretion (secretion is lost in POFUT2−/− but not B3GLCT−/− cells); the geleophysic dysplasia mutation S641L in TSR3 eliminates O-fucosylation of TSR3 and reduces secretion.","method":"Mass spectrometry glycan mapping; POFUT2−/− and B3GLCT−/− cell secretion assays; site-directed mutagenesis of GPHYSD1 mutations","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 — MS identification of glycan sites, knockout cell lines, mutagenesis; multiple orthogonal methods in one study","pmids":["32913123"],"is_preprint":false},{"year":2019,"finding":"Pathogenic ADAMTSL2 missense variants result in defective intracellular localization of the mutant protein, failure to accumulate in lysosome-like inclusions, reduced secretion into medium, and increased SMAD2 phosphorylation in transfected HEK293 cells, linking impaired secretion to TGF-β signaling dysregulation.","method":"Electron microscopy of patient skin fibroblasts; transfection of HEK293 cells; SMAD2 phosphorylation assay","journal":"Molecular genetics and metabolism reports","confidence":"Medium","confidence_rationale":"Tier 2-3 — electron microscopy localization plus functional TGF-β signaling readout in transfected cells","pmids":["31516831"],"is_preprint":false},{"year":2021,"finding":"ADAMTSL2 overexpression or extracellular treatment in human cardiac fibroblasts reduces TGF-β production and signaling, attenuates myofibroblast differentiation (reduced α-smooth muscle actin and osteopontin), and inhibits pro-fibrotic phenotypes including proliferation, migration, and contractility.","method":"Overexpression and recombinant protein treatment in human cardiac fibroblasts; TGFβ signaling assays; myofibroblast differentiation markers; functional assays for proliferation, migration, contractility","journal":"Scientific reports","confidence":"Medium","confidence_rationale":"Tier 2 — gain-of-function with recombinant protein plus overexpression, multiple functional readouts in human cells","pmids":["34611183"],"is_preprint":false},{"year":2021,"finding":"Mutated ADAMTSL2 variants identified in adolescent idiopathic scoliosis patients affect the interaction between ADAMTSL2 and LTBP4, and these variant pairs upregulate TGF-β signaling in human fibroblasts.","method":"Co-immunoprecipitation/interaction assay with ADAMTSL2 and LTBP4 variants; TGF-β signaling assay in human fibroblasts","journal":"Gene","confidence":"Medium","confidence_rationale":"Tier 3 — single lab, interaction assay with mutant proteins plus signaling readout","pmids":["34958866"],"is_preprint":false},{"year":2025,"finding":"Fibroblast-secreted ADAMTSL2 directly binds to LRP6 (as shown by Co-IP) and promotes LRP6 phosphorylation, leading to β-catenin stabilization and nuclear translocation in cardiomyocytes, protecting against apoptosis post-myocardial infarction; fibroblast-targeted overexpression in vivo reduces infarct size and adverse remodeling.","method":"Co-immunoprecipitation; LRP6 phosphorylation assay; β-catenin nuclear translocation; cardiomyocyte apoptosis assay; adenoviral overexpression in mouse MI model","journal":"Cellular signalling","confidence":"Medium","confidence_rationale":"Tier 2 — direct binding by Co-IP with downstream phosphorylation and nuclear translocation readouts, in vivo validation","pmids":["40975504"],"is_preprint":false},{"year":2025,"finding":"ADAMTSL2 activates Notch signaling to transcriptionally upregulate ACLY, driving lipid metabolic reprogramming in colorectal cancer cells; ADAMTSL2 knockdown suppresses proliferation and migration in HCT116 and SW620 cells and in patient-derived organoids.","method":"ADAMTSL2 knockdown in CRC cell lines and patient-derived organoids; xenograft models; Notch signaling pathway analysis; ACLY expression assay","journal":"Cellular signalling","confidence":"Low","confidence_rationale":"Tier 3 — single lab, knockdown phenotype with pathway inference, no direct binding demonstrated","pmids":["41407175"],"is_preprint":false},{"year":2025,"finding":"Primary dermal fibroblasts from GD patients with ADAMTSL2 variants show impaired secretion of ECM proteins (ADAMTSL2, FBN1, fibronectin), increased cell migration associated with upregulation of MMP-1 and MMP-14; these findings were corroborated in Adamtsl2-knockout mouse fibroblasts and lung/heart tissues; pan-MMP inhibitor GM6001 inhibits GD fibroblast migration.","method":"Primary human and mouse fibroblast isolation; ECM secretion assays; cell migration assay; MMP-1/MMP-14 expression; GM6001 pharmacological inhibition; Adamtsl2 KO mouse tissue analysis","journal":"bioRxiv","confidence":"Medium","confidence_rationale":"Tier 2 — human patient and mouse model fibroblasts, pharmacological rescue, multiple orthogonal methods; preprint","pmids":[],"is_preprint":true},{"year":2023,"finding":"Adamtsl2 nonsense mutation in mice causes disturbed endochondral ossification with a reduced hypertrophic chondrocyte layer, stiff skin with thickened dermis, uterine hypoplasia, and irregular estrous cycles; reduced IGF1 plasma levels in mutant females suggest Adamtsl2 acts in the ovary/pituitary to regulate reproductive development.","method":"Linkage analysis; histology of growth plate and skin; Adamtsl2 mRNA expression in reproductive organs; plasma IGF1 and estradiol measurement; Gh expression in pituitary","journal":"Mammalian genome","confidence":"Medium","confidence_rationale":"Tier 2 — loss-of-function mouse with multiple tissue phenotypes and hormonal readouts","pmids":["37656189"],"is_preprint":false}],"current_model":"ADAMTSL2 is a secreted extracellular matrix glycoprotein whose TSRs are modified by O-fucosylation (required for secretion); it interacts with LTBP1, LTBP4, FBN1, and FBN2 to regulate fibrillin microfibril assembly and TGF-β bioavailability, and also binds LRP6 to activate β-catenin signaling, with loss of function leading to microfibril dysregulation, enhanced TGF-β/SMAD2 signaling, impaired chondrogenesis and tendon growth, and increased MMP-driven cell migration, collectively explaining the connective tissue, skeletal, and cardiac pathology of geleophysic dysplasia."},"narrative":{"teleology":[{"year":2007,"claim":"Establishing ADAMTSL2 as a heavily glycosylated secreted ECM protein with TSR repeats, and linking its expression to MyoD-driven myogenesis, provided the first molecular characterization of the gene product.","evidence":"Protein expression in HEK293F/COS-1 cells; northern blotting; in vitro myogenic differentiation assay","pmids":["17509843"],"confidence":"Medium","gaps":["No binding partners or functional role in ECM assembly identified","Relevance beyond myogenesis unknown"]},{"year":2008,"claim":"Identifying LTBP1 as a direct ADAMTSL2 interactor and showing that ADAMTSL2 loss-of-function mutations cause elevated TGF-β and nuclear pSMAD2 established the gene as a regulator of TGF-β bioavailability and linked it to geleophysic dysplasia.","evidence":"Yeast two-hybrid screen; functional studies in HEK293 cells; pSMAD2 immunostaining in patient fibroblasts","pmids":["18677313"],"confidence":"High","gaps":["Mechanism by which ADAMTSL2–LTBP1 interaction constrains TGF-β release not resolved","Relationship to fibrillin microfibrils not yet tested"]},{"year":2010,"claim":"Demonstrating that the MLS founder mutation p.R221C generates anomalous disulfide-bonded dimers with reduced secretion showed that pathogenic variants impair ADAMTSL2 export rather than simply altering ECM function.","evidence":"SDS-PAGE under reducing/non-reducing conditions in COS-1, HEK293F, CHO cells","pmids":["20862248"],"confidence":"Medium","gaps":["Canine model; direct translation to human geleophysic dysplasia mechanism not confirmed","Downstream ECM and signaling consequences of reduced secretion not measured"]},{"year":2015,"claim":"Showing that ADAMTSL2 binds FBN2 directly and that Adamtsl2-null mice accumulate excess fibrillin microfibrils with enhanced bronchial TGF-β signaling revealed ADAMTSL2 as a negative regulator of microfibril assembly.","evidence":"Solid-phase binding assay; immunostaining and TGF-β-neutralizing antibody treatment in Adamtsl2−/− mouse tissues","pmids":["25762570"],"confidence":"High","gaps":["Mechanism by which ADAMTSL2 limits microfibril assembly (inhibition vs. turnover) not distinguished","Relative contributions of FBN1 vs. FBN2 binding not dissected"]},{"year":2018,"claim":"Conditional deletion in chondrocytes demonstrated that ADAMTSL2 is required cell-autonomously for growth plate formation, chondrocyte differentiation, TGF-β signaling in limbs, and establishment of a fibrillin-1/LTBP1 microfibrillar network.","evidence":"Total and chondrocyte-specific Adamtsl2 knockout mice; growth plate histology; immunostaining; TGF-β assays","pmids":["30303737"],"confidence":"High","gaps":["Whether ADAMTSL2 promotes microfibril assembly directly or stabilizes it indirectly unclear","Signaling consequences in hypertrophic vs. proliferative chondrocytes not separated"]},{"year":2019,"claim":"Two advances refined tissue-specific roles: (1) conditional limb deletion showed ADAMTSL2 limits fibrillin microfibril assembly in tendons, and (2) pathogenic missense variants caused intracellular retention with defective secretion and increased pSMAD2, linking secretion failure to TGF-β dysregulation.","evidence":"Conditional KO with Prx1-Cre/Scx-Cre; in vitro colocalization; electron microscopy of patient fibroblasts; SMAD2 phosphorylation in HEK293 cells","pmids":["30738849","31516831"],"confidence":"High","gaps":["Whether ADAMTSL2 acts by sequestering latent TGF-β vs. promoting its degradation not resolved","The fate of intracellularly retained mutant ADAMTSL2 (ER stress vs. degradation) not fully characterized"]},{"year":2020,"claim":"Mapping O-fucosylation of ADAMTSL2 TSRs and showing that POFUT2-dependent modification is essential for secretion established glycosylation as a quality-control checkpoint and explained how the GD mutation S641L impairs secretion by eliminating TSR3 O-fucosylation.","evidence":"Mass spectrometry glycan mapping; POFUT2−/− and B3GLCT−/− cell secretion assays; site-directed mutagenesis","pmids":["32913123"],"confidence":"High","gaps":["Whether O-fucosylation also affects ADAMTSL2 binding to fibrillin or LTBPs not tested","Contribution of each individual TSR to secretion not fully mapped"]},{"year":2021,"claim":"Two studies expanded ADAMTSL2 functions beyond skeletal tissues: recombinant ADAMTSL2 attenuated TGF-β signaling and myofibroblast differentiation in cardiac fibroblasts, and ADAMTSL2–LTBP4 interaction disruption by scoliosis-associated variants upregulated TGF-β signaling.","evidence":"Overexpression and recombinant protein in human cardiac fibroblasts; Co-IP of ADAMTSL2–LTBP4 variants; TGF-β assays in fibroblasts","pmids":["34611183","34958866"],"confidence":"Medium","gaps":["LTBP4 interaction confirmed by single Co-IP approach; reciprocal domain-mapping not performed","Cardiac anti-fibrotic role demonstrated only in vitro"]},{"year":2023,"claim":"Adamtsl2 nonsense mutation in mice recapitulated endochondral ossification defects, stiff skin, and additionally revealed uterine hypoplasia and reduced IGF1, broadening the phenotypic spectrum to reproductive and endocrine systems.","evidence":"Mouse linkage analysis; growth plate and skin histology; plasma IGF1 and estradiol measurement","pmids":["37656189"],"confidence":"Medium","gaps":["Whether IGF1 reduction is a direct consequence of ECM disruption or a secondary endocrine defect is unknown","Ovarian and pituitary mechanisms not dissected at the molecular level"]},{"year":2025,"claim":"ADAMTSL2 was shown to bind LRP6, activate β-catenin signaling in cardiomyocytes, and protect against post-MI apoptosis, revealing a TGF-β-independent signaling axis through Wnt/β-catenin.","evidence":"Co-immunoprecipitation; LRP6 phosphorylation; β-catenin nuclear translocation; adenoviral overexpression in mouse MI model","pmids":["40975504"],"confidence":"Medium","gaps":["Single Co-IP without reciprocal pull-down or domain mapping for LRP6 interaction","Whether LRP6 binding and LTBP/fibrillin binding are independent or coordinated is unknown","In vivo cardiac benefit demonstrated only in acute MI; chronic effects not assessed"]},{"year":null,"claim":"Key unresolved questions include the structural basis for ADAMTSL2 binding to fibrillins/LTBPs, the precise mechanism by which ADAMTSL2 limits microfibril assembly (competitive inhibition vs. promoting turnover), and whether the LRP6/Wnt signaling axis operates in skeletal tissues affected in geleophysic dysplasia.","evidence":"","pmids":[],"confidence":"High","gaps":["No crystal or cryo-EM structure of ADAMTSL2 or its complexes","Mechanism of microfibril assembly limitation (sequestration vs. turnover) not distinguished","Crosstalk between TGF-β and Wnt/β-catenin axes downstream of ADAMTSL2 not explored"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[0,3,4,5,8]},{"term_id":"GO:0060089","term_label":"molecular transducer activity","supporting_discovery_ids":[10]}],"localization":[{"term_id":"GO:0031012","term_label":"extracellular matrix","supporting_discovery_ids":[1,3,5]},{"term_id":"GO:0005576","term_label":"extracellular region","supporting_discovery_ids":[1,6]}],"pathway":[{"term_id":"R-HSA-1474244","term_label":"Extracellular matrix organization","supporting_discovery_ids":[3,4,5]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[0,8,10]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[4,13]}],"complexes":[],"partners":["LTBP1","LTBP4","FBN1","FBN2","LRP6","POFUT2"],"other_free_text":[]},"mechanistic_narrative":"ADAMTSL2 is a secreted extracellular matrix glycoprotein that orchestrates fibrillin microfibril assembly and TGF-β bioavailability in connective tissues. It directly binds LTBP1, LTBP4, FBN1, and FBN2, and loss of ADAMTSL2 leads to excessive fibrillin microfibril accumulation, increased TGF-β release, and enhanced phospho-SMAD2 signaling, disrupting chondrocyte differentiation, growth plate formation, and tendon integrity [PMID:18677313, PMID:25762570, PMID:30303737, PMID:30738849]. O-Fucosylation of its thrombospondin type-1 repeats by POFUT2 is required for secretion, and geleophysic dysplasia mutations impair this modification and reduce ADAMTSL2 export, causally linking secretion defects to the skeletal and connective tissue pathology of geleophysic dysplasia [PMID:32913123, PMID:18677313]. ADAMTSL2 also signals through LRP6/β-catenin in cardiomyocytes to limit apoptosis after ischemic injury and attenuates myofibroblast differentiation in cardiac fibroblasts by suppressing TGF-β production [PMID:40975504, PMID:34611183]."},"prefetch_data":{"uniprot":{"accession":"Q86TH1","full_name":"ADAMTS-like protein 2","aliases":[],"length_aa":951,"mass_kda":104.6,"function":"","subcellular_location":"Secreted","url":"https://www.uniprot.org/uniprotkb/Q86TH1/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/ADAMTSL2","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/ADAMTSL2","total_profiled":1310},"omim":[{"mim_id":"617809","title":"GELEOPHYSIC DYSPLASIA 3; GPHYSD3","url":"https://www.omim.org/entry/617809"},{"mim_id":"614185","title":"GELEOPHYSIC DYSPLASIA 2; GPHYSD2","url":"https://www.omim.org/entry/614185"},{"mim_id":"612277","title":"ADAMTS-LIKE PROTEIN 2; ADAMTSL2","url":"https://www.omim.org/entry/612277"},{"mim_id":"602194","title":"HTRA SERINE PEPTIDASE 1; HTRA1","url":"https://www.omim.org/entry/602194"},{"mim_id":"600142","title":"CEREBRAL ARTERIOPATHY, AUTOSOMAL RECESSIVE, WITH SUBCORTICAL INFARCTS AND LEUKOENCEPHALOPATHY 2; CARASIL2","url":"https://www.omim.org/entry/600142"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Vesicles","reliability":"Approved"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"heart muscle","ntpm":71.2},{"tissue":"liver","ntpm":35.6}],"url":"https://www.proteinatlas.org/search/ADAMTSL2"},"hgnc":{"alias_symbol":["KIAA0605"],"prev_symbol":[]},"alphafold":{"accession":"Q86TH1","domains":[{"cath_id":"2.20.100.10","chopping":"49-79_93-195","consensus_level":"medium","plddt":81.252,"start":49,"end":195},{"cath_id":"2.60.120.830","chopping":"214-332","consensus_level":"high","plddt":84.9936,"start":214,"end":332},{"cath_id":"2.20.100,2.20.100","chopping":"567-620","consensus_level":"medium","plddt":80.2191,"start":567,"end":620},{"cath_id":"-","chopping":"740-853","consensus_level":"medium","plddt":85.8639,"start":740,"end":853},{"cath_id":"-","chopping":"911-951","consensus_level":"medium","plddt":68.7246,"start":911,"end":951}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q86TH1","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q86TH1-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q86TH1-F1-predicted_aligned_error_v6.png","plddt_mean":66.5},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=ADAMTSL2","jax_strain_url":"https://www.jax.org/strain/search?query=ADAMTSL2"},"sequence":{"accession":"Q86TH1","fasta_url":"https://rest.uniprot.org/uniprotkb/Q86TH1.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q86TH1/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q86TH1"}},"corpus_meta":[{"pmid":"18677313","id":"PMC_18677313","title":"ADAMTSL2 mutations in geleophysic dysplasia demonstrate a role for ADAMTS-like proteins in TGF-beta bioavailability regulation.","date":"2008","source":"Nature genetics","url":"https://pubmed.ncbi.nlm.nih.gov/18677313","citation_count":195,"is_preprint":false},{"pmid":"34600973","id":"PMC_34600973","title":"ADAMTSL2 protein and a soluble biomarker signature identify at-risk non-alcoholic steatohepatitis and fibrosis in adults with NAFLD.","date":"2021","source":"Journal of hepatology","url":"https://pubmed.ncbi.nlm.nih.gov/34600973","citation_count":63,"is_preprint":false},{"pmid":"25762570","id":"PMC_25762570","title":"Adamtsl2 deletion results in bronchial fibrillin microfibril accumulation and bronchial epithelial dysplasia--a novel mouse model providing insights into geleophysic dysplasia.","date":"2015","source":"Disease models & mechanisms","url":"https://pubmed.ncbi.nlm.nih.gov/25762570","citation_count":57,"is_preprint":false},{"pmid":"17509843","id":"PMC_17509843","title":"ADAMTS-like 2 (ADAMTSL2) is a secreted glycoprotein that is widely expressed during mouse embryogenesis and is regulated during skeletal myogenesis.","date":"2007","source":"Matrix biology : journal of the International Society for Matrix Biology","url":"https://pubmed.ncbi.nlm.nih.gov/17509843","citation_count":50,"is_preprint":false},{"pmid":"21415077","id":"PMC_21415077","title":"Molecular screening of ADAMTSL2 gene in 33 patients reveals the genetic heterogeneity of geleophysic dysplasia.","date":"2011","source":"Journal of medical genetics","url":"https://pubmed.ncbi.nlm.nih.gov/21415077","citation_count":46,"is_preprint":false},{"pmid":"34611183","id":"PMC_34611183","title":"The extracellular matrix glycoprotein ADAMTSL2 is increased in heart failure and inhibits TGFβ signalling in cardiac fibroblasts.","date":"2021","source":"Scientific 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the International Society for Matrix Biology","url":"https://pubmed.ncbi.nlm.nih.gov/30738849","citation_count":24,"is_preprint":false},{"pmid":"32913123","id":"PMC_32913123","title":"O-Fucosylation of ADAMTSL2 is required for secretion and is impacted by geleophysic dysplasia-causing mutations.","date":"2020","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/32913123","citation_count":22,"is_preprint":false},{"pmid":"31516831","id":"PMC_31516831","title":"Geleophysic dysplasia: novel missense variants and insights into ADAMTSL2 intracellular trafficking.","date":"2019","source":"Molecular genetics and metabolism reports","url":"https://pubmed.ncbi.nlm.nih.gov/31516831","citation_count":16,"is_preprint":false},{"pmid":"33369194","id":"PMC_33369194","title":"ADAMTSL2 gene variant in patients with features of autosomal dominant connective tissue disorders.","date":"2020","source":"American journal of medical genetics. Part A","url":"https://pubmed.ncbi.nlm.nih.gov/33369194","citation_count":13,"is_preprint":false},{"pmid":"34958866","id":"PMC_34958866","title":"Aberrant interaction between mutated ADAMTSL2 and LTBP4 is associated with adolescent idiopathic scoliosis.","date":"2021","source":"Gene","url":"https://pubmed.ncbi.nlm.nih.gov/34958866","citation_count":8,"is_preprint":false},{"pmid":"24014090","id":"PMC_24014090","title":"Novel mutations in ADAMTSL2 gene underlying geleophysic dysplasia in families from United Arab Emirates.","date":"2013","source":"Birth defects research. Part A, Clinical and molecular teratology","url":"https://pubmed.ncbi.nlm.nih.gov/24014090","citation_count":8,"is_preprint":false},{"pmid":"28917829","id":"PMC_28917829","title":"A chinese boy with geleophysic dysplasia caused by compound heterozygous mutations in ADAMTSL2.","date":"2017","source":"European journal of medical genetics","url":"https://pubmed.ncbi.nlm.nih.gov/28917829","citation_count":7,"is_preprint":false},{"pmid":"34936547","id":"PMC_34936547","title":"The relationship of ADAMTSL2 and LRPAP1 gene methylation level with rheumatoid arthritis activity.","date":"2021","source":"Clinical and experimental rheumatology","url":"https://pubmed.ncbi.nlm.nih.gov/34936547","citation_count":4,"is_preprint":false},{"pmid":"36246610","id":"PMC_36246610","title":"Case report: A homozygous ADAMTSL2 missense variant causes geleophysic dysplasia with high similarity to Weill-Marchesani syndrome.","date":"2022","source":"Frontiers in genetics","url":"https://pubmed.ncbi.nlm.nih.gov/36246610","citation_count":4,"is_preprint":false},{"pmid":"39384622","id":"PMC_39384622","title":"Exploring the role of ADAMTSL2 across multiple cancer types: A pan-cancer analysis and validated in colorectal cancer.","date":"2024","source":"Discover oncology","url":"https://pubmed.ncbi.nlm.nih.gov/39384622","citation_count":4,"is_preprint":false},{"pmid":"37656189","id":"PMC_37656189","title":"A nonsense mutation in mouse Adamtsl2 causes uterine hypoplasia and an irregular estrous cycle.","date":"2023","source":"Mammalian genome : official journal of the International Mammalian Genome Society","url":"https://pubmed.ncbi.nlm.nih.gov/37656189","citation_count":2,"is_preprint":false},{"pmid":"39044700","id":"PMC_39044700","title":"Geleophysic dysplasia and Weill-Marchesani syndrome: ADAMTSL2 a possible common gene.","date":"2024","source":"Ophthalmic 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Resolution","date":"2025-07-31","source":"bioRxiv","url":"https://doi.org/10.1101/2025.07.30.667675","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2025.06.08.658488","title":"Random survival forests identify myocardial gene signatures associated with survival in heart failure with preserved ejection fraction","date":"2025-06-11","source":"bioRxiv","url":"https://doi.org/10.1101/2025.06.08.658488","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":16690,"output_tokens":3626,"usd":0.05223},"stage2":{"model":"claude-opus-4-6","input_tokens":7127,"output_tokens":3013,"usd":0.16644},"total_usd":0.21867,"stage1_batch_id":"msgbatch_01TqNM6p6FsoMBT2jzQTwKBr","stage2_batch_id":"msgbatch_01Ya473eco8sTHbvRymQaU8o","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2008,\n      \"finding\": \"ADAMTSL2 interacts with latent TGF-β-binding protein 1 (LTBP1), as identified by yeast two-hybrid screen; loss-of-function mutations in ADAMTSL2 lead to increased total and active TGF-β in culture medium and nuclear localization of phosphorylated SMAD2 in patient fibroblasts, demonstrating ADAMTSL2 as a regulator of TGF-β bioavailability.\",\n      \"method\": \"Yeast two-hybrid screen; functional studies in HEK293 cells; phospho-SMAD2 nuclear localization in patient fibroblasts\",\n      \"journal\": \"Nature genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal interaction identified by Y2H, functional TGF-β signaling readout in patient cells, replicated across labs in subsequent studies\",\n      \"pmids\": [\"18677313\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"ADAMTSL2 is a secreted glycoprotein that binds to the cell surface and extracellular matrix; it contains 7 thrombospondin type-1 repeats and an unusually long spacer module with six N-glycosylation sites, with N-linked carbohydrate constituting ~20% of its mass; expression is regulated during skeletal myogenesis downstream of MyoD.\",\n      \"method\": \"Protein expression in HEK293F and COS-1 cells; northern blotting; in situ hybridization; immunohistochemistry; in vitro myogenic differentiation assay\",\n      \"journal\": \"Matrix biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — direct localization and biochemical characterization in multiple cell systems, functional link to myogenesis via MyoD activation\",\n      \"pmids\": [\"17509843\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"The Musladin-Lueke Syndrome (MLS) founder mutation p.R221C in ADAMTSL2 causes formation of anomalous disulfide-bonded dimers when expressed in COS-1, HEK293F and CHO cells, and results in reduced secretion of the mutant protein into the medium.\",\n      \"method\": \"Transient expression in COS-1, HEK293F, CHO cells; SDS-PAGE under reducing/non-reducing conditions; medium protein quantification\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — direct biochemical demonstration of aberrant disulfide bonding in multiple cell lines\",\n      \"pmids\": [\"20862248\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"ADAMTSL2 binds directly to fibrillin-2 (FBN2) with an affinity comparable to fibrillin-1 (FBN1); loss of Adamtsl2 in mice leads to accumulation of fibrillin microfibrils, increased FBN2 and MAGP1 staining, increased LTBP1 in bronchial epithelium, and increased bronchial epithelial TGFβ signaling, revealing a role for ADAMTSL2 in modulating microfibril formation.\",\n      \"method\": \"Direct binding assay (solid-phase binding); immunostaining of Adamtsl2−/− mouse tissue; TGFβ-neutralizing antibody treatment; lacZ reporter expression analysis\",\n      \"journal\": \"Disease models & mechanisms\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — direct binding assay for FBN2, knockout mouse model with multiple orthogonal readouts including signaling and matrix staining\",\n      \"pmids\": [\"25762570\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Adamtsl2 deletion in chondrocytes impairs growth plate formation, disrupts chondrocyte differentiation and proliferation, impairs TGF-β signaling in limbs, and prevents establishment of a microfibrillar network composed of fibrillin-1 and LTBP1 fibrils in chondrocytes.\",\n      \"method\": \"Total and chondrocyte-specific Adamtsl2 knockout mice; histology of growth plates; immunostaining for fibrillin-1, LTBP1; TGF-β signaling assays\",\n      \"journal\": \"FASEB journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — conditional and total KO mice with multiple orthogonal mechanistic readouts\",\n      \"pmids\": [\"30303737\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"ADAMTSL2 is strongly expressed in limb tendons and regulates microfibril assembly therein; conditional deletion using Prx1-Cre causes tendon anomalies and distal limb shortening; recombinant ADAMTSL2 colocalizes with fibrillin microfibrils in vitro; enhanced fibrillin-1 microfibril staining is observed in Prx1-Cre Adamtsl2 tendons, suggesting ADAMTSL2 limits fibrillin microfibril assembly.\",\n      \"method\": \"Intragenic lacZ reporter expression analysis; conditional KO with Prx1-Cre and Scx-Cre; in vitro colocalization assay with recombinant ADAMTSL2; immunostaining\",\n      \"journal\": \"Matrix biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — conditional KO with two independent Cre lines, in vitro colocalization, immunostaining, multiple orthogonal approaches\",\n      \"pmids\": [\"30738849\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"ADAMTSL2 thrombospondin type-1 repeats (TSRs) are modified by O-fucosylation via POFUT2 and subsequently elongated to a Glcβ1-3Fuc disaccharide by B3GLCT; O-fucosylation is required for ADAMTSL2 secretion (secretion is lost in POFUT2−/− but not B3GLCT−/− cells); the geleophysic dysplasia mutation S641L in TSR3 eliminates O-fucosylation of TSR3 and reduces secretion.\",\n      \"method\": \"Mass spectrometry glycan mapping; POFUT2−/− and B3GLCT−/− cell secretion assays; site-directed mutagenesis of GPHYSD1 mutations\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — MS identification of glycan sites, knockout cell lines, mutagenesis; multiple orthogonal methods in one study\",\n      \"pmids\": [\"32913123\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Pathogenic ADAMTSL2 missense variants result in defective intracellular localization of the mutant protein, failure to accumulate in lysosome-like inclusions, reduced secretion into medium, and increased SMAD2 phosphorylation in transfected HEK293 cells, linking impaired secretion to TGF-β signaling dysregulation.\",\n      \"method\": \"Electron microscopy of patient skin fibroblasts; transfection of HEK293 cells; SMAD2 phosphorylation assay\",\n      \"journal\": \"Molecular genetics and metabolism reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — electron microscopy localization plus functional TGF-β signaling readout in transfected cells\",\n      \"pmids\": [\"31516831\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"ADAMTSL2 overexpression or extracellular treatment in human cardiac fibroblasts reduces TGF-β production and signaling, attenuates myofibroblast differentiation (reduced α-smooth muscle actin and osteopontin), and inhibits pro-fibrotic phenotypes including proliferation, migration, and contractility.\",\n      \"method\": \"Overexpression and recombinant protein treatment in human cardiac fibroblasts; TGFβ signaling assays; myofibroblast differentiation markers; functional assays for proliferation, migration, contractility\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — gain-of-function with recombinant protein plus overexpression, multiple functional readouts in human cells\",\n      \"pmids\": [\"34611183\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Mutated ADAMTSL2 variants identified in adolescent idiopathic scoliosis patients affect the interaction between ADAMTSL2 and LTBP4, and these variant pairs upregulate TGF-β signaling in human fibroblasts.\",\n      \"method\": \"Co-immunoprecipitation/interaction assay with ADAMTSL2 and LTBP4 variants; TGF-β signaling assay in human fibroblasts\",\n      \"journal\": \"Gene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — single lab, interaction assay with mutant proteins plus signaling readout\",\n      \"pmids\": [\"34958866\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Fibroblast-secreted ADAMTSL2 directly binds to LRP6 (as shown by Co-IP) and promotes LRP6 phosphorylation, leading to β-catenin stabilization and nuclear translocation in cardiomyocytes, protecting against apoptosis post-myocardial infarction; fibroblast-targeted overexpression in vivo reduces infarct size and adverse remodeling.\",\n      \"method\": \"Co-immunoprecipitation; LRP6 phosphorylation assay; β-catenin nuclear translocation; cardiomyocyte apoptosis assay; adenoviral overexpression in mouse MI model\",\n      \"journal\": \"Cellular signalling\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — direct binding by Co-IP with downstream phosphorylation and nuclear translocation readouts, in vivo validation\",\n      \"pmids\": [\"40975504\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"ADAMTSL2 activates Notch signaling to transcriptionally upregulate ACLY, driving lipid metabolic reprogramming in colorectal cancer cells; ADAMTSL2 knockdown suppresses proliferation and migration in HCT116 and SW620 cells and in patient-derived organoids.\",\n      \"method\": \"ADAMTSL2 knockdown in CRC cell lines and patient-derived organoids; xenograft models; Notch signaling pathway analysis; ACLY expression assay\",\n      \"journal\": \"Cellular signalling\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 — single lab, knockdown phenotype with pathway inference, no direct binding demonstrated\",\n      \"pmids\": [\"41407175\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Primary dermal fibroblasts from GD patients with ADAMTSL2 variants show impaired secretion of ECM proteins (ADAMTSL2, FBN1, fibronectin), increased cell migration associated with upregulation of MMP-1 and MMP-14; these findings were corroborated in Adamtsl2-knockout mouse fibroblasts and lung/heart tissues; pan-MMP inhibitor GM6001 inhibits GD fibroblast migration.\",\n      \"method\": \"Primary human and mouse fibroblast isolation; ECM secretion assays; cell migration assay; MMP-1/MMP-14 expression; GM6001 pharmacological inhibition; Adamtsl2 KO mouse tissue analysis\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — human patient and mouse model fibroblasts, pharmacological rescue, multiple orthogonal methods; preprint\",\n      \"pmids\": [],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Adamtsl2 nonsense mutation in mice causes disturbed endochondral ossification with a reduced hypertrophic chondrocyte layer, stiff skin with thickened dermis, uterine hypoplasia, and irregular estrous cycles; reduced IGF1 plasma levels in mutant females suggest Adamtsl2 acts in the ovary/pituitary to regulate reproductive development.\",\n      \"method\": \"Linkage analysis; histology of growth plate and skin; Adamtsl2 mRNA expression in reproductive organs; plasma IGF1 and estradiol measurement; Gh expression in pituitary\",\n      \"journal\": \"Mammalian genome\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — loss-of-function mouse with multiple tissue phenotypes and hormonal readouts\",\n      \"pmids\": [\"37656189\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"ADAMTSL2 is a secreted extracellular matrix glycoprotein whose TSRs are modified by O-fucosylation (required for secretion); it interacts with LTBP1, LTBP4, FBN1, and FBN2 to regulate fibrillin microfibril assembly and TGF-β bioavailability, and also binds LRP6 to activate β-catenin signaling, with loss of function leading to microfibril dysregulation, enhanced TGF-β/SMAD2 signaling, impaired chondrogenesis and tendon growth, and increased MMP-driven cell migration, collectively explaining the connective tissue, skeletal, and cardiac pathology of geleophysic dysplasia.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"ADAMTSL2 is a secreted extracellular matrix glycoprotein that orchestrates fibrillin microfibril assembly and TGF-β bioavailability in connective tissues. It directly binds LTBP1, LTBP4, FBN1, and FBN2, and loss of ADAMTSL2 leads to excessive fibrillin microfibril accumulation, increased TGF-β release, and enhanced phospho-SMAD2 signaling, disrupting chondrocyte differentiation, growth plate formation, and tendon integrity [PMID:18677313, PMID:25762570, PMID:30303737, PMID:30738849]. O-Fucosylation of its thrombospondin type-1 repeats by POFUT2 is required for secretion, and geleophysic dysplasia mutations impair this modification and reduce ADAMTSL2 export, causally linking secretion defects to the skeletal and connective tissue pathology of geleophysic dysplasia [PMID:32913123, PMID:18677313]. ADAMTSL2 also signals through LRP6/β-catenin in cardiomyocytes to limit apoptosis after ischemic injury and attenuates myofibroblast differentiation in cardiac fibroblasts by suppressing TGF-β production [PMID:40975504, PMID:34611183].\",\n  \"teleology\": [\n    {\n      \"year\": 2007,\n      \"claim\": \"Establishing ADAMTSL2 as a heavily glycosylated secreted ECM protein with TSR repeats, and linking its expression to MyoD-driven myogenesis, provided the first molecular characterization of the gene product.\",\n      \"evidence\": \"Protein expression in HEK293F/COS-1 cells; northern blotting; in vitro myogenic differentiation assay\",\n      \"pmids\": [\"17509843\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"No binding partners or functional role in ECM assembly identified\",\n        \"Relevance beyond myogenesis unknown\"\n      ]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Identifying LTBP1 as a direct ADAMTSL2 interactor and showing that ADAMTSL2 loss-of-function mutations cause elevated TGF-β and nuclear pSMAD2 established the gene as a regulator of TGF-β bioavailability and linked it to geleophysic dysplasia.\",\n      \"evidence\": \"Yeast two-hybrid screen; functional studies in HEK293 cells; pSMAD2 immunostaining in patient fibroblasts\",\n      \"pmids\": [\"18677313\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Mechanism by which ADAMTSL2–LTBP1 interaction constrains TGF-β release not resolved\",\n        \"Relationship to fibrillin microfibrils not yet tested\"\n      ]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Demonstrating that the MLS founder mutation p.R221C generates anomalous disulfide-bonded dimers with reduced secretion showed that pathogenic variants impair ADAMTSL2 export rather than simply altering ECM function.\",\n      \"evidence\": \"SDS-PAGE under reducing/non-reducing conditions in COS-1, HEK293F, CHO cells\",\n      \"pmids\": [\"20862248\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Canine model; direct translation to human geleophysic dysplasia mechanism not confirmed\",\n        \"Downstream ECM and signaling consequences of reduced secretion not measured\"\n      ]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Showing that ADAMTSL2 binds FBN2 directly and that Adamtsl2-null mice accumulate excess fibrillin microfibrils with enhanced bronchial TGF-β signaling revealed ADAMTSL2 as a negative regulator of microfibril assembly.\",\n      \"evidence\": \"Solid-phase binding assay; immunostaining and TGF-β-neutralizing antibody treatment in Adamtsl2−/− mouse tissues\",\n      \"pmids\": [\"25762570\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Mechanism by which ADAMTSL2 limits microfibril assembly (inhibition vs. turnover) not distinguished\",\n        \"Relative contributions of FBN1 vs. FBN2 binding not dissected\"\n      ]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Conditional deletion in chondrocytes demonstrated that ADAMTSL2 is required cell-autonomously for growth plate formation, chondrocyte differentiation, TGF-β signaling in limbs, and establishment of a fibrillin-1/LTBP1 microfibrillar network.\",\n      \"evidence\": \"Total and chondrocyte-specific Adamtsl2 knockout mice; growth plate histology; immunostaining; TGF-β assays\",\n      \"pmids\": [\"30303737\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Whether ADAMTSL2 promotes microfibril assembly directly or stabilizes it indirectly unclear\",\n        \"Signaling consequences in hypertrophic vs. proliferative chondrocytes not separated\"\n      ]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Two advances refined tissue-specific roles: (1) conditional limb deletion showed ADAMTSL2 limits fibrillin microfibril assembly in tendons, and (2) pathogenic missense variants caused intracellular retention with defective secretion and increased pSMAD2, linking secretion failure to TGF-β dysregulation.\",\n      \"evidence\": \"Conditional KO with Prx1-Cre/Scx-Cre; in vitro colocalization; electron microscopy of patient fibroblasts; SMAD2 phosphorylation in HEK293 cells\",\n      \"pmids\": [\"30738849\", \"31516831\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Whether ADAMTSL2 acts by sequestering latent TGF-β vs. promoting its degradation not resolved\",\n        \"The fate of intracellularly retained mutant ADAMTSL2 (ER stress vs. degradation) not fully characterized\"\n      ]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Mapping O-fucosylation of ADAMTSL2 TSRs and showing that POFUT2-dependent modification is essential for secretion established glycosylation as a quality-control checkpoint and explained how the GD mutation S641L impairs secretion by eliminating TSR3 O-fucosylation.\",\n      \"evidence\": \"Mass spectrometry glycan mapping; POFUT2−/− and B3GLCT−/− cell secretion assays; site-directed mutagenesis\",\n      \"pmids\": [\"32913123\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Whether O-fucosylation also affects ADAMTSL2 binding to fibrillin or LTBPs not tested\",\n        \"Contribution of each individual TSR to secretion not fully mapped\"\n      ]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Two studies expanded ADAMTSL2 functions beyond skeletal tissues: recombinant ADAMTSL2 attenuated TGF-β signaling and myofibroblast differentiation in cardiac fibroblasts, and ADAMTSL2–LTBP4 interaction disruption by scoliosis-associated variants upregulated TGF-β signaling.\",\n      \"evidence\": \"Overexpression and recombinant protein in human cardiac fibroblasts; Co-IP of ADAMTSL2–LTBP4 variants; TGF-β assays in fibroblasts\",\n      \"pmids\": [\"34611183\", \"34958866\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"LTBP4 interaction confirmed by single Co-IP approach; reciprocal domain-mapping not performed\",\n        \"Cardiac anti-fibrotic role demonstrated only in vitro\"\n      ]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Adamtsl2 nonsense mutation in mice recapitulated endochondral ossification defects, stiff skin, and additionally revealed uterine hypoplasia and reduced IGF1, broadening the phenotypic spectrum to reproductive and endocrine systems.\",\n      \"evidence\": \"Mouse linkage analysis; growth plate and skin histology; plasma IGF1 and estradiol measurement\",\n      \"pmids\": [\"37656189\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Whether IGF1 reduction is a direct consequence of ECM disruption or a secondary endocrine defect is unknown\",\n        \"Ovarian and pituitary mechanisms not dissected at the molecular level\"\n      ]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"ADAMTSL2 was shown to bind LRP6, activate β-catenin signaling in cardiomyocytes, and protect against post-MI apoptosis, revealing a TGF-β-independent signaling axis through Wnt/β-catenin.\",\n      \"evidence\": \"Co-immunoprecipitation; LRP6 phosphorylation; β-catenin nuclear translocation; adenoviral overexpression in mouse MI model\",\n      \"pmids\": [\"40975504\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Single Co-IP without reciprocal pull-down or domain mapping for LRP6 interaction\",\n        \"Whether LRP6 binding and LTBP/fibrillin binding are independent or coordinated is unknown\",\n        \"In vivo cardiac benefit demonstrated only in acute MI; chronic effects not assessed\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"Key unresolved questions include the structural basis for ADAMTSL2 binding to fibrillins/LTBPs, the precise mechanism by which ADAMTSL2 limits microfibril assembly (competitive inhibition vs. promoting turnover), and whether the LRP6/Wnt signaling axis operates in skeletal tissues affected in geleophysic dysplasia.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"No crystal or cryo-EM structure of ADAMTSL2 or its complexes\",\n        \"Mechanism of microfibril assembly limitation (sequestration vs. turnover) not distinguished\",\n        \"Crosstalk between TGF-β and Wnt/β-catenin axes downstream of ADAMTSL2 not explored\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [0, 3, 4, 5, 8]},\n      {\"term_id\": \"GO:0060089\", \"supporting_discovery_ids\": [10]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0031012\", \"supporting_discovery_ids\": [1, 3, 5]},\n      {\"term_id\": \"GO:0005576\", \"supporting_discovery_ids\": [1, 6]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1474244\", \"supporting_discovery_ids\": [3, 4, 5]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [0, 8, 10]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [4, 13]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\n      \"LTBP1\",\n      \"LTBP4\",\n      \"FBN1\",\n      \"FBN2\",\n      \"LRP6\",\n      \"POFUT2\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}