{"gene":"ADAMTSL1","run_date":"2026-04-28T17:12:37","timeline":{"discoveries":[{"year":2002,"finding":"ADAMTSL1 (punctin) is a secreted glycoprotein that localizes to the cell substratum in a punctate pattern, excluded from focal contacts, when expressed in transfected COS-1 cells. It contains four thrombospondin type I repeats, disulfide bonds, and a single N-linked glycosylation site, and adopts a hatchet-shaped structure with a globular region attached to a short stem as determined by rotary shadowing electron microscopy.","method":"Stable transfection in insect cells, Edman degradation for N-terminus, LC-ESI-MS for mass determination, glycosylation analysis with tunicamycin, rotary shadowing EM, immunofluorescence in COS-1 cells","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1-2 — multiple orthogonal biochemical methods in a single foundational study with rigorous characterization","pmids":["11805097"],"is_preprint":false},{"year":2009,"finding":"ADAMTSL1 contains thrombospondin type I repeats (TSRs) that are substrates for the beta1,3-glucosyltransferase B3GLCT (responsible for Peters'-plus syndrome), which adds a glucose moiety to O-linked fucose on these TSR domains, forming a glucose-beta1,3-fucose disaccharide modification. The disaccharide modification on ADAMTSL1 was directly demonstrated.","method":"Biochemical demonstration of O-glucosylation on purified ADAMTSL1 TSR domains; genetic and enzymatic analysis of B3GLCT substrate specificity","journal":"Annals of medicine","confidence":"Medium","confidence_rationale":"Tier 2 — direct biochemical demonstration of PTM on ADAMTSL1, single study","pmids":["18720094"],"is_preprint":false},{"year":2011,"finding":"The C. elegans ortholog of ADAMTSL1, MADD-4, functions as a secreted guidance cue from the dorsal and ventral nerve cords that attracts sensory axons and muscle arms; this activity is dependent on the netrin receptor UNC-40/DCC acting cell-autonomously. This defines a conserved role for ADAMTSL orthologs as extracellular guidance proteins acting through DCC-family receptors.","method":"Genetic loss-of-function, epistasis analysis with unc-40/DCC mutants, cell-autonomous rescue experiments, secretion assays in C. elegans","journal":"Developmental cell","confidence":"High","confidence_rationale":"Tier 1-2 — genetic epistasis with defined receptor, multiple orthogonal genetic approaches, replicated functional readouts","pmids":["22014523"],"is_preprint":false},{"year":2013,"finding":"ADAMTSL1 is a direct substrate of matrix metalloproteinase 10 (MMP10), which cleaves ADAMTSL1 in fibroblast secretomes, as identified by time-resolved degradomics.","method":"Multiplexed terminal amine isotopic labeling of substrates (TAILS) degradomics; mass spectrometry identification of cleavage sites in fibroblast secretomes","journal":"Molecular & cellular proteomics : MCP","confidence":"Medium","confidence_rationale":"Tier 2 — system-wide substrate identification with neo-terminus quantification; single study","pmids":["24281761"],"is_preprint":false},{"year":2014,"finding":"ADAMTSL1 expression is regulated by the Hedgehog signaling pathway in chondrosarcoma, and ADAMTSL1 regulates chondrosarcoma cell proliferation, as demonstrated by downregulation following Smoothened inhibitor IPI-926 treatment and functional studies.","method":"Gene expression profiling of IPI-926-treated chondrosarcoma xenografts; functional proliferation assays after ADAMTSL1 modulation","journal":"Molecular cancer therapeutics","confidence":"Medium","confidence_rationale":"Tier 2 — gene profiling combined with functional proliferation assay; single study","pmids":["24634412"],"is_preprint":false},{"year":2017,"finding":"A heterozygous p.Trp42Arg mutation in ADAMTSL1 (affecting the C-mannosylation motif W-x-x-W) causes intracellular retention of the mutant protein rather than secretion, and the mutant protein also reduces secretion of co-transfected wild-type ADAMTSL1, demonstrating a dominant negative mechanism. This establishes that C-mannosylation of Trp42 is required for proper ADAMTSL1 folding and secretion.","method":"In vitro transfection with ADAMTSL1-WT and ADAMTSL1-p.Trp42Arg constructs; secretion assays comparing conditioned medium and cell lysate fractions; co-transfection dominant negative experiment; clinical cosegregation in a three-generation pedigree","journal":"Human mutation","confidence":"High","confidence_rationale":"Tier 1-2 — in vitro functional assay with mutagenesis, dominant negative mechanism demonstrated, cosegregation in human pedigree","pmids":["28722276"],"is_preprint":false},{"year":2019,"finding":"Missense mutations in ADAMTSL1 are associated with mandibular prognathism, and Adamtsl1 is strongly expressed in condensed mesenchymal cells of the mouse condyle but not in long bone cartilage. The authors hypothesize that ADAMTSL1 mutations cause failure to cleave aggrecan in condylar cartilage leading to mandibular overgrowth.","method":"Whole exome sequencing, mutation analysis in patients, in situ expression analysis in mouse condyle tissues","journal":"Clinical genetics","confidence":"Medium","confidence_rationale":"Tier 2-3 — genetic evidence plus direct in situ localization in mouse condyle; aggrecan cleavage mechanism is hypothetical","pmids":["30714143"],"is_preprint":false},{"year":2021,"finding":"C-mannosylation of ADAMTSL1 at the W-x-x-W motif (Trp42) is required for its secretion; a disease-associated variant disrupting this motif prevents secretion, providing direct evidence that DPY19-family C-mannosyltransferases act on ADAMTSL1 TSR domains to enable proper protein folding and trafficking.","method":"Review integrating published biochemical data on C-mannosylation of ADAMTSL1; functional secretion experiments described in prior work (Hendee et al. 2017)","journal":"Molecules (Basel, Switzerland)","confidence":"Medium","confidence_rationale":"Tier 2 — mechanistic synthesis supported by direct functional secretion data from cited experiments","pmids":["34500691"],"is_preprint":false},{"year":2022,"finding":"A subpopulation of Schwann cells (SCs) identified by co-expression of Adamtsl1, Cldn14, and Pmp2 preferentially myelinates/ensheathes large-caliber motor axons in peripheral nerve, and this SC subtype is selectively reduced in ALS mouse models and human ALS nerve samples.","method":"Single-nuclei RNA sequencing of mouse peripheral nerves; cross-validation in ALS SOD1G93A mouse model; analysis of human ALS nerve samples","journal":"Nature neuroscience","confidence":"Medium","confidence_rationale":"Tier 2 — snRNA-seq with disease model validation; Adamtsl1 used as a marker gene rather than direct functional target","pmids":["35115729"],"is_preprint":false},{"year":2023,"finding":"ADAMTSL1 protein is enriched at the myotendinous junction (MTJ) of human skeletal muscle, as confirmed at the protein level by immunofluorescence, suggesting a structural or regulatory ECM role at this mechanically stressed interface.","method":"Single-nucleus RNA sequencing of human muscle-tendon samples; spatial transcriptomics; immunofluorescence protein validation at the MTJ","journal":"Journal of cell science","confidence":"Medium","confidence_rationale":"Tier 2 — direct protein localization confirmed by immunofluorescence; functional consequence not yet established","pmids":["36924352"],"is_preprint":false},{"year":2025,"finding":"Genetic ablation of Pmp2+ Schwann cells (which co-express Adamtsl1) leads to significant loss of large-caliber motor axons with behavioral, electrophysiological, and ultrastructural deficits; restoration of Pmp2+ SCs rescues motor axon survival, demonstrating that this SC subtype is required for large-caliber motor axon maintenance.","method":"Tamoxifen-inducible Pmp2-CreERT2 mouse with diphtheria toxin-mediated SC ablation; behavioral tests, electrophysiology, electron microscopy; recovery experiments","journal":"The Journal of neuroscience","confidence":"High","confidence_rationale":"Tier 1-2 — conditional genetic ablation with multiple orthogonal functional readouts and rescue experiment","pmids":["39880678"],"is_preprint":false}],"current_model":"ADAMTSL1 (punctin) is a secreted extracellular matrix glycoprotein whose proper folding and secretion requires C-mannosylation of Trp42 by DPY19-family transferases; it is proteolytically processed by MMP10, is expressed in specific mesenchymal and glial cell populations (including motor-axon-associated Schwann cells and myotendinous junction myonuclei), regulates chondrosarcoma cell proliferation downstream of Hedgehog signaling, and its orthologs function as secreted guidance cues acting through DCC-family receptors."},"narrative":{"teleology":[{"year":2002,"claim":"Initial biochemical characterization established ADAMTSL1 as a secreted, glycosylated ECM protein with a defined domain architecture, resolving its basic identity as a TSR-containing matrix component deposited in punctate patterns outside focal contacts.","evidence":"Recombinant expression in insect and COS-1 cells; rotary shadowing EM; Edman degradation and LC-ESI-MS","pmids":["11805097"],"confidence":"High","gaps":["No binding partners or receptors identified","In vivo tissue localization not established","Function of punctate substratum deposition unknown"]},{"year":2009,"claim":"Identification of ADAMTSL1 TSRs as substrates for B3GLCT-mediated O-glucosylation revealed that its thrombospondin repeats carry a glucose-β1,3-fucose disaccharide, linking ADAMTSL1 post-translational modification to Peters-plus syndrome biology.","evidence":"Biochemical demonstration of O-glucosylation on purified ADAMTSL1 TSR domains","pmids":["18720094"],"confidence":"Medium","gaps":["Functional consequence of O-glucosylation for ADAMTSL1 activity not tested","In vivo relevance of TSR glycosylation not demonstrated"]},{"year":2011,"claim":"Genetic analysis of the C. elegans ortholog MADD-4 demonstrated that ADAMTSL family proteins function as secreted guidance cues acting through the DCC-family receptor UNC-40, establishing a signaling paradigm beyond a purely structural ECM role.","evidence":"Loss-of-function genetics, epistasis with unc-40/DCC, cell-autonomous rescue in C. elegans","pmids":["22014523"],"confidence":"High","gaps":["Whether mammalian ADAMTSL1 similarly signals through DCC is untested","Ligand-receptor binding mechanism not defined biochemically"]},{"year":2013,"claim":"Degradomic profiling identified ADAMTSL1 as a direct substrate of MMP10, revealing that its ECM function is regulated by proteolytic processing.","evidence":"TAILS degradomics with mass spectrometry in fibroblast secretomes","pmids":["24281761"],"confidence":"Medium","gaps":["Cleavage site(s) and functional consequences of processing not characterized in detail","Relevance to in vivo tissue remodeling not established"]},{"year":2014,"claim":"Placing ADAMTSL1 downstream of Hedgehog/Smoothened signaling and demonstrating its role in chondrosarcoma proliferation revealed a context-dependent growth-regulatory function for this ECM protein.","evidence":"Gene expression profiling of IPI-926-treated chondrosarcoma xenografts; functional proliferation assays","pmids":["24634412"],"confidence":"Medium","gaps":["Mechanism by which ADAMTSL1 regulates proliferation unknown","Not clear if this is autocrine ECM signaling or structural"]},{"year":2017,"claim":"Demonstrating that the p.Trp42Arg mutation disrupts C-mannosylation, causes intracellular retention, and exerts a dominant-negative effect on wild-type ADAMTSL1 secretion established that C-mannosylation is essential for proper folding and export.","evidence":"In vitro secretion assays with wild-type and mutant constructs; co-transfection experiments; cosegregation in a three-generation pedigree","pmids":["28722276"],"confidence":"High","gaps":["Structural basis for why loss of C-mannosylation causes misfolding not determined","Whether dominant-negative effect operates in vivo in relevant tissues not shown"]},{"year":2019,"claim":"Identification of ADAMTSL1 mutations in mandibular prognathism patients, combined with restricted expression in condylar mesenchyme, linked the gene to craniofacial skeletal growth, though the proposed aggrecan-cleavage mechanism remains hypothetical.","evidence":"Whole-exome sequencing in patients; in situ expression in mouse condyle","pmids":["30714143"],"confidence":"Medium","gaps":["Aggrecan cleavage by ADAMTSL1 is hypothetical — no direct enzymatic or binding evidence","No animal model confirming craniofacial phenotype","Functional characterization of patient mutations not performed"]},{"year":2022,"claim":"Single-nucleus transcriptomics identified Adamtsl1 as a marker of a Schwann cell subtype that preferentially ensheathes large-caliber motor axons, and this subtype is selectively reduced in ALS, placing ADAMTSL1 in the context of motor neuron support.","evidence":"snRNA-seq of mouse peripheral nerves; validation in SOD1-G93A ALS mice and human ALS nerve samples","pmids":["35115729"],"confidence":"Medium","gaps":["ADAMTSL1 is a marker rather than a proven functional mediator of this SC subtype's activity","Whether ADAMTSL1 itself contributes to axon maintenance is untested"]},{"year":2023,"claim":"Protein-level localization of ADAMTSL1 at the human myotendinous junction confirmed that it occupies a mechanically stressed ECM niche, consistent with a structural or signaling role at muscle-tendon interfaces.","evidence":"snRNA-seq, spatial transcriptomics, and immunofluorescence of human muscle-tendon samples","pmids":["36924352"],"confidence":"Medium","gaps":["Functional role of ADAMTSL1 at the MTJ not tested","Binding partners at the MTJ unknown"]},{"year":2025,"claim":"Conditional ablation of Pmp2+/Adamtsl1+ Schwann cells proved that this subtype is required for large-caliber motor axon survival, with rescue confirming the dependency, but the specific contribution of ADAMTSL1 protein within these cells remains unresolved.","evidence":"Tamoxifen-inducible Pmp2-CreERT2 diphtheria toxin ablation in mice; behavioral, electrophysiological, and ultrastructural analyses; recovery experiments","pmids":["39880678"],"confidence":"High","gaps":["Ablation targets the entire SC subtype, not ADAMTSL1 specifically","Whether ADAMTSL1 secretion from these SCs mediates the axon-protective effect is unknown"]},{"year":null,"claim":"The mammalian receptor for ADAMTSL1 signaling, the functional consequences of its MMP10-mediated cleavage, and whether it directly contributes to motor axon maintenance or MTJ integrity remain unresolved.","evidence":"","pmids":[],"confidence":"Low","gaps":["No mammalian receptor identified","No ADAMTSL1-specific knockout phenotype reported in mice","Structural basis for TSR-dependent ECM interactions undefined"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0048018","term_label":"receptor ligand activity","supporting_discovery_ids":[2]}],"localization":[{"term_id":"GO:0031012","term_label":"extracellular matrix","supporting_discovery_ids":[0,9]},{"term_id":"GO:0005576","term_label":"extracellular region","supporting_discovery_ids":[0,2,3]}],"pathway":[{"term_id":"R-HSA-1474244","term_label":"Extracellular matrix organization","supporting_discovery_ids":[0,3,9]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[2,4]}],"complexes":[],"partners":["MMP10","B3GLCT","UNC-40"],"other_free_text":[]},"mechanistic_narrative":"ADAMTSL1 (punctin) is a secreted extracellular matrix glycoprotein that functions at mechanically and developmentally critical tissue interfaces, including the myotendinous junction, condylar mesenchyme, and peripheral nerve. It adopts a hatchet-shaped structure with four thrombospondin type I repeats (TSRs) bearing O-fucose/glucose disaccharide modifications and requires C-mannosylation of Trp42 for proper folding and secretion; a dominant-negative p.Trp42Arg mutation causes intracellular retention and is associated with mandibular prognathism [PMID:11805097, PMID:28722276, PMID:30714143]. The C. elegans ortholog MADD-4 acts as a secreted guidance cue that attracts axons and muscle arms through the netrin receptor UNC-40/DCC, establishing a conserved role for ADAMTSL family members as extracellular signaling ligands [PMID:22014523]. ADAMTSL1 is proteolytically processed by MMP10 in fibroblast secretomes, is transcriptionally regulated by Hedgehog signaling in chondrosarcoma where it controls cell proliferation, and marks a Schwann cell subpopulation essential for large-caliber motor axon maintenance [PMID:24281761, PMID:24634412, PMID:39880678]."},"prefetch_data":{"uniprot":{"accession":"Q8N6G6","full_name":"ADAMTS-like protein 1","aliases":["Punctin-1"],"length_aa":1762,"mass_kda":193.4,"function":"","subcellular_location":"Secreted, extracellular space, extracellular matrix","url":"https://www.uniprot.org/uniprotkb/Q8N6G6/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/ADAMTSL1","classification":"Not Classified","n_dependent_lines":1,"n_total_lines":1208,"dependency_fraction":0.0008278145695364238},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/ADAMTSL1","total_profiled":1310},"omim":[{"mim_id":"609199","title":"ADAMTS-LIKE PROTEIN 3; ADAMTSL3","url":"https://www.omim.org/entry/609199"},{"mim_id":"609198","title":"ADAMTS-LIKE PROTEIN 1; ADAMTSL1","url":"https://www.omim.org/entry/609198"},{"mim_id":"112250","title":"DIAPHYSEAL MEDULLARY STENOSIS WITH MALIGNANT FIBROUS HISTIOCYTOMA; DMSMFH","url":"https://www.omim.org/entry/112250"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Vesicles","reliability":"Approved"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"endometrium 1","ntpm":12.5}],"url":"https://www.proteinatlas.org/search/ADAMTSL1"},"hgnc":{"alias_symbol":["ADAMTSR1","FLJ35283"],"prev_symbol":["C9orf94"]},"alphafold":{"accession":"Q8N6G6","domains":[{"cath_id":"2.20.100.10","chopping":"38-171","consensus_level":"high","plddt":78.8474,"start":38,"end":171},{"cath_id":"2.60.120","chopping":"186-355","consensus_level":"medium","plddt":79.4694,"start":186,"end":355},{"cath_id":"-","chopping":"614-646_657-665","consensus_level":"medium","plddt":75.6738,"start":614,"end":665},{"cath_id":"-","chopping":"682-697_723-735_751-769","consensus_level":"medium","plddt":78.6946,"start":682,"end":769},{"cath_id":"2.60.40.10","chopping":"867-968","consensus_level":"medium","plddt":82.3965,"start":867,"end":968},{"cath_id":"2.60.40.10","chopping":"1163-1268","consensus_level":"medium","plddt":77.0594,"start":1163,"end":1268},{"cath_id":"2.60.40.10","chopping":"1397-1487","consensus_level":"medium","plddt":81.5262,"start":1397,"end":1487},{"cath_id":"-","chopping":"1609-1667","consensus_level":"medium","plddt":78.7078,"start":1609,"end":1667},{"cath_id":"1.10.10","chopping":"1728-1762","consensus_level":"medium","plddt":70.0103,"start":1728,"end":1762}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q8N6G6","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q8N6G6-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q8N6G6-F1-predicted_aligned_error_v6.png","plddt_mean":70.94},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=ADAMTSL1","jax_strain_url":"https://www.jax.org/strain/search?query=ADAMTSL1"},"sequence":{"accession":"Q8N6G6","fasta_url":"https://rest.uniprot.org/uniprotkb/Q8N6G6.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q8N6G6/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q8N6G6"}},"corpus_meta":[{"pmid":"22464253","id":"PMC_22464253","title":"Identification of IRF8, TMEM39A, and IKZF3-ZPBP2 as susceptibility loci for systemic lupus erythematosus in a large-scale multiracial replication study.","date":"2012","source":"American journal of human genetics","url":"https://pubmed.ncbi.nlm.nih.gov/22464253","citation_count":156,"is_preprint":false},{"pmid":"11805097","id":"PMC_11805097","title":"Punctin, a novel ADAMTS-like molecule, ADAMTSL-1, in extracellular matrix.","date":"2002","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/11805097","citation_count":85,"is_preprint":false},{"pmid":"37081215","id":"PMC_37081215","title":"Genetics of myocardial interstitial fibrosis in the human heart and association with disease.","date":"2023","source":"Nature genetics","url":"https://pubmed.ncbi.nlm.nih.gov/37081215","citation_count":67,"is_preprint":false},{"pmid":"35115729","id":"PMC_35115729","title":"Disentangling glial diversity in peripheral nerves at single-nuclei resolution.","date":"2022","source":"Nature neuroscience","url":"https://pubmed.ncbi.nlm.nih.gov/35115729","citation_count":66,"is_preprint":false},{"pmid":"24634412","id":"PMC_24634412","title":"Hedgehog pathway inhibition in chondrosarcoma using the smoothened inhibitor IPI-926 directly inhibits sarcoma cell growth.","date":"2014","source":"Molecular cancer therapeutics","url":"https://pubmed.ncbi.nlm.nih.gov/24634412","citation_count":63,"is_preprint":false},{"pmid":"24281761","id":"PMC_24281761","title":"Time-resolved analysis of the matrix metalloproteinase 10 substrate degradome.","date":"2013","source":"Molecular & cellular proteomics : MCP","url":"https://pubmed.ncbi.nlm.nih.gov/24281761","citation_count":49,"is_preprint":false},{"pmid":"25636590","id":"PMC_25636590","title":"Methylation profiling of 48 candidate genes in tumor and matched normal tissues from breast cancer patients.","date":"2015","source":"Breast cancer research and treatment","url":"https://pubmed.ncbi.nlm.nih.gov/25636590","citation_count":48,"is_preprint":false},{"pmid":"31887783","id":"PMC_31887783","title":"Genome-wide scan of selection signatures in Dehong humped cattle for heat tolerance and disease resistance.","date":"2019","source":"Animal genetics","url":"https://pubmed.ncbi.nlm.nih.gov/31887783","citation_count":43,"is_preprint":false},{"pmid":"22014523","id":"PMC_22014523","title":"MADD-4 is a secreted cue required for midline-oriented guidance in Caenorhabditis elegans.","date":"2011","source":"Developmental cell","url":"https://pubmed.ncbi.nlm.nih.gov/22014523","citation_count":39,"is_preprint":false},{"pmid":"18720094","id":"PMC_18720094","title":"Peters'-plus syndrome is a congenital disorder of glycosylation caused by a defect in the beta1,3-glucosyltransferase that modifies thrombospondin type 1 repeats.","date":"2009","source":"Annals of medicine","url":"https://pubmed.ncbi.nlm.nih.gov/18720094","citation_count":37,"is_preprint":false},{"pmid":"36924352","id":"PMC_36924352","title":"Distinct myofibre domains of the human myotendinous junction revealed by single-nucleus RNA sequencing.","date":"2023","source":"Journal of cell science","url":"https://pubmed.ncbi.nlm.nih.gov/36924352","citation_count":31,"is_preprint":false},{"pmid":"28722276","id":"PMC_28722276","title":"Identification and functional analysis of an ADAMTSL1 variant associated with a complex phenotype including congenital glaucoma, craniofacial, and other systemic features in a three-generation human pedigree.","date":"2017","source":"Human mutation","url":"https://pubmed.ncbi.nlm.nih.gov/28722276","citation_count":29,"is_preprint":false},{"pmid":"34500691","id":"PMC_34500691","title":"Protein C-Mannosylation and C-Mannosyl Tryptophan in Chemical Biology and Medicine.","date":"2021","source":"Molecules (Basel, Switzerland)","url":"https://pubmed.ncbi.nlm.nih.gov/34500691","citation_count":28,"is_preprint":false},{"pmid":"32590948","id":"PMC_32590948","title":"Transcriptome analysis of genes related to gonad differentiation and development in Muscovy ducks.","date":"2020","source":"BMC genomics","url":"https://pubmed.ncbi.nlm.nih.gov/32590948","citation_count":23,"is_preprint":false},{"pmid":"33109206","id":"PMC_33109206","title":"Identification of potential causal variants for premature ovarian failure by whole exome sequencing.","date":"2020","source":"BMC medical genomics","url":"https://pubmed.ncbi.nlm.nih.gov/33109206","citation_count":21,"is_preprint":false},{"pmid":"28570682","id":"PMC_28570682","title":"ADAMTS-1 in abdominal aortic aneurysm.","date":"2017","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/28570682","citation_count":19,"is_preprint":false},{"pmid":"36339449","id":"PMC_36339449","title":"Combining bioinformatics, network pharmacology and artificial intelligence to predict the mechanism of celastrol in the treatment of type 2 diabetes.","date":"2022","source":"Frontiers in endocrinology","url":"https://pubmed.ncbi.nlm.nih.gov/36339449","citation_count":18,"is_preprint":false},{"pmid":"30714143","id":"PMC_30714143","title":"ADAMTSL1 and mandibular prognathism.","date":"2019","source":"Clinical genetics","url":"https://pubmed.ncbi.nlm.nih.gov/30714143","citation_count":14,"is_preprint":false},{"pmid":"38284126","id":"PMC_38284126","title":"Secreted ADAMTS-like proteins as regulators of connective tissue function.","date":"2024","source":"American journal of physiology. Cell physiology","url":"https://pubmed.ncbi.nlm.nih.gov/38284126","citation_count":14,"is_preprint":false},{"pmid":"32240779","id":"PMC_32240779","title":"Lumbar intervertebral disc mRNA sequencing identifies the regulatory pathway in patients with disc herniation and spondylolisthesis.","date":"2020","source":"Gene","url":"https://pubmed.ncbi.nlm.nih.gov/32240779","citation_count":14,"is_preprint":false},{"pmid":"34222226","id":"PMC_34222226","title":"Whole-Exome Sequencing in a Cohort of High Myopia Patients in Northwest China.","date":"2021","source":"Frontiers in cell and developmental biology","url":"https://pubmed.ncbi.nlm.nih.gov/34222226","citation_count":14,"is_preprint":false},{"pmid":"28440896","id":"PMC_28440896","title":"Genome-wide meta-analysis identifies a novel susceptibility signal at CACNA2D3 for nicotine dependence.","date":"2017","source":"American journal of medical genetics. Part B, Neuropsychiatric genetics : the official publication of the International Society of Psychiatric Genetics","url":"https://pubmed.ncbi.nlm.nih.gov/28440896","citation_count":13,"is_preprint":false},{"pmid":"34499774","id":"PMC_34499774","title":"Longitudinal peripheral tissue RNA-Seq transcriptomic profiling, hyperalgesia, and wound healing in the rat plantar surgical incision model.","date":"2021","source":"FASEB journal : official publication of the Federation of American Societies for Experimental Biology","url":"https://pubmed.ncbi.nlm.nih.gov/34499774","citation_count":12,"is_preprint":false},{"pmid":"19824886","id":"PMC_19824886","title":"Association and interaction analyses of eight genes under asthma linkage peaks.","date":"2009","source":"Allergy","url":"https://pubmed.ncbi.nlm.nih.gov/19824886","citation_count":12,"is_preprint":false},{"pmid":"32095376","id":"PMC_32095376","title":"Intracranial aneurysm's association with genetic variants, transcription abnormality, and methylation changes in ADAMTS genes.","date":"2020","source":"PeerJ","url":"https://pubmed.ncbi.nlm.nih.gov/32095376","citation_count":8,"is_preprint":false},{"pmid":"29049012","id":"PMC_29049012","title":"Transcriptome Profiling Uncovers Potential Common Mechanisms in Fetal Trisomies 18 and 21.","date":"2017","source":"Omics : a journal of integrative biology","url":"https://pubmed.ncbi.nlm.nih.gov/29049012","citation_count":8,"is_preprint":false},{"pmid":"37061115","id":"PMC_37061115","title":"Critical role of transcriptome-wide m6A methylation in the aqueous humor of patients with pseudoexfoliation glaucoma.","date":"2023","source":"Experimental eye research","url":"https://pubmed.ncbi.nlm.nih.gov/37061115","citation_count":8,"is_preprint":false},{"pmid":"33510659","id":"PMC_33510659","title":"CNVs and Chromosomal Aneuploidy in Patients With Early-Onset Schizophrenia and Bipolar Disorder: Genotype-Phenotype Associations.","date":"2021","source":"Frontiers in psychiatry","url":"https://pubmed.ncbi.nlm.nih.gov/33510659","citation_count":5,"is_preprint":false},{"pmid":"30458339","id":"PMC_30458339","title":"Candidate gene and pathway analyses identifying genetic variations associated with prasugrel pharmacokinetics and pharmacodynamics.","date":"2018","source":"Thrombosis research","url":"https://pubmed.ncbi.nlm.nih.gov/30458339","citation_count":5,"is_preprint":false},{"pmid":"39880678","id":"PMC_39880678","title":"Pmp2+ Schwann Cells Maintain the Survival of Large-Caliber Motor Axons.","date":"2025","source":"The Journal of neuroscience : the official journal of the Society for Neuroscience","url":"https://pubmed.ncbi.nlm.nih.gov/39880678","citation_count":5,"is_preprint":false},{"pmid":"24340086","id":"PMC_24340086","title":"Utilizing twins as controls for non-twin case-materials in genome wide association studies.","date":"2013","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/24340086","citation_count":5,"is_preprint":false},{"pmid":"36912952","id":"PMC_36912952","title":"Unravelling morphoea aetiopathogenesis by next-generation sequencing of paired skin biopsies.","date":"2023","source":"Archives of dermatological research","url":"https://pubmed.ncbi.nlm.nih.gov/36912952","citation_count":2,"is_preprint":false},{"pmid":"41534528","id":"PMC_41534528","title":"Genetic regulation of fatty acid content in adipose tissue.","date":"2026","source":"American journal of human genetics","url":"https://pubmed.ncbi.nlm.nih.gov/41534528","citation_count":2,"is_preprint":false},{"pmid":"40869199","id":"PMC_40869199","title":"Multi-Omics Reveals Molecular and Genetic Mechanisms Underlying Egg Albumen Quality Decline in Aging Laying Hens.","date":"2025","source":"International journal of molecular sciences","url":"https://pubmed.ncbi.nlm.nih.gov/40869199","citation_count":1,"is_preprint":false},{"pmid":"41263672","id":"PMC_41263672","title":"Genetic and Molecular Determinants of Familial Transmission of Skeletal Malocclusions.","date":"2025","source":"Orthodontics & craniofacial research","url":"https://pubmed.ncbi.nlm.nih.gov/41263672","citation_count":1,"is_preprint":false},{"pmid":"39999946","id":"PMC_39999946","title":"Seven loci associated with schizophrenia and bipolar I disorder in selected southern African population groups.","date":"2025","source":"European journal of medical genetics","url":"https://pubmed.ncbi.nlm.nih.gov/39999946","citation_count":0,"is_preprint":false},{"pmid":"41890990","id":"PMC_41890990","title":"Separating the genetics of disease, treatment, and treatment response using graphical modeling and large-scale electronic health records.","date":"2026","source":"medRxiv : the preprint server for health sciences","url":"https://pubmed.ncbi.nlm.nih.gov/41890990","citation_count":0,"is_preprint":false},{"pmid":null,"id":"bio_10.1101_2025.02.21.25322653","title":"Integrative Multi-omics of Gynecological Tumors Identifies Novel Singular Biomarkers of Disease Progression","date":"2025-02-23","source":"bioRxiv","url":"https://doi.org/10.1101/2025.02.21.25322653","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":21334,"output_tokens":2717,"usd":0.052379},"stage2":{"model":"claude-opus-4-6","input_tokens":6043,"output_tokens":2495,"usd":0.138885},"total_usd":0.191264,"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\": 2002,\n      \"finding\": \"ADAMTSL1 (punctin) is a secreted glycoprotein that localizes to the cell substratum in a punctate pattern, excluded from focal contacts, when expressed in transfected COS-1 cells. It contains four thrombospondin type I repeats, disulfide bonds, and a single N-linked glycosylation site, and adopts a hatchet-shaped structure with a globular region attached to a short stem as determined by rotary shadowing electron microscopy.\",\n      \"method\": \"Stable transfection in insect cells, Edman degradation for N-terminus, LC-ESI-MS for mass determination, glycosylation analysis with tunicamycin, rotary shadowing EM, immunofluorescence in COS-1 cells\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — multiple orthogonal biochemical methods in a single foundational study with rigorous characterization\",\n      \"pmids\": [\"11805097\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"ADAMTSL1 contains thrombospondin type I repeats (TSRs) that are substrates for the beta1,3-glucosyltransferase B3GLCT (responsible for Peters'-plus syndrome), which adds a glucose moiety to O-linked fucose on these TSR domains, forming a glucose-beta1,3-fucose disaccharide modification. The disaccharide modification on ADAMTSL1 was directly demonstrated.\",\n      \"method\": \"Biochemical demonstration of O-glucosylation on purified ADAMTSL1 TSR domains; genetic and enzymatic analysis of B3GLCT substrate specificity\",\n      \"journal\": \"Annals of medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — direct biochemical demonstration of PTM on ADAMTSL1, single study\",\n      \"pmids\": [\"18720094\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"The C. elegans ortholog of ADAMTSL1, MADD-4, functions as a secreted guidance cue from the dorsal and ventral nerve cords that attracts sensory axons and muscle arms; this activity is dependent on the netrin receptor UNC-40/DCC acting cell-autonomously. This defines a conserved role for ADAMTSL orthologs as extracellular guidance proteins acting through DCC-family receptors.\",\n      \"method\": \"Genetic loss-of-function, epistasis analysis with unc-40/DCC mutants, cell-autonomous rescue experiments, secretion assays in C. elegans\",\n      \"journal\": \"Developmental cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — genetic epistasis with defined receptor, multiple orthogonal genetic approaches, replicated functional readouts\",\n      \"pmids\": [\"22014523\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"ADAMTSL1 is a direct substrate of matrix metalloproteinase 10 (MMP10), which cleaves ADAMTSL1 in fibroblast secretomes, as identified by time-resolved degradomics.\",\n      \"method\": \"Multiplexed terminal amine isotopic labeling of substrates (TAILS) degradomics; mass spectrometry identification of cleavage sites in fibroblast secretomes\",\n      \"journal\": \"Molecular & cellular proteomics : MCP\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — system-wide substrate identification with neo-terminus quantification; single study\",\n      \"pmids\": [\"24281761\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"ADAMTSL1 expression is regulated by the Hedgehog signaling pathway in chondrosarcoma, and ADAMTSL1 regulates chondrosarcoma cell proliferation, as demonstrated by downregulation following Smoothened inhibitor IPI-926 treatment and functional studies.\",\n      \"method\": \"Gene expression profiling of IPI-926-treated chondrosarcoma xenografts; functional proliferation assays after ADAMTSL1 modulation\",\n      \"journal\": \"Molecular cancer therapeutics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — gene profiling combined with functional proliferation assay; single study\",\n      \"pmids\": [\"24634412\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"A heterozygous p.Trp42Arg mutation in ADAMTSL1 (affecting the C-mannosylation motif W-x-x-W) causes intracellular retention of the mutant protein rather than secretion, and the mutant protein also reduces secretion of co-transfected wild-type ADAMTSL1, demonstrating a dominant negative mechanism. This establishes that C-mannosylation of Trp42 is required for proper ADAMTSL1 folding and secretion.\",\n      \"method\": \"In vitro transfection with ADAMTSL1-WT and ADAMTSL1-p.Trp42Arg constructs; secretion assays comparing conditioned medium and cell lysate fractions; co-transfection dominant negative experiment; clinical cosegregation in a three-generation pedigree\",\n      \"journal\": \"Human mutation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — in vitro functional assay with mutagenesis, dominant negative mechanism demonstrated, cosegregation in human pedigree\",\n      \"pmids\": [\"28722276\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Missense mutations in ADAMTSL1 are associated with mandibular prognathism, and Adamtsl1 is strongly expressed in condensed mesenchymal cells of the mouse condyle but not in long bone cartilage. The authors hypothesize that ADAMTSL1 mutations cause failure to cleave aggrecan in condylar cartilage leading to mandibular overgrowth.\",\n      \"method\": \"Whole exome sequencing, mutation analysis in patients, in situ expression analysis in mouse condyle tissues\",\n      \"journal\": \"Clinical genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — genetic evidence plus direct in situ localization in mouse condyle; aggrecan cleavage mechanism is hypothetical\",\n      \"pmids\": [\"30714143\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"C-mannosylation of ADAMTSL1 at the W-x-x-W motif (Trp42) is required for its secretion; a disease-associated variant disrupting this motif prevents secretion, providing direct evidence that DPY19-family C-mannosyltransferases act on ADAMTSL1 TSR domains to enable proper protein folding and trafficking.\",\n      \"method\": \"Review integrating published biochemical data on C-mannosylation of ADAMTSL1; functional secretion experiments described in prior work (Hendee et al. 2017)\",\n      \"journal\": \"Molecules (Basel, Switzerland)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — mechanistic synthesis supported by direct functional secretion data from cited experiments\",\n      \"pmids\": [\"34500691\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"A subpopulation of Schwann cells (SCs) identified by co-expression of Adamtsl1, Cldn14, and Pmp2 preferentially myelinates/ensheathes large-caliber motor axons in peripheral nerve, and this SC subtype is selectively reduced in ALS mouse models and human ALS nerve samples.\",\n      \"method\": \"Single-nuclei RNA sequencing of mouse peripheral nerves; cross-validation in ALS SOD1G93A mouse model; analysis of human ALS nerve samples\",\n      \"journal\": \"Nature neuroscience\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — snRNA-seq with disease model validation; Adamtsl1 used as a marker gene rather than direct functional target\",\n      \"pmids\": [\"35115729\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"ADAMTSL1 protein is enriched at the myotendinous junction (MTJ) of human skeletal muscle, as confirmed at the protein level by immunofluorescence, suggesting a structural or regulatory ECM role at this mechanically stressed interface.\",\n      \"method\": \"Single-nucleus RNA sequencing of human muscle-tendon samples; spatial transcriptomics; immunofluorescence protein validation at the MTJ\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — direct protein localization confirmed by immunofluorescence; functional consequence not yet established\",\n      \"pmids\": [\"36924352\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Genetic ablation of Pmp2+ Schwann cells (which co-express Adamtsl1) leads to significant loss of large-caliber motor axons with behavioral, electrophysiological, and ultrastructural deficits; restoration of Pmp2+ SCs rescues motor axon survival, demonstrating that this SC subtype is required for large-caliber motor axon maintenance.\",\n      \"method\": \"Tamoxifen-inducible Pmp2-CreERT2 mouse with diphtheria toxin-mediated SC ablation; behavioral tests, electrophysiology, electron microscopy; recovery experiments\",\n      \"journal\": \"The Journal of neuroscience\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — conditional genetic ablation with multiple orthogonal functional readouts and rescue experiment\",\n      \"pmids\": [\"39880678\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"ADAMTSL1 (punctin) is a secreted extracellular matrix glycoprotein whose proper folding and secretion requires C-mannosylation of Trp42 by DPY19-family transferases; it is proteolytically processed by MMP10, is expressed in specific mesenchymal and glial cell populations (including motor-axon-associated Schwann cells and myotendinous junction myonuclei), regulates chondrosarcoma cell proliferation downstream of Hedgehog signaling, and its orthologs function as secreted guidance cues acting through DCC-family receptors.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"ADAMTSL1 (punctin) is a secreted extracellular matrix glycoprotein that functions at mechanically and developmentally critical tissue interfaces, including the myotendinous junction, condylar mesenchyme, and peripheral nerve. It adopts a hatchet-shaped structure with four thrombospondin type I repeats (TSRs) bearing O-fucose/glucose disaccharide modifications and requires C-mannosylation of Trp42 for proper folding and secretion; a dominant-negative p.Trp42Arg mutation causes intracellular retention and is associated with mandibular prognathism [PMID:11805097, PMID:28722276, PMID:30714143]. The C. elegans ortholog MADD-4 acts as a secreted guidance cue that attracts axons and muscle arms through the netrin receptor UNC-40/DCC, establishing a conserved role for ADAMTSL family members as extracellular signaling ligands [PMID:22014523]. ADAMTSL1 is proteolytically processed by MMP10 in fibroblast secretomes, is transcriptionally regulated by Hedgehog signaling in chondrosarcoma where it controls cell proliferation, and marks a Schwann cell subpopulation essential for large-caliber motor axon maintenance [PMID:24281761, PMID:24634412, PMID:39880678].\",\n  \"teleology\": [\n    {\n      \"year\": 2002,\n      \"claim\": \"Initial biochemical characterization established ADAMTSL1 as a secreted, glycosylated ECM protein with a defined domain architecture, resolving its basic identity as a TSR-containing matrix component deposited in punctate patterns outside focal contacts.\",\n      \"evidence\": \"Recombinant expression in insect and COS-1 cells; rotary shadowing EM; Edman degradation and LC-ESI-MS\",\n      \"pmids\": [\"11805097\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No binding partners or receptors identified\", \"In vivo tissue localization not established\", \"Function of punctate substratum deposition unknown\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Identification of ADAMTSL1 TSRs as substrates for B3GLCT-mediated O-glucosylation revealed that its thrombospondin repeats carry a glucose-β1,3-fucose disaccharide, linking ADAMTSL1 post-translational modification to Peters-plus syndrome biology.\",\n      \"evidence\": \"Biochemical demonstration of O-glucosylation on purified ADAMTSL1 TSR domains\",\n      \"pmids\": [\"18720094\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Functional consequence of O-glucosylation for ADAMTSL1 activity not tested\", \"In vivo relevance of TSR glycosylation not demonstrated\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Genetic analysis of the C. elegans ortholog MADD-4 demonstrated that ADAMTSL family proteins function as secreted guidance cues acting through the DCC-family receptor UNC-40, establishing a signaling paradigm beyond a purely structural ECM role.\",\n      \"evidence\": \"Loss-of-function genetics, epistasis with unc-40/DCC, cell-autonomous rescue in C. elegans\",\n      \"pmids\": [\"22014523\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether mammalian ADAMTSL1 similarly signals through DCC is untested\", \"Ligand-receptor binding mechanism not defined biochemically\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Degradomic profiling identified ADAMTSL1 as a direct substrate of MMP10, revealing that its ECM function is regulated by proteolytic processing.\",\n      \"evidence\": \"TAILS degradomics with mass spectrometry in fibroblast secretomes\",\n      \"pmids\": [\"24281761\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Cleavage site(s) and functional consequences of processing not characterized in detail\", \"Relevance to in vivo tissue remodeling not established\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Placing ADAMTSL1 downstream of Hedgehog/Smoothened signaling and demonstrating its role in chondrosarcoma proliferation revealed a context-dependent growth-regulatory function for this ECM protein.\",\n      \"evidence\": \"Gene expression profiling of IPI-926-treated chondrosarcoma xenografts; functional proliferation assays\",\n      \"pmids\": [\"24634412\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism by which ADAMTSL1 regulates proliferation unknown\", \"Not clear if this is autocrine ECM signaling or structural\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Demonstrating that the p.Trp42Arg mutation disrupts C-mannosylation, causes intracellular retention, and exerts a dominant-negative effect on wild-type ADAMTSL1 secretion established that C-mannosylation is essential for proper folding and export.\",\n      \"evidence\": \"In vitro secretion assays with wild-type and mutant constructs; co-transfection experiments; cosegregation in a three-generation pedigree\",\n      \"pmids\": [\"28722276\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis for why loss of C-mannosylation causes misfolding not determined\", \"Whether dominant-negative effect operates in vivo in relevant tissues not shown\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Identification of ADAMTSL1 mutations in mandibular prognathism patients, combined with restricted expression in condylar mesenchyme, linked the gene to craniofacial skeletal growth, though the proposed aggrecan-cleavage mechanism remains hypothetical.\",\n      \"evidence\": \"Whole-exome sequencing in patients; in situ expression in mouse condyle\",\n      \"pmids\": [\"30714143\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Aggrecan cleavage by ADAMTSL1 is hypothetical — no direct enzymatic or binding evidence\", \"No animal model confirming craniofacial phenotype\", \"Functional characterization of patient mutations not performed\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Single-nucleus transcriptomics identified Adamtsl1 as a marker of a Schwann cell subtype that preferentially ensheathes large-caliber motor axons, and this subtype is selectively reduced in ALS, placing ADAMTSL1 in the context of motor neuron support.\",\n      \"evidence\": \"snRNA-seq of mouse peripheral nerves; validation in SOD1-G93A ALS mice and human ALS nerve samples\",\n      \"pmids\": [\"35115729\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"ADAMTSL1 is a marker rather than a proven functional mediator of this SC subtype's activity\", \"Whether ADAMTSL1 itself contributes to axon maintenance is untested\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Protein-level localization of ADAMTSL1 at the human myotendinous junction confirmed that it occupies a mechanically stressed ECM niche, consistent with a structural or signaling role at muscle-tendon interfaces.\",\n      \"evidence\": \"snRNA-seq, spatial transcriptomics, and immunofluorescence of human muscle-tendon samples\",\n      \"pmids\": [\"36924352\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Functional role of ADAMTSL1 at the MTJ not tested\", \"Binding partners at the MTJ unknown\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Conditional ablation of Pmp2+/Adamtsl1+ Schwann cells proved that this subtype is required for large-caliber motor axon survival, with rescue confirming the dependency, but the specific contribution of ADAMTSL1 protein within these cells remains unresolved.\",\n      \"evidence\": \"Tamoxifen-inducible Pmp2-CreERT2 diphtheria toxin ablation in mice; behavioral, electrophysiological, and ultrastructural analyses; recovery experiments\",\n      \"pmids\": [\"39880678\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Ablation targets the entire SC subtype, not ADAMTSL1 specifically\", \"Whether ADAMTSL1 secretion from these SCs mediates the axon-protective effect is unknown\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The mammalian receptor for ADAMTSL1 signaling, the functional consequences of its MMP10-mediated cleavage, and whether it directly contributes to motor axon maintenance or MTJ integrity remain unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No mammalian receptor identified\", \"No ADAMTSL1-specific knockout phenotype reported in mice\", \"Structural basis for TSR-dependent ECM interactions undefined\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0048018\", \"supporting_discovery_ids\": [2]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0031012\", \"supporting_discovery_ids\": [0, 9]},\n      {\"term_id\": \"GO:0005576\", \"supporting_discovery_ids\": [0, 2, 3]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1474244\", \"supporting_discovery_ids\": [0, 3, 9]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [2, 4]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\n      \"MMP10\",\n      \"B3GLCT\",\n      \"UNC-40\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}