{"gene":"ADAMTSL2","run_date":"2026-06-09T22:02:41","timeline":{"discoveries":[{"year":2008,"finding":"ADAMTSL2 interacts with latent TGF-β-binding protein 1 (LTBP1), identified by yeast two-hybrid screen. Disease-causing mutations in ADAMTSL2 reduce secretion of the mutated proteins (likely due to misfolding) and result in increased total and active TGF-β in culture medium and nuclear localization of phosphorylated SMAD2 in patient fibroblasts, indicating ADAMTSL2 regulates TGF-β bioavailability.","method":"Yeast two-hybrid screen for LTBP1 interaction; functional secretion assay in HEK293 cells; TGF-β measurement in culture medium; pSMAD2 immunolocalization in patient fibroblasts","journal":"Nature genetics","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (Y2H, secretion assay, TGF-β quantification, pSMAD2 localization), replicated across multiple patient-derived cell lines and independently confirmed in subsequent studies","pmids":["18677313"],"is_preprint":false},{"year":2007,"finding":"ADAMTSL2 is a secreted glycoprotein that binds cell surface and extracellular matrix; N-linked carbohydrate constitutes ~20% of its mass. Expression is regulated during skeletal myogenesis: Adamtsl2 mRNA is induced coordinately with myogenin upon myogenic differentiation in C2C12 and 23A2 cells, and by MyoD activation in 10T1/2 fibroblasts, but is absent in non-myogenic 9A2 cells.","method":"Expression in HEK293F and COS-1 cells with fractionation; northern blotting; in situ hybridization; immunohistochemistry; in vitro myogenic differentiation assays with serum starvation; MyoD forced expression","journal":"Matrix biology : journal of the International Society for Matrix Biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct cell fractionation showing ECM/cell-surface localization, and regulated expression linked to defined myogenic program using multiple cell lines and MyoD activation, single lab","pmids":["17509843"],"is_preprint":false},{"year":2010,"finding":"A missense mutation (p.R221C) in ADAMTSL2 causing Musladin-Lueke Syndrome (MLS) in beagles leads to formation of anomalous disulfide-bonded dimers and reduced secretion of the mutant protein compared to wild-type ADAMTSL2.","method":"Transient expression in COS-1, HEK293F, and CHO cells; SDS-PAGE/immunoblot analysis of disulfide bonding; conditioned medium quantification","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct biochemical characterization of mutant protein in multiple cell lines, single lab, orthogonal to human disease mutations","pmids":["20862248"],"is_preprint":false},{"year":2015,"finding":"ADAMTSL2 binds directly to fibrillin-2 (FBN2) with an affinity comparable to fibrillin-1 (FBN1). In Adamtsl2-/- mice, loss of ADAMTSL2 leads to accumulation of fibrillin microfibrils (increased FBN2 and MAGP1) and increased LTBP1 staining in bronchial epithelium, with increased bronchial epithelial TGFβ signaling. However, TGFβ-neutralizing antibody treatment did not correct the bronchial epithelial dysplasia in knockout mice.","method":"Direct binding assay (affinity measurement); Adamtsl2 global knockout mouse model; immunohistochemistry for FBN1, FBN2, MAGP1, LTBP1; TGFβ-neutralizing antibody treatment experiment; intragenic lacZ reporter for expression mapping","journal":"Disease models & mechanisms","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — direct binding affinity measurement for FBN2, combined with in vivo knockout model showing microfibril accumulation and negative result for TGFβ-neutralization rescue, multiple orthogonal methods","pmids":["25762570"],"is_preprint":false},{"year":2018,"finding":"ADAMTSL2 deficiency in chondrocytes impairs growth plate formation, causing abnormal chondrocyte differentiation and proliferation. Adamtsl2 KO chondrocytes fail to establish a microfibrillar network composed of fibrillin-1 and LTBP1 fibrils, and TGFβ signaling is impaired in Adamtsl2-deficient limbs.","method":"Total and chondrocyte-specific Adamtsl2 knockout mouse models; histological analysis of growth plate; immunofluorescence for fibrillin-1 and LTBP1 microfibril network; TGFβ signaling readouts in limb tissue","journal":"FASEB journal : official publication of the Federation of American Societies for Experimental Biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — two complementary conditional KO models with specific cellular phenotype (growth plate, microfibril network, TGFβ signaling), multiple orthogonal readouts, replicated findings","pmids":["30303737"],"is_preprint":false},{"year":2019,"finding":"ADAMTSL2 is strongly expressed in limb tendons and colocalizes with fibrillin microfibrils in vitro. Conditional deletion of Adamtsl2 in limb mesenchyme (Prx1-Cre) causes tendon anomalies, enhanced fibrillin-1 microfibril staining in tendons, and distal limb shortening. Tendon-specific deletion (Scx-Cre) also impairs skeletal growth, establishing that proper microfibril composition in tendons regulated by ADAMTSL2 is required for tendon and bone growth.","method":"Intragenic lacZ reporter for expression mapping; Prx1-Cre and Scx-Cre conditional knockout mice; recombinant ADAMTSL2 colocalization with fibrillin microfibrils in vitro; immunofluorescence for fibrillin-1 in tendons; skeletal morphometry","journal":"Matrix biology : journal of the International Society for Matrix Biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — two independent tissue-specific Cre lines producing consistent phenotypes, combined with in vitro colocalization and expression mapping, multiple orthogonal methods","pmids":["30738849"],"is_preprint":false},{"year":2019,"finding":"Disease-causing ADAMTSL2 missense variants impair intracellular trafficking of the mutant protein, which fails to accumulate in lysosome-like intracytoplasmic inclusions (shown by electron microscopy in patient skin fibroblasts). Mutant ADAMTSL2 is less secreted and results in increased SMAD2 phosphorylation when expressed in HEK293 cells.","method":"Electron microscopy of patient skin fibroblasts; transfection of mutant ADAMTSL2 in HEK293 cells; SMAD2 phosphorylation immunoblot; conditioned medium analysis","journal":"Molecular genetics and metabolism reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — electron microscopy for trafficking defect, combined with cell-based secretion and signaling assays, single lab","pmids":["31516831"],"is_preprint":false},{"year":2020,"finding":"ADAMTSL2 thrombospondin type-1 repeats (TSRs) are modified with O-fucose (by POFUT2) and glucose-β1,3-fucose disaccharide (by B3GLCT), as well as C-mannose. Loss of POFUT2 (but not B3GLCT) abolishes ADAMTSL2 secretion. The GD-causing mutation S641L in TSR3 eliminates O-fucosylation at that site and reduces secretion, establishing that O-fucosylation is required for ADAMTSL2 secretion.","method":"Mass spectrometry identification of glycan modifications on mouse ADAMTSL2; secretion assays in POFUT2-/- and B3GLCT-/- cells; site-directed mutagenesis of GD mutations (S641L, G817R); quantitative secretion measurement","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Strong — mass spectrometry identification of modifications combined with genetic KO cell lines and specific mutagenesis of disease alleles, multiple orthogonal methods","pmids":["32913123"],"is_preprint":false},{"year":2021,"finding":"ADAMTSL2 overexpression or treatment with extracellular ADAMTSL2 in human cardiac fibroblasts reduces TGFβ production and signaling, attenuates myofibroblast differentiation (reduced α-SMA and osteopontin), and mitigates pro-fibrotic phenotypes including proliferation, migration, and contractility. ADAMTSL2 functions as a negative regulator of TGFβ in cardiac fibroblasts.","method":"Overexpression and recombinant protein treatment in human cardiac fibroblasts; TGFβ ELISA; western blot for TGFβ signaling markers; myofibroblast differentiation assays; proliferation, migration, and contractility assays","journal":"Scientific reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — gain-of-function and recombinant protein treatment with multiple functional readouts in human primary cells, single lab","pmids":["34611183"],"is_preprint":false},{"year":2021,"finding":"Mutated ADAMTSL2 variants identified in adolescent idiopathic scoliosis patients disrupt the interaction between ADAMTSL2 and LTBP4, and variant pairs in ADAMTSL2-LTBP4 upregulate TGFβ signaling in human fibroblasts.","method":"Exome sequencing; co-immunoprecipitation or interaction assay for ADAMTSL2-LTBP4 variants; TGFβ signaling measurement in human fibroblasts","journal":"Gene","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — interaction assay for ADAMTSL2-LTBP4 with mutant variants and cell-based TGFβ signaling readout, single lab","pmids":["34958866"],"is_preprint":false},{"year":2023,"finding":"A nonsense mutation in mouse Adamtsl2 (stubby mouse) causes uterine hypoplasia and irregular estrous cycles. Adamtsl2 is expressed in ovary and pituitary gland. Loss of Adamtsl2 reduces plasma IGF1 levels (to 54-59% of wild-type) without affecting GH expression or estradiol levels, implicating Adamtsl2 in IGF1-dependent uterine development.","method":"Linkage analysis and identification of Adamtsl2 nonsense mutation; histological analysis of uterus and skin; estrous cycle monitoring; qRT-PCR for Gh; ELISA for plasma estradiol and IGF1","journal":"Mammalian genome : official journal of the International Mammalian Genome Society","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — loss-of-function mouse model with defined reproductive phenotype and mechanistic hormone measurements, single lab","pmids":["37656189"],"is_preprint":false},{"year":2025,"finding":"Fibroblast-secreted ADAMTSL2 directly binds LRP6 (shown by co-immunoprecipitation) and promotes LRP6 phosphorylation, leading to β-catenin stabilization and nuclear translocation in cardiomyocytes. ADAMTSL2 overexpression in cardiac fibroblasts attenuates OGD-induced cardiomyocyte apoptosis in vitro and reduces infarct size and adverse ventricular remodeling in vivo.","method":"Co-immunoprecipitation of ADAMTSL2 with LRP6; western blot for β-catenin and LRP6 phosphorylation; ADAMTSL2 overexpression/knockdown in neonatal rat cardiac fibroblasts with cardiomyocyte co-culture; adenovirus-mediated fibroblast-targeted overexpression in mouse MI model; apoptosis assays","journal":"Cellular signalling","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct binding shown by Co-IP with functional downstream signaling readouts and in vivo MI model, single lab","pmids":["40975504"],"is_preprint":false},{"year":2025,"finding":"In GD patient-derived dermal fibroblasts carrying ADAMTSL2 variants, secretion of ADAMTSL2, FBN1, and fibronectin is impaired. ADAMTSL2-variant fibroblasts show increased cell migration associated with upregulation of MMP-1 and MMP-14. Pan-MMP inhibitor GM6001 inhibits migration of GD fibroblasts, and MMP-1/MMP-14 upregulation is corroborated in Adamtsl2-knockout mouse tissues.","method":"Primary human and mouse dermal fibroblasts from GD patients/KO mice; secretion assays; migration assays; western blot and qRT-PCR for MMP-1/MMP-14; GM6001 pharmacological inhibition; lung/heart tissue analysis from Adamtsl2 KO mice","journal":"bioRxiv","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — patient-derived fibroblasts and KO mouse tissue with pharmacological rescue, multiple orthogonal methods, preprint only","pmids":["bio_10.1101_2025.01.30.635317"],"is_preprint":true},{"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 CRC cell lines and patient-derived organoids, and reduces tumor growth in xenograft models.","method":"ADAMTSL2 knockdown in HCT116 and SW620 cell lines; patient-derived organoids; xenograft models; Notch signaling pathway analysis; ACLY expression and activity assays","journal":"Cellular signalling","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, pathway activation inferred from knockdown experiments without direct binding or reconstitution of ADAMTSL2-Notch interaction","pmids":["41407175"],"is_preprint":false}],"current_model":"ADAMTSL2 is a secreted, O-fucosylated extracellular matrix glycoprotein that binds latent TGF-β-binding proteins (LTBP1, LTBP4) and fibrillin microfibrils (FBN1 and FBN2) to regulate microfibril assembly and TGF-β bioavailability; loss-of-function mutations reduce ADAMTSL2 secretion (impaired by misfolding or loss of O-fucosylation on TSRs), disrupt the fibrillin microfibril network in tendons, bronchial wall, and growth plate, increase active TGF-β and SMAD2 signaling, and cause geleophysic dysplasia, while extracellular ADAMTSL2 can also promote cardiac repair by directly binding LRP6 to activate β-catenin signaling and suppress fibroblast-to-myofibroblast differentiation by inhibiting TGFβ."},"narrative":{"mechanistic_narrative":"ADAMTSL2 is a secreted, glycosylated extracellular matrix protein that controls fibrillin microfibril assembly and TGF-β bioavailability during skeletal and connective tissue development [PMID:17509843, PMID:25762570, PMID:30303737]. It binds the latent TGF-β-binding proteins LTBP1 and LTBP4 and the fibrillins FBN1 and FBN2 with comparable affinity, and colocalizes with fibrillin microfibrils [PMID:18677313, PMID:25762570, PMID:30738849, PMID:34958866]. Through these interactions ADAMTSL2 organizes the microfibrillar network: its loss in mice causes accumulation of fibrillin microfibrils, LTBP1, and MAGP1 in bronchial epithelium and dysregulated TGFβ signaling, while chondrocyte- and tendon-specific deletion disrupts the FBN1/LTBP1 network and impairs growth plate formation, tendon integrity, and skeletal growth [PMID:25762570, PMID:30303737, PMID:30738849]. Proper biogenesis requires O-fucosylation of its thrombospondin type-1 repeats by POFUT2; loss of POFUT2 or the geleophysic dysplasia mutation S641L abolishes O-fucose at TSR3 and blocks secretion [PMID:32913123]. Disease-causing missense mutations cause misfolding, anomalous disulfide-bonded dimers, defective intracellular trafficking, and reduced secretion, with consequent increases in active TGF-β and nuclear phospho-SMAD2 in patient fibroblasts, establishing ADAMTSL2 loss-of-function as the basis of geleophysic dysplasia [PMID:18677313, PMID:20862248, PMID:31516831, PMID:32913123]. Beyond development, extracellular ADAMTSL2 acts as a negative regulator of TGFβ in cardiac fibroblasts to suppress myofibroblast differentiation, and directly binds LRP6 to drive LRP6 phosphorylation and β-catenin stabilization, promoting cardiac repair [PMID:34611183, PMID:40975504].","teleology":[{"year":2007,"claim":"Establishing ADAMTSL2 as a secreted ECM/cell-surface glycoprotein whose expression tracks the myogenic differentiation program gave the first clue to a developmental, matrix-associated role.","evidence":"Cell fractionation, northern blot, in situ hybridization, and myogenic differentiation assays in C2C12, 10T1/2, and other cell lines","pmids":["17509843"],"confidence":"Medium","gaps":["No binding partners identified","Functional consequence of myogenic induction not tested in vivo"]},{"year":2008,"claim":"Identifying LTBP1 as a binding partner and showing disease mutations reduce secretion while raising active TGF-β and nuclear pSMAD2 connected ADAMTSL2 to TGF-β bioavailability and geleophysic dysplasia.","evidence":"Yeast two-hybrid screen, secretion assays in HEK293, TGF-β quantification, and pSMAD2 immunolocalization in patient fibroblasts","pmids":["18677313"],"confidence":"High","gaps":["Direct mechanism linking ADAMTSL2 to TGF-β activation not resolved","Whether ADAMTSL2 acts via LTBP1 sequestration unclear"]},{"year":2010,"claim":"A canine MLS missense allele (R221C) demonstrated that ADAMTSL2 point mutations cause anomalous disulfide-bonded dimers and impaired secretion, linking misfolding to disease across species.","evidence":"Transient expression in COS-1/HEK293F/CHO with SDS-PAGE disulfide analysis and conditioned medium quantification","pmids":["20862248"],"confidence":"Medium","gaps":["Effect on ligand binding not tested","In vivo consequences not modeled in this study"]},{"year":2015,"claim":"Direct FBN2 binding and an Adamtsl2 knockout mouse showed ADAMTSL2 limits fibrillin microfibril accumulation, but failed TGFβ-neutralization rescue indicated the phenotype is not solely TGFβ-driven.","evidence":"Affinity binding assay, global KO mouse, immunohistochemistry for FBN1/FBN2/MAGP1/LTBP1, and TGFβ-neutralizing antibody treatment","pmids":["25762570"],"confidence":"High","gaps":["TGFβ-independent mechanism of bronchial dysplasia not defined","Stoichiometry of microfibril regulation unknown"]},{"year":2018,"claim":"Chondrocyte-specific knockouts established that ADAMTSL2 is required to build the FBN1/LTBP1 microfibril network in the growth plate, mechanistically tying it to chondrocyte differentiation and skeletal growth.","evidence":"Total and chondrocyte-specific Adamtsl2 KO mice with growth plate histology, microfibril immunofluorescence, and TGFβ readouts","pmids":["30303737"],"confidence":"High","gaps":["Direction of TGFβ change context-dependent across tissues","Molecular trigger of abnormal chondrocyte proliferation unresolved"]},{"year":2019,"claim":"Tendon-directed conditional knockouts and trafficking analysis of patient mutations extended the microfibril-organizing role to tendons and confirmed that disease alleles fail intracellular trafficking and secretion.","evidence":"Prx1-Cre and Scx-Cre conditional KO mice, in vitro microfibril colocalization, electron microscopy of patient fibroblasts, and HEK293 secretion/pSMAD2 assays","pmids":["30738849","31516831"],"confidence":"High","gaps":["How altered microfibril composition limits bone elongation mechanistically unclear","Inclusion-body fate of mutant protein not fully characterized"]},{"year":2020,"claim":"Defining the TSR glycosylation code and showing POFUT2-dependent O-fucosylation is required for secretion explained why TSR mutations like S641L cause disease through secretion failure.","evidence":"Mass spectrometry of glycan modifications, POFUT2-/- and B3GLCT-/- secretion assays, and site-directed mutagenesis of GD alleles","pmids":["32913123"],"confidence":"High","gaps":["Role of C-mannose and B3GLCT-added glucose unresolved","Whether glycosylation affects ligand binding beyond secretion untested"]},{"year":2021,"claim":"Cardiac fibroblast studies and AIS variant analysis showed extracellular ADAMTSL2 acts as a negative regulator of TGFβ and that LTBP4-binding variants upregulate TGFβ signaling, broadening its regulatory role beyond LTBP1.","evidence":"Overexpression and recombinant protein treatment in human cardiac fibroblasts with TGFβ/myofibroblast readouts; exome sequencing and ADAMTSL2-LTBP4 interaction/TGFβ assays","pmids":["34611183","34958866"],"confidence":"Medium","gaps":["Mechanism by which ADAMTSL2 lowers TGFβ production not defined","Causality of AIS variants from single-lab interaction data"]},{"year":2023,"claim":"A stubby mouse nonsense allele linked Adamtsl2 to IGF1-dependent uterine development, indicating a reproductive function distinct from its TGFβ/microfibril activities.","evidence":"Linkage mapping, uterine/skin histology, estrous monitoring, and plasma IGF1/estradiol ELISA in Adamtsl2 nonsense mice","pmids":["37656189"],"confidence":"Medium","gaps":["Mechanism connecting ADAMTSL2 to IGF1 levels unknown","Tissue source of the IGF1 defect not localized"]},{"year":2025,"claim":"Co-IP demonstration of direct ADAMTSL2-LRP6 binding driving β-catenin signaling, plus MMP dysregulation in GD fibroblasts, revealed signaling and protease axes downstream of ADAMTSL2 in cardiac repair and matrix turnover.","evidence":"Co-IP of ADAMTSL2 with LRP6 and β-catenin/LRP6 phosphorylation blots with MI model (peer-reviewed); GD/KO fibroblast migration and MMP-1/MMP-14 analysis with GM6001 rescue (preprint)","pmids":["40975504","bio_10.1101_2025.01.30.635317"],"confidence":"Medium","gaps":["LRP6 binding shown by single Co-IP without reciprocal/structural validation","MMP findings remain preprint-stage","Relationship between Wnt/LRP6 and TGFβ axes unintegrated"]},{"year":null,"claim":"How ADAMTSL2 mechanistically integrates its parallel roles in fibrillin microfibril assembly, bidirectional TGFβ regulation, Wnt/LRP6-β-catenin signaling, and IGF1 homeostasis into tissue-specific outcomes remains unresolved.","evidence":"","pmids":[],"confidence":"Low","gaps":["No structural model of ADAMTSL2-ligand complexes","Tissue-context determinants of TGFβ up- vs down-regulation undefined","Notch/ACLY cancer mechanism rests on low-confidence knockdown data without direct interaction"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0005198","term_label":"structural molecule activity","supporting_discovery_ids":[3,4,5]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[0,3,8]},{"term_id":"GO:0060089","term_label":"molecular transducer activity","supporting_discovery_ids":[11]}],"localization":[{"term_id":"GO:0005576","term_label":"extracellular region","supporting_discovery_ids":[1,7]},{"term_id":"GO:0031012","term_label":"extracellular matrix","supporting_discovery_ids":[1,3,5]}],"pathway":[{"term_id":"R-HSA-1474244","term_label":"Extracellular matrix organization","supporting_discovery_ids":[3,5]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[0,8,11]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[4,5]}],"complexes":[],"partners":["LTBP1","LTBP4","FBN1","FBN2","LRP6","POFUT2"],"other_free_text":[]}},"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":199,"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":67,"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":59,"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":53,"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":49,"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":26,"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":24,"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":19,"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. 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Part A, Clinical and molecular teratology","url":"https://pubmed.ncbi.nlm.nih.gov/24014090","citation_count":10,"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":9,"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":8,"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 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compound heterozygous mutations in geleophysic dysplasia with bilateral glaucoma and keratoconus-like corneal ectasia.","date":"2026","source":"Frontiers in genetics","url":"https://pubmed.ncbi.nlm.nih.gov/41664703","citation_count":1,"is_preprint":false},{"pmid":"41407175","id":"PMC_41407175","title":"ADAMTSL2 facilitates ACLY-mediated lipid metabolism in colorectal cancer by activating Notch signaling pathway.","date":"2025","source":"Cellular signalling","url":"https://pubmed.ncbi.nlm.nih.gov/41407175","citation_count":0,"is_preprint":false},{"pmid":"31463909","id":"PMC_31463909","title":"Molecular Cloning, Lentiviral Transduction, and Expression of Recombinant ADAMTSL2 and ADAMTSL4.","date":"2020","source":"Methods in molecular biology (Clifton, N.J.)","url":"https://pubmed.ncbi.nlm.nih.gov/31463909","citation_count":0,"is_preprint":false},{"pmid":"41864337","id":"PMC_41864337","title":"The Pathogenic ADAMTSL2 D167N Variant Causes Geleophysic Dysplasia-Like Connective Tissue 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with latent TGF-β-binding protein 1 (LTBP1), identified by yeast two-hybrid screen. Disease-causing mutations in ADAMTSL2 reduce secretion of the mutated proteins (likely due to misfolding) and result in increased total and active TGF-β in culture medium and nuclear localization of phosphorylated SMAD2 in patient fibroblasts, indicating ADAMTSL2 regulates TGF-β bioavailability.\",\n      \"method\": \"Yeast two-hybrid screen for LTBP1 interaction; functional secretion assay in HEK293 cells; TGF-β measurement in culture medium; pSMAD2 immunolocalization in patient fibroblasts\",\n      \"journal\": \"Nature genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (Y2H, secretion assay, TGF-β quantification, pSMAD2 localization), replicated across multiple patient-derived cell lines and independently confirmed in subsequent studies\",\n      \"pmids\": [\"18677313\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"ADAMTSL2 is a secreted glycoprotein that binds cell surface and extracellular matrix; N-linked carbohydrate constitutes ~20% of its mass. Expression is regulated during skeletal myogenesis: Adamtsl2 mRNA is induced coordinately with myogenin upon myogenic differentiation in C2C12 and 23A2 cells, and by MyoD activation in 10T1/2 fibroblasts, but is absent in non-myogenic 9A2 cells.\",\n      \"method\": \"Expression in HEK293F and COS-1 cells with fractionation; northern blotting; in situ hybridization; immunohistochemistry; in vitro myogenic differentiation assays with serum starvation; MyoD forced expression\",\n      \"journal\": \"Matrix biology : journal of the International Society for Matrix Biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct cell fractionation showing ECM/cell-surface localization, and regulated expression linked to defined myogenic program using multiple cell lines and MyoD activation, single lab\",\n      \"pmids\": [\"17509843\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"A missense mutation (p.R221C) in ADAMTSL2 causing Musladin-Lueke Syndrome (MLS) in beagles leads to formation of anomalous disulfide-bonded dimers and reduced secretion of the mutant protein compared to wild-type ADAMTSL2.\",\n      \"method\": \"Transient expression in COS-1, HEK293F, and CHO cells; SDS-PAGE/immunoblot analysis of disulfide bonding; conditioned medium quantification\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct biochemical characterization of mutant protein in multiple cell lines, single lab, orthogonal to human disease mutations\",\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). In Adamtsl2-/- mice, loss of ADAMTSL2 leads to accumulation of fibrillin microfibrils (increased FBN2 and MAGP1) and increased LTBP1 staining in bronchial epithelium, with increased bronchial epithelial TGFβ signaling. However, TGFβ-neutralizing antibody treatment did not correct the bronchial epithelial dysplasia in knockout mice.\",\n      \"method\": \"Direct binding assay (affinity measurement); Adamtsl2 global knockout mouse model; immunohistochemistry for FBN1, FBN2, MAGP1, LTBP1; TGFβ-neutralizing antibody treatment experiment; intragenic lacZ reporter for expression mapping\",\n      \"journal\": \"Disease models & mechanisms\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — direct binding affinity measurement for FBN2, combined with in vivo knockout model showing microfibril accumulation and negative result for TGFβ-neutralization rescue, multiple orthogonal methods\",\n      \"pmids\": [\"25762570\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"ADAMTSL2 deficiency in chondrocytes impairs growth plate formation, causing abnormal chondrocyte differentiation and proliferation. Adamtsl2 KO chondrocytes fail to establish a microfibrillar network composed of fibrillin-1 and LTBP1 fibrils, and TGFβ signaling is impaired in Adamtsl2-deficient limbs.\",\n      \"method\": \"Total and chondrocyte-specific Adamtsl2 knockout mouse models; histological analysis of growth plate; immunofluorescence for fibrillin-1 and LTBP1 microfibril network; TGFβ signaling readouts in limb tissue\",\n      \"journal\": \"FASEB journal : official publication of the Federation of American Societies for Experimental Biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — two complementary conditional KO models with specific cellular phenotype (growth plate, microfibril network, TGFβ signaling), multiple orthogonal readouts, replicated findings\",\n      \"pmids\": [\"30303737\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"ADAMTSL2 is strongly expressed in limb tendons and colocalizes with fibrillin microfibrils in vitro. Conditional deletion of Adamtsl2 in limb mesenchyme (Prx1-Cre) causes tendon anomalies, enhanced fibrillin-1 microfibril staining in tendons, and distal limb shortening. Tendon-specific deletion (Scx-Cre) also impairs skeletal growth, establishing that proper microfibril composition in tendons regulated by ADAMTSL2 is required for tendon and bone growth.\",\n      \"method\": \"Intragenic lacZ reporter for expression mapping; Prx1-Cre and Scx-Cre conditional knockout mice; recombinant ADAMTSL2 colocalization with fibrillin microfibrils in vitro; immunofluorescence for fibrillin-1 in tendons; skeletal morphometry\",\n      \"journal\": \"Matrix biology : journal of the International Society for Matrix Biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — two independent tissue-specific Cre lines producing consistent phenotypes, combined with in vitro colocalization and expression mapping, multiple orthogonal methods\",\n      \"pmids\": [\"30738849\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Disease-causing ADAMTSL2 missense variants impair intracellular trafficking of the mutant protein, which fails to accumulate in lysosome-like intracytoplasmic inclusions (shown by electron microscopy in patient skin fibroblasts). Mutant ADAMTSL2 is less secreted and results in increased SMAD2 phosphorylation when expressed in HEK293 cells.\",\n      \"method\": \"Electron microscopy of patient skin fibroblasts; transfection of mutant ADAMTSL2 in HEK293 cells; SMAD2 phosphorylation immunoblot; conditioned medium analysis\",\n      \"journal\": \"Molecular genetics and metabolism reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — electron microscopy for trafficking defect, combined with cell-based secretion and signaling assays, single lab\",\n      \"pmids\": [\"31516831\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"ADAMTSL2 thrombospondin type-1 repeats (TSRs) are modified with O-fucose (by POFUT2) and glucose-β1,3-fucose disaccharide (by B3GLCT), as well as C-mannose. Loss of POFUT2 (but not B3GLCT) abolishes ADAMTSL2 secretion. The GD-causing mutation S641L in TSR3 eliminates O-fucosylation at that site and reduces secretion, establishing that O-fucosylation is required for ADAMTSL2 secretion.\",\n      \"method\": \"Mass spectrometry identification of glycan modifications on mouse ADAMTSL2; secretion assays in POFUT2-/- and B3GLCT-/- cells; site-directed mutagenesis of GD mutations (S641L, G817R); quantitative secretion measurement\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — mass spectrometry identification of modifications combined with genetic KO cell lines and specific mutagenesis of disease alleles, multiple orthogonal methods\",\n      \"pmids\": [\"32913123\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"ADAMTSL2 overexpression or treatment with extracellular ADAMTSL2 in human cardiac fibroblasts reduces TGFβ production and signaling, attenuates myofibroblast differentiation (reduced α-SMA and osteopontin), and mitigates pro-fibrotic phenotypes including proliferation, migration, and contractility. ADAMTSL2 functions as a negative regulator of TGFβ in cardiac fibroblasts.\",\n      \"method\": \"Overexpression and recombinant protein treatment in human cardiac fibroblasts; TGFβ ELISA; western blot for TGFβ signaling markers; myofibroblast differentiation assays; proliferation, migration, and contractility assays\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — gain-of-function and recombinant protein treatment with multiple functional readouts in human primary cells, single lab\",\n      \"pmids\": [\"34611183\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Mutated ADAMTSL2 variants identified in adolescent idiopathic scoliosis patients disrupt the interaction between ADAMTSL2 and LTBP4, and variant pairs in ADAMTSL2-LTBP4 upregulate TGFβ signaling in human fibroblasts.\",\n      \"method\": \"Exome sequencing; co-immunoprecipitation or interaction assay for ADAMTSL2-LTBP4 variants; TGFβ signaling measurement in human fibroblasts\",\n      \"journal\": \"Gene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — interaction assay for ADAMTSL2-LTBP4 with mutant variants and cell-based TGFβ signaling readout, single lab\",\n      \"pmids\": [\"34958866\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"A nonsense mutation in mouse Adamtsl2 (stubby mouse) causes uterine hypoplasia and irregular estrous cycles. Adamtsl2 is expressed in ovary and pituitary gland. Loss of Adamtsl2 reduces plasma IGF1 levels (to 54-59% of wild-type) without affecting GH expression or estradiol levels, implicating Adamtsl2 in IGF1-dependent uterine development.\",\n      \"method\": \"Linkage analysis and identification of Adamtsl2 nonsense mutation; histological analysis of uterus and skin; estrous cycle monitoring; qRT-PCR for Gh; ELISA for plasma estradiol and IGF1\",\n      \"journal\": \"Mammalian genome : official journal of the International Mammalian Genome Society\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — loss-of-function mouse model with defined reproductive phenotype and mechanistic hormone measurements, single lab\",\n      \"pmids\": [\"37656189\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Fibroblast-secreted ADAMTSL2 directly binds LRP6 (shown by co-immunoprecipitation) and promotes LRP6 phosphorylation, leading to β-catenin stabilization and nuclear translocation in cardiomyocytes. ADAMTSL2 overexpression in cardiac fibroblasts attenuates OGD-induced cardiomyocyte apoptosis in vitro and reduces infarct size and adverse ventricular remodeling in vivo.\",\n      \"method\": \"Co-immunoprecipitation of ADAMTSL2 with LRP6; western blot for β-catenin and LRP6 phosphorylation; ADAMTSL2 overexpression/knockdown in neonatal rat cardiac fibroblasts with cardiomyocyte co-culture; adenovirus-mediated fibroblast-targeted overexpression in mouse MI model; apoptosis assays\",\n      \"journal\": \"Cellular signalling\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct binding shown by Co-IP with functional downstream signaling readouts and in vivo MI model, single lab\",\n      \"pmids\": [\"40975504\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"In GD patient-derived dermal fibroblasts carrying ADAMTSL2 variants, secretion of ADAMTSL2, FBN1, and fibronectin is impaired. ADAMTSL2-variant fibroblasts show increased cell migration associated with upregulation of MMP-1 and MMP-14. Pan-MMP inhibitor GM6001 inhibits migration of GD fibroblasts, and MMP-1/MMP-14 upregulation is corroborated in Adamtsl2-knockout mouse tissues.\",\n      \"method\": \"Primary human and mouse dermal fibroblasts from GD patients/KO mice; secretion assays; migration assays; western blot and qRT-PCR for MMP-1/MMP-14; GM6001 pharmacological inhibition; lung/heart tissue analysis from Adamtsl2 KO mice\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — patient-derived fibroblasts and KO mouse tissue with pharmacological rescue, multiple orthogonal methods, preprint only\",\n      \"pmids\": [\"bio_10.1101_2025.01.30.635317\"],\n      \"is_preprint\": true\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 CRC cell lines and patient-derived organoids, and reduces tumor growth in xenograft models.\",\n      \"method\": \"ADAMTSL2 knockdown in HCT116 and SW620 cell lines; patient-derived organoids; xenograft models; Notch signaling pathway analysis; ACLY expression and activity assays\",\n      \"journal\": \"Cellular signalling\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, pathway activation inferred from knockdown experiments without direct binding or reconstitution of ADAMTSL2-Notch interaction\",\n      \"pmids\": [\"41407175\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"ADAMTSL2 is a secreted, O-fucosylated extracellular matrix glycoprotein that binds latent TGF-β-binding proteins (LTBP1, LTBP4) and fibrillin microfibrils (FBN1 and FBN2) to regulate microfibril assembly and TGF-β bioavailability; loss-of-function mutations reduce ADAMTSL2 secretion (impaired by misfolding or loss of O-fucosylation on TSRs), disrupt the fibrillin microfibril network in tendons, bronchial wall, and growth plate, increase active TGF-β and SMAD2 signaling, and cause geleophysic dysplasia, while extracellular ADAMTSL2 can also promote cardiac repair by directly binding LRP6 to activate β-catenin signaling and suppress fibroblast-to-myofibroblast differentiation by inhibiting TGFβ.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"ADAMTSL2 is a secreted, glycosylated extracellular matrix protein that controls fibrillin microfibril assembly and TGF-\\u03b2 bioavailability during skeletal and connective tissue development [#1, #3, #4]. It binds the latent TGF-\\u03b2-binding proteins LTBP1 and LTBP4 and the fibrillins FBN1 and FBN2 with comparable affinity, and colocalizes with fibrillin microfibrils [#0, #3, #5, #9]. Through these interactions ADAMTSL2 organizes the microfibrillar network: its loss in mice causes accumulation of fibrillin microfibrils, LTBP1, and MAGP1 in bronchial epithelium and dysregulated TGF\\u03b2 signaling, while chondrocyte- and tendon-specific deletion disrupts the FBN1/LTBP1 network and impairs growth plate formation, tendon integrity, and skeletal growth [#3, #4, #5]. Proper biogenesis requires O-fucosylation of its thrombospondin type-1 repeats by POFUT2; loss of POFUT2 or the geleophysic dysplasia mutation S641L abolishes O-fucose at TSR3 and blocks secretion [#7]. Disease-causing missense mutations cause misfolding, anomalous disulfide-bonded dimers, defective intracellular trafficking, and reduced secretion, with consequent increases in active TGF-\\u03b2 and nuclear phospho-SMAD2 in patient fibroblasts, establishing ADAMTSL2 loss-of-function as the basis of geleophysic dysplasia [#0, #2, #6, #7]. Beyond development, extracellular ADAMTSL2 acts as a negative regulator of TGF\\u03b2 in cardiac fibroblasts to suppress myofibroblast differentiation, and directly binds LRP6 to drive LRP6 phosphorylation and \\u03b2-catenin stabilization, promoting cardiac repair [#8, #11].\",\n  \"teleology\": [\n    {\n      \"year\": 2007,\n      \"claim\": \"Establishing ADAMTSL2 as a secreted ECM/cell-surface glycoprotein whose expression tracks the myogenic differentiation program gave the first clue to a developmental, matrix-associated role.\",\n      \"evidence\": \"Cell fractionation, northern blot, in situ hybridization, and myogenic differentiation assays in C2C12, 10T1/2, and other cell lines\",\n      \"pmids\": [\"17509843\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No binding partners identified\", \"Functional consequence of myogenic induction not tested in vivo\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Identifying LTBP1 as a binding partner and showing disease mutations reduce secretion while raising active TGF-\\u03b2 and nuclear pSMAD2 connected ADAMTSL2 to TGF-\\u03b2 bioavailability and geleophysic dysplasia.\",\n      \"evidence\": \"Yeast two-hybrid screen, secretion assays in HEK293, TGF-\\u03b2 quantification, and pSMAD2 immunolocalization in patient fibroblasts\",\n      \"pmids\": [\"18677313\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct mechanism linking ADAMTSL2 to TGF-\\u03b2 activation not resolved\", \"Whether ADAMTSL2 acts via LTBP1 sequestration unclear\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"A canine MLS missense allele (R221C) demonstrated that ADAMTSL2 point mutations cause anomalous disulfide-bonded dimers and impaired secretion, linking misfolding to disease across species.\",\n      \"evidence\": \"Transient expression in COS-1/HEK293F/CHO with SDS-PAGE disulfide analysis and conditioned medium quantification\",\n      \"pmids\": [\"20862248\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Effect on ligand binding not tested\", \"In vivo consequences not modeled in this study\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Direct FBN2 binding and an Adamtsl2 knockout mouse showed ADAMTSL2 limits fibrillin microfibril accumulation, but failed TGF\\u03b2-neutralization rescue indicated the phenotype is not solely TGF\\u03b2-driven.\",\n      \"evidence\": \"Affinity binding assay, global KO mouse, immunohistochemistry for FBN1/FBN2/MAGP1/LTBP1, and TGF\\u03b2-neutralizing antibody treatment\",\n      \"pmids\": [\"25762570\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"TGF\\u03b2-independent mechanism of bronchial dysplasia not defined\", \"Stoichiometry of microfibril regulation unknown\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Chondrocyte-specific knockouts established that ADAMTSL2 is required to build the FBN1/LTBP1 microfibril network in the growth plate, mechanistically tying it to chondrocyte differentiation and skeletal growth.\",\n      \"evidence\": \"Total and chondrocyte-specific Adamtsl2 KO mice with growth plate histology, microfibril immunofluorescence, and TGF\\u03b2 readouts\",\n      \"pmids\": [\"30303737\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direction of TGF\\u03b2 change context-dependent across tissues\", \"Molecular trigger of abnormal chondrocyte proliferation unresolved\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Tendon-directed conditional knockouts and trafficking analysis of patient mutations extended the microfibril-organizing role to tendons and confirmed that disease alleles fail intracellular trafficking and secretion.\",\n      \"evidence\": \"Prx1-Cre and Scx-Cre conditional KO mice, in vitro microfibril colocalization, electron microscopy of patient fibroblasts, and HEK293 secretion/pSMAD2 assays\",\n      \"pmids\": [\"30738849\", \"31516831\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How altered microfibril composition limits bone elongation mechanistically unclear\", \"Inclusion-body fate of mutant protein not fully characterized\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Defining the TSR glycosylation code and showing POFUT2-dependent O-fucosylation is required for secretion explained why TSR mutations like S641L cause disease through secretion failure.\",\n      \"evidence\": \"Mass spectrometry of glycan modifications, POFUT2-/- and B3GLCT-/- secretion assays, and site-directed mutagenesis of GD alleles\",\n      \"pmids\": [\"32913123\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Role of C-mannose and B3GLCT-added glucose unresolved\", \"Whether glycosylation affects ligand binding beyond secretion untested\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Cardiac fibroblast studies and AIS variant analysis showed extracellular ADAMTSL2 acts as a negative regulator of TGF\\u03b2 and that LTBP4-binding variants upregulate TGF\\u03b2 signaling, broadening its regulatory role beyond LTBP1.\",\n      \"evidence\": \"Overexpression and recombinant protein treatment in human cardiac fibroblasts with TGF\\u03b2/myofibroblast readouts; exome sequencing and ADAMTSL2-LTBP4 interaction/TGF\\u03b2 assays\",\n      \"pmids\": [\"34611183\", \"34958866\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism by which ADAMTSL2 lowers TGF\\u03b2 production not defined\", \"Causality of AIS variants from single-lab interaction data\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"A stubby mouse nonsense allele linked Adamtsl2 to IGF1-dependent uterine development, indicating a reproductive function distinct from its TGF\\u03b2/microfibril activities.\",\n      \"evidence\": \"Linkage mapping, uterine/skin histology, estrous monitoring, and plasma IGF1/estradiol ELISA in Adamtsl2 nonsense mice\",\n      \"pmids\": [\"37656189\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism connecting ADAMTSL2 to IGF1 levels unknown\", \"Tissue source of the IGF1 defect not localized\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Co-IP demonstration of direct ADAMTSL2-LRP6 binding driving \\u03b2-catenin signaling, plus MMP dysregulation in GD fibroblasts, revealed signaling and protease axes downstream of ADAMTSL2 in cardiac repair and matrix turnover.\",\n      \"evidence\": \"Co-IP of ADAMTSL2 with LRP6 and \\u03b2-catenin/LRP6 phosphorylation blots with MI model (peer-reviewed); GD/KO fibroblast migration and MMP-1/MMP-14 analysis with GM6001 rescue (preprint)\",\n      \"pmids\": [\"40975504\", \"bio_10.1101_2025.01.30.635317\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"LRP6 binding shown by single Co-IP without reciprocal/structural validation\", \"MMP findings remain preprint-stage\", \"Relationship between Wnt/LRP6 and TGF\\u03b2 axes unintegrated\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How ADAMTSL2 mechanistically integrates its parallel roles in fibrillin microfibril assembly, bidirectional TGF\\u03b2 regulation, Wnt/LRP6-\\u03b2-catenin signaling, and IGF1 homeostasis into tissue-specific outcomes remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No structural model of ADAMTSL2-ligand complexes\", \"Tissue-context determinants of TGF\\u03b2 up- vs down-regulation undefined\", \"Notch/ACLY cancer mechanism rests on low-confidence knockdown data without direct interaction\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0005198\", \"supporting_discovery_ids\": [3, 4, 5]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [0, 3, 8]},\n      {\"term_id\": \"GO:0060089\", \"supporting_discovery_ids\": [11]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005576\", \"supporting_discovery_ids\": [1, 7]},\n      {\"term_id\": \"GO:0031012\", \"supporting_discovery_ids\": [1, 3, 5]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1474244\", \"supporting_discovery_ids\": [3, 5]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [0, 8, 11]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [4, 5]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"LTBP1\", \"LTBP4\", \"FBN1\", \"FBN2\", \"LRP6\", \"POFUT2\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"faith_supported":6,"faith_total":6,"faith_pct":100.0}}