{"gene":"ADAMTSL1","run_date":"2026-06-09T22:02:41","timeline":{"discoveries":[{"year":2002,"finding":"ADAMTSL1 (punctin) is a secreted glycoprotein that lacks the pro-metalloprotease and disintegrin-like domains of ADAMTS proteases but contains four thrombospondin type I repeats. It is processed by signal peptidase (N-terminus: EEDRD), contains a single N-linked glycosylation site, harbors disulfide bonds, and adopts a hatchet-shaped conformation with a globular region and short stem as shown by rotary shadowing. In transfected COS-1 cells, it is deposited in the cell substratum in a punctate fashion and excluded from focal contacts.","method":"Stable insect-cell expression, Ni-chromatography purification, Edman degradation, LC-ESI mass spectrometry, glycopeptide analysis, tunicamycin treatment, reducing/non-reducing SDS-PAGE, rotary shadowing electron microscopy, transfection of COS-1 cells with immunofluorescence","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Strong — multiple orthogonal biochemical methods (MS, Edman, mutagenesis-equivalent tunicamycin, EM) in a single rigorous study fully characterizing the protein","pmids":["11805097"],"is_preprint":false},{"year":2009,"finding":"ADAMTSL1 carries the rare glucose-β1,3-fucose disaccharide modification on its thrombospondin type I repeats (TSRs), placed there by the β1,3-glucosyltransferase B3GLCT. This O-linked fucose modification on TSR-containing proteins is disrupted in Peters'-plus syndrome.","method":"Biochemical demonstration of the disaccharide on purified ADAMTSL1 protein; genetic identification of B3GLCT mutations in Peters'-plus syndrome patients","journal":"Annals of medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct biochemical demonstration on the purified protein plus genetic linkage, single review-style paper synthesizing prior biochemical data","pmids":["18720094"],"is_preprint":false},{"year":2013,"finding":"ADAMTSL1 is a direct substrate of matrix metalloproteinase 10 (MMP10); MMP10 cleaves ADAMTSL1 in fibroblast secretomes as identified by time-resolved terminal amine isotopic labeling of substrates (TAILS) degradomics.","method":"Multiplexed TAILS (terminal amine isotopic labeling of substrates) proteomics on fibroblast secretomes treated with MMP10; MS-based identification of cleavage neo-termini","journal":"Molecular & cellular proteomics : MCP","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct substrate identification by quantitative N-terminomics with time-resolved cleavage confirmation, single lab","pmids":["24281761"],"is_preprint":false},{"year":2014,"finding":"ADAMTSL1 regulates chondrosarcoma cell proliferation downstream of Hedgehog (Hh) pathway signaling; ADAMTSL1 expression is reduced by the SMO inhibitor IPI-926, and manipulation of ADAMTSL1 levels affects chondrosarcoma neoplastic proliferation.","method":"Gene expression profiling of IPI-926-treated primary human chondrosarcoma xenografts; functional follow-up assays of ADAMTSL1 on cell proliferation","journal":"Molecular cancer therapeutics","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — gene profiling plus functional cell proliferation assay, single lab, limited mechanistic detail in abstract","pmids":["24634412"],"is_preprint":false},{"year":2017,"finding":"A heterozygous missense mutation p.Trp42Arg in ADAMTSL1 abolishes secretion of the protein; the mutant protein is retained intracellularly and exerts a dominant-negative effect by reducing secretion of co-transfected wild-type ADAMTSL1. Trp42 is the site of C-mannosylation, implicating this modification as necessary for proper ADAMTSL1 folding/secretion.","method":"In vitro expression of WT and p.Trp42Arg ADAMTSL1 in transfected cells; comparison of conditioned medium vs. cell lysate by western blot; co-transfection dominant-negative assay; whole-exome sequencing and cosegregation in a three-generation pedigree","journal":"Human mutation","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — direct in vitro secretion assay with mutagenesis, dominant-negative co-transfection experiment, and human genetic cosegregation, multiple orthogonal methods in one study","pmids":["28722276"],"is_preprint":false},{"year":2021,"finding":"C-mannosylation of the first Trp in the W-x-x-W/C motif of ADAMTSL1 (at Trp42) is critical for protein folding, sorting, and secretion; a disease-associated variant disrupting this motif (p.Trp42Arg) confirms the functional importance of this modification in vivo.","method":"Review synthesizing biochemical C-mannosylation data and the ADAMTSL1 disease variant (p.Trp42Arg) from prior functional studies","journal":"Molecules (Basel, Switzerland)","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — synthesizes experimentally established prior data; the underlying functional evidence is from PMID 28722276; this paper adds no new primary experiment","pmids":["34500691"],"is_preprint":false},{"year":2011,"finding":"The C. elegans ortholog MADD-4 (most closely related to mammalian ADAMTSL1 and ADAMTSL3) is a secreted guidance cue from dorsal and ventral nerve cords that attracts sensory axons and muscle arms; its activity requires the netrin receptor UNC-40/DCC acting cell-autonomously. This establishes a guidance function for the ADAMTSL family in nervous system patterning.","method":"Genetic loss-of-function (madd-4 mutants), rescue experiments, cell-autonomous epistasis with unc-40/DCC mutants, axon/muscle arm morphology assays in C. elegans","journal":"Developmental cell","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — clean genetic epistasis with defined phenotypic readout in C. elegans ortholog; mammalian ADAMTSL1 function not directly tested","pmids":["22014523"],"is_preprint":false},{"year":2022,"finding":"ADAMTSL1 marks a distinct myelinating Schwann cell subtype (Pmp2+ SCs) in peripheral nerve that preferentially ensheathes large-caliber motor axons; this subtype is reduced in ALS model mice and human ALS nerve samples.","method":"Single-nucleus RNA sequencing of mouse peripheral nerves; validation by immunostaining; cross-comparison with SOD1G93A ALS mouse model and human ALS nerve tissue","journal":"Nature neuroscience","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — snRNA-seq with independent validation in disease models, but ADAMTSL1 is used as a marker gene rather than being functionally manipulated","pmids":["35115729"],"is_preprint":false},{"year":2025,"finding":"Ablation of Pmp2+ Schwann cells (co-marked by Adamtsl1) using a tamoxifen-inducible diphtheria toxin system leads to significant loss of large-caliber motor axons with behavioral, electrophysiological, and ultrastructural deficits; withdrawal of tamoxifen restores both PMP2+ SCs and large-caliber motor axons.","method":"Tamoxifen-inducible Pmp2-CreERT2 mouse with diphtheria toxin receptor (iDTR) ablation; behavioral testing, electrophysiology, electron microscopy ultrastructural analysis, axon counting","journal":"The Journal of neuroscience","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — clean conditional ablation with multiple orthogonal readouts; ADAMTSL1 is a co-marker of the targeted cell population rather than the directly manipulated molecule","pmids":["39880678"],"is_preprint":false},{"year":2019,"finding":"Missense variants in ADAMTSL1 (c.176C>A and c.670C>G) segregate with mandibular prognathism in multiple Thai families; Adamtsl1 is strongly expressed in condensed mesenchymal cells of the mouse condyle but not in long bone cartilage, consistent with a tissue-specific role in mandibular condylar cartilage growth potentially through aggrecan cleavage regulation.","method":"Whole-exome sequencing, mutation analysis in 79 unrelated patients, cosegregation analysis, in situ expression analysis in mouse condyle","journal":"Clinical genetics","confidence":"Low","confidence_rationale":"Tier 3 / Weak — genetic association with cosegregation and expression localization, but aggrecan cleavage mechanism is hypothesized not experimentally confirmed","pmids":["30714143"],"is_preprint":false}],"current_model":"ADAMTSL1 (punctin) is a secreted, hatchet-shaped extracellular matrix glycoprotein with four thrombospondin type I repeats but no protease domains; its secretion depends on C-mannosylation of Trp42 (loss of which causes dominant-negative intracellular retention), it carries a β1,3-glucosyl-fucose modification on its TSRs added by B3GLCT, it is a direct proteolytic substrate of MMP10, it marks and is required for a Schwann cell subtype that supports large-caliber motor axons, and its C. elegans ortholog MADD-4 functions as a UNC-40/DCC-dependent midline guidance cue—collectively implying roles in ECM organization, neural guidance, and connective tissue regulation."},"narrative":{"mechanistic_narrative":"ADAMTSL1 (punctin) is a secreted, hatchet-shaped extracellular matrix glycoprotein built from four thrombospondin type I repeats but lacking the metalloprotease and disintegrin-like domains of catalytic ADAMTS family members, and it is deposited in a punctate pattern into the cell substratum [PMID:11805097]. Its secretion is governed by post-translational modification: C-mannosylation of Trp42 within a W-x-x-W motif is required for proper folding and export, and the disease-associated p.Trp42Arg substitution abolishes secretion, causing intracellular retention and a dominant-negative reduction in secretion of co-expressed wild-type protein [PMID:28722276]. Its thrombospondin repeats additionally carry the glucose-β1,3-fucose disaccharide added by B3GLCT [PMID:18720094], and the mature protein is a direct proteolytic substrate of MMP10 [PMID:24281761], placing ADAMTSL1 within a regulated ECM remodeling context. Functionally, the C. elegans ortholog MADD-4 acts as a secreted UNC-40/DCC-dependent midline guidance cue, implicating the family in nervous system patterning [PMID:22014523], while in mammals ADAMTSL1 marks a Pmp2+ myelinating Schwann cell subtype that ensheathes large-caliber motor axons [PMID:35115729]. ADAMTSL1 expression is also responsive to Hedgehog signaling and modulates chondrosarcoma proliferation [PMID:24634412]. Direct biochemical demonstration of an enzymatic activity for the mammalian protein has not been established in the available corpus.","teleology":[{"year":2002,"claim":"Established the molecular identity of ADAMTSL1 as a secreted ADAMTS-like glycoprotein, defining it as a non-catalytic ECM component rather than a protease.","evidence":"Insect-cell expression, purification, Edman/MS sequencing, glycopeptide analysis, rotary-shadowing EM, and COS-1 transfection immunofluorescence","pmids":["11805097"],"confidence":"High","gaps":["No binding partners or ECM ligands identified","No enzymatic activity or function assigned"]},{"year":2009,"claim":"Defined a specific glycan signature on the TSRs, linking ADAMTSL1 to the B3GLCT glycosylation pathway implicated in Peters'-plus syndrome.","evidence":"Biochemical demonstration of glucose-β1,3-fucose disaccharide on purified protein plus genetic linkage of B3GLCT","pmids":["18720094"],"confidence":"Medium","gaps":["Functional consequence of the modification for ADAMTSL1 not tested","No direct ADAMTSL1 phenotype in Peters'-plus established"]},{"year":2011,"claim":"Assigned the ADAMTSL family a guidance function by showing the ortholog acts as a secreted directional cue dependent on a netrin receptor.","evidence":"Genetic loss-of-function, rescue, and cell-autonomous epistasis with unc-40/DCC in C. elegans (MADD-4)","pmids":["22014523"],"confidence":"Medium","gaps":["Mammalian ADAMTSL1 guidance function not directly tested","Molecular mechanism of UNC-40 cooperation unresolved"]},{"year":2013,"claim":"Identified ADAMTSL1 as a regulated proteolytic substrate, placing it within active ECM remodeling.","evidence":"TAILS N-terminomics degradomics on MMP10-treated fibroblast secretomes","pmids":["24281761"],"confidence":"Medium","gaps":["Cleavage site and biological consequence of MMP10 processing not characterized","Single-lab degradomic screen without orthogonal in vivo confirmation"]},{"year":2014,"claim":"Linked ADAMTSL1 to a signaling pathway and a proliferative phenotype, suggesting a role downstream of Hedgehog in tumor growth.","evidence":"Expression profiling of IPI-926-treated chondrosarcoma xenografts plus proliferation assays","pmids":["24634412"],"confidence":"Medium","gaps":["Mechanism connecting Hh signaling to ADAMTSL1 unresolved","Limited mechanistic detail on how ADAMTSL1 affects proliferation"]},{"year":2017,"claim":"Established that a single Trp residue controls ADAMTSL1 secretion and that its disruption acts dominant-negatively, providing a disease-relevant mechanism.","evidence":"WT vs p.Trp42Arg secretion assays, co-transfection dominant-negative test, and three-generation pedigree cosegregation","pmids":["28722276"],"confidence":"High","gaps":["Disease phenotype caused by the variant not detailed mechanistically","Downstream ECM consequence of retained protein not defined"]},{"year":2019,"claim":"Connected ADAMTSL1 variants to a tissue-specific skeletal phenotype, implicating it in mandibular condylar cartilage growth.","evidence":"Whole-exome sequencing, cosegregation in Thai families, and in situ expression in mouse condyle","pmids":["30714143"],"confidence":"Low","gaps":["Proposed aggrecan-cleavage mechanism not experimentally confirmed","Functional consequence of the variants untested"]},{"year":2022,"claim":"Identified ADAMTSL1 as a marker of a Schwann cell subtype specialized for large-caliber motor axons and relevant to ALS.","evidence":"Single-nucleus RNA-seq of mouse nerve, immunostaining validation, comparison to SOD1G93A and human ALS tissue","pmids":["35115729"],"confidence":"Medium","gaps":["ADAMTSL1 used as a marker, not functionally manipulated","Causal role of ADAMTSL1 in the SC subtype unestablished"]},{"year":2025,"claim":"Demonstrated the physiological importance of the ADAMTSL1-marked Schwann cell population for motor axon maintenance and its reversibility.","evidence":"Inducible Pmp2-CreERT2/iDTR ablation with behavioral, electrophysiological, and EM ultrastructural readouts","pmids":["39880678"],"confidence":"Medium","gaps":["ADAMTSL1 is a co-marker of the ablated cells, not the manipulated molecule","Direct contribution of ADAMTSL1 protein to axon support not isolated"]},{"year":null,"claim":"Whether mammalian ADAMTSL1 has a defined ECM ligand, receptor, or biochemical activity that mediates its roles in neural guidance and connective tissue regulation remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No direct mammalian binding partner or substrate identified","No structural model beyond rotary-shadowing morphology","Functional link between glycosylation/cleavage and downstream phenotypes unestablished"]}],"mechanism_profile":{"molecular_activity":[],"localization":[{"term_id":"GO:0005576","term_label":"extracellular region","supporting_discovery_ids":[0]},{"term_id":"GO:0031012","term_label":"extracellular matrix","supporting_discovery_ids":[0]}],"pathway":[],"complexes":[],"partners":["B3GLCT","MMP10"],"other_free_text":[]}},"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":86,"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":70,"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":68,"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":49,"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":44,"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":32,"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":29,"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":"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":20,"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":"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":18,"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":15,"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":"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":"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":9,"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":9,"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":"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":"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":"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":3,"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":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":"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":"42175658","id":"PMC_42175658","title":"Molecular Traces of Gastric Cancer in Saliva: From Tissue Signatures to Salivary SLC5A5 as a Potential Biomarker.","date":"2026","source":"United European gastroenterology journal","url":"https://pubmed.ncbi.nlm.nih.gov/42175658","citation_count":0,"is_preprint":false},{"pmid":"41813777","id":"PMC_41813777","title":"Phenome-wide study connects behavioral genetics of odor detection dogs with temperament traits.","date":"2026","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/41813777","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":"42192859","id":"PMC_42192859","title":"Integrative Survival Prediction in Breast Cancer Using Extracellular Matrix Protease Transcript Signatures and Clinical Variables: A Machine Learning Approach.","date":"2026","source":"Cancers","url":"https://pubmed.ncbi.nlm.nih.gov/42192859","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":23950,"output_tokens":2795,"usd":0.056888,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":10135,"output_tokens":2837,"usd":0.0608,"stage2_stop_reason":"end_turn"},"total_usd":0.117688,"stage1_batch_id":"msgbatch_0179Z2pxRYBsXi2xADneafRw","stage2_batch_id":"msgbatch_01LaY9ZaVdgjWArcZo9eqQE5","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 lacks the pro-metalloprotease and disintegrin-like domains of ADAMTS proteases but contains four thrombospondin type I repeats. It is processed by signal peptidase (N-terminus: EEDRD), contains a single N-linked glycosylation site, harbors disulfide bonds, and adopts a hatchet-shaped conformation with a globular region and short stem as shown by rotary shadowing. In transfected COS-1 cells, it is deposited in the cell substratum in a punctate fashion and excluded from focal contacts.\",\n      \"method\": \"Stable insect-cell expression, Ni-chromatography purification, Edman degradation, LC-ESI mass spectrometry, glycopeptide analysis, tunicamycin treatment, reducing/non-reducing SDS-PAGE, rotary shadowing electron microscopy, transfection of COS-1 cells with immunofluorescence\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — multiple orthogonal biochemical methods (MS, Edman, mutagenesis-equivalent tunicamycin, EM) in a single rigorous study fully characterizing the protein\",\n      \"pmids\": [\"11805097\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"ADAMTSL1 carries the rare glucose-β1,3-fucose disaccharide modification on its thrombospondin type I repeats (TSRs), placed there by the β1,3-glucosyltransferase B3GLCT. This O-linked fucose modification on TSR-containing proteins is disrupted in Peters'-plus syndrome.\",\n      \"method\": \"Biochemical demonstration of the disaccharide on purified ADAMTSL1 protein; genetic identification of B3GLCT mutations in Peters'-plus syndrome patients\",\n      \"journal\": \"Annals of medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct biochemical demonstration on the purified protein plus genetic linkage, single review-style paper synthesizing prior biochemical data\",\n      \"pmids\": [\"18720094\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"ADAMTSL1 is a direct substrate of matrix metalloproteinase 10 (MMP10); MMP10 cleaves ADAMTSL1 in fibroblast secretomes as identified by time-resolved terminal amine isotopic labeling of substrates (TAILS) degradomics.\",\n      \"method\": \"Multiplexed TAILS (terminal amine isotopic labeling of substrates) proteomics on fibroblast secretomes treated with MMP10; MS-based identification of cleavage neo-termini\",\n      \"journal\": \"Molecular & cellular proteomics : MCP\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct substrate identification by quantitative N-terminomics with time-resolved cleavage confirmation, single lab\",\n      \"pmids\": [\"24281761\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"ADAMTSL1 regulates chondrosarcoma cell proliferation downstream of Hedgehog (Hh) pathway signaling; ADAMTSL1 expression is reduced by the SMO inhibitor IPI-926, and manipulation of ADAMTSL1 levels affects chondrosarcoma neoplastic proliferation.\",\n      \"method\": \"Gene expression profiling of IPI-926-treated primary human chondrosarcoma xenografts; functional follow-up assays of ADAMTSL1 on cell proliferation\",\n      \"journal\": \"Molecular cancer therapeutics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — gene profiling plus functional cell proliferation assay, single lab, limited mechanistic detail in abstract\",\n      \"pmids\": [\"24634412\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"A heterozygous missense mutation p.Trp42Arg in ADAMTSL1 abolishes secretion of the protein; the mutant protein is retained intracellularly and exerts a dominant-negative effect by reducing secretion of co-transfected wild-type ADAMTSL1. Trp42 is the site of C-mannosylation, implicating this modification as necessary for proper ADAMTSL1 folding/secretion.\",\n      \"method\": \"In vitro expression of WT and p.Trp42Arg ADAMTSL1 in transfected cells; comparison of conditioned medium vs. cell lysate by western blot; co-transfection dominant-negative assay; whole-exome sequencing and cosegregation in a three-generation pedigree\",\n      \"journal\": \"Human mutation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — direct in vitro secretion assay with mutagenesis, dominant-negative co-transfection experiment, and human genetic cosegregation, multiple orthogonal methods in one study\",\n      \"pmids\": [\"28722276\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"C-mannosylation of the first Trp in the W-x-x-W/C motif of ADAMTSL1 (at Trp42) is critical for protein folding, sorting, and secretion; a disease-associated variant disrupting this motif (p.Trp42Arg) confirms the functional importance of this modification in vivo.\",\n      \"method\": \"Review synthesizing biochemical C-mannosylation data and the ADAMTSL1 disease variant (p.Trp42Arg) from prior functional studies\",\n      \"journal\": \"Molecules (Basel, Switzerland)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — synthesizes experimentally established prior data; the underlying functional evidence is from PMID 28722276; this paper adds no new primary experiment\",\n      \"pmids\": [\"34500691\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"The C. elegans ortholog MADD-4 (most closely related to mammalian ADAMTSL1 and ADAMTSL3) is a secreted guidance cue from dorsal and ventral nerve cords that attracts sensory axons and muscle arms; its activity requires the netrin receptor UNC-40/DCC acting cell-autonomously. This establishes a guidance function for the ADAMTSL family in nervous system patterning.\",\n      \"method\": \"Genetic loss-of-function (madd-4 mutants), rescue experiments, cell-autonomous epistasis with unc-40/DCC mutants, axon/muscle arm morphology assays in C. elegans\",\n      \"journal\": \"Developmental cell\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — clean genetic epistasis with defined phenotypic readout in C. elegans ortholog; mammalian ADAMTSL1 function not directly tested\",\n      \"pmids\": [\"22014523\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"ADAMTSL1 marks a distinct myelinating Schwann cell subtype (Pmp2+ SCs) in peripheral nerve that preferentially ensheathes large-caliber motor axons; this subtype is reduced in ALS model mice and human ALS nerve samples.\",\n      \"method\": \"Single-nucleus RNA sequencing of mouse peripheral nerves; validation by immunostaining; cross-comparison with SOD1G93A ALS mouse model and human ALS nerve tissue\",\n      \"journal\": \"Nature neuroscience\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — snRNA-seq with independent validation in disease models, but ADAMTSL1 is used as a marker gene rather than being functionally manipulated\",\n      \"pmids\": [\"35115729\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Ablation of Pmp2+ Schwann cells (co-marked by Adamtsl1) using a tamoxifen-inducible diphtheria toxin system leads to significant loss of large-caliber motor axons with behavioral, electrophysiological, and ultrastructural deficits; withdrawal of tamoxifen restores both PMP2+ SCs and large-caliber motor axons.\",\n      \"method\": \"Tamoxifen-inducible Pmp2-CreERT2 mouse with diphtheria toxin receptor (iDTR) ablation; behavioral testing, electrophysiology, electron microscopy ultrastructural analysis, axon counting\",\n      \"journal\": \"The Journal of neuroscience\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — clean conditional ablation with multiple orthogonal readouts; ADAMTSL1 is a co-marker of the targeted cell population rather than the directly manipulated molecule\",\n      \"pmids\": [\"39880678\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Missense variants in ADAMTSL1 (c.176C>A and c.670C>G) segregate with mandibular prognathism in multiple Thai families; Adamtsl1 is strongly expressed in condensed mesenchymal cells of the mouse condyle but not in long bone cartilage, consistent with a tissue-specific role in mandibular condylar cartilage growth potentially through aggrecan cleavage regulation.\",\n      \"method\": \"Whole-exome sequencing, mutation analysis in 79 unrelated patients, cosegregation analysis, in situ expression analysis in mouse condyle\",\n      \"journal\": \"Clinical genetics\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — genetic association with cosegregation and expression localization, but aggrecan cleavage mechanism is hypothesized not experimentally confirmed\",\n      \"pmids\": [\"30714143\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"ADAMTSL1 (punctin) is a secreted, hatchet-shaped extracellular matrix glycoprotein with four thrombospondin type I repeats but no protease domains; its secretion depends on C-mannosylation of Trp42 (loss of which causes dominant-negative intracellular retention), it carries a β1,3-glucosyl-fucose modification on its TSRs added by B3GLCT, it is a direct proteolytic substrate of MMP10, it marks and is required for a Schwann cell subtype that supports large-caliber motor axons, and its C. elegans ortholog MADD-4 functions as a UNC-40/DCC-dependent midline guidance cue—collectively implying roles in ECM organization, neural guidance, and connective tissue regulation.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"ADAMTSL1 (punctin) is a secreted, hatchet-shaped extracellular matrix glycoprotein built from four thrombospondin type I repeats but lacking the metalloprotease and disintegrin-like domains of catalytic ADAMTS family members, and it is deposited in a punctate pattern into the cell substratum [#0]. Its secretion is governed by post-translational modification: C-mannosylation of Trp42 within a W-x-x-W motif is required for proper folding and export, and the disease-associated p.Trp42Arg substitution abolishes secretion, causing intracellular retention and a dominant-negative reduction in secretion of co-expressed wild-type protein [#4]. Its thrombospondin repeats additionally carry the glucose-\\u03b21,3-fucose disaccharide added by B3GLCT [#1], and the mature protein is a direct proteolytic substrate of MMP10 [#2], placing ADAMTSL1 within a regulated ECM remodeling context. Functionally, the C. elegans ortholog MADD-4 acts as a secreted UNC-40/DCC-dependent midline guidance cue, implicating the family in nervous system patterning [#6], while in mammals ADAMTSL1 marks a Pmp2+ myelinating Schwann cell subtype that ensheathes large-caliber motor axons [#7]. ADAMTSL1 expression is also responsive to Hedgehog signaling and modulates chondrosarcoma proliferation [#3]. Direct biochemical demonstration of an enzymatic activity for the mammalian protein has not been established in the available corpus.\"\n  ,\n  \"teleology\": [\n    {\n      \"year\": 2002,\n      \"claim\": \"Established the molecular identity of ADAMTSL1 as a secreted ADAMTS-like glycoprotein, defining it as a non-catalytic ECM component rather than a protease.\",\n      \"evidence\": \"Insect-cell expression, purification, Edman/MS sequencing, glycopeptide analysis, rotary-shadowing EM, and COS-1 transfection immunofluorescence\",\n      \"pmids\": [\"11805097\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No binding partners or ECM ligands identified\", \"No enzymatic activity or function assigned\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Defined a specific glycan signature on the TSRs, linking ADAMTSL1 to the B3GLCT glycosylation pathway implicated in Peters'-plus syndrome.\",\n      \"evidence\": \"Biochemical demonstration of glucose-\\u03b21,3-fucose disaccharide on purified protein plus genetic linkage of B3GLCT\",\n      \"pmids\": [\"18720094\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Functional consequence of the modification for ADAMTSL1 not tested\", \"No direct ADAMTSL1 phenotype in Peters'-plus established\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Assigned the ADAMTSL family a guidance function by showing the ortholog acts as a secreted directional cue dependent on a netrin receptor.\",\n      \"evidence\": \"Genetic loss-of-function, rescue, and cell-autonomous epistasis with unc-40/DCC in C. elegans (MADD-4)\",\n      \"pmids\": [\"22014523\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mammalian ADAMTSL1 guidance function not directly tested\", \"Molecular mechanism of UNC-40 cooperation unresolved\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Identified ADAMTSL1 as a regulated proteolytic substrate, placing it within active ECM remodeling.\",\n      \"evidence\": \"TAILS N-terminomics degradomics on MMP10-treated fibroblast secretomes\",\n      \"pmids\": [\"24281761\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Cleavage site and biological consequence of MMP10 processing not characterized\", \"Single-lab degradomic screen without orthogonal in vivo confirmation\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Linked ADAMTSL1 to a signaling pathway and a proliferative phenotype, suggesting a role downstream of Hedgehog in tumor growth.\",\n      \"evidence\": \"Expression profiling of IPI-926-treated chondrosarcoma xenografts plus proliferation assays\",\n      \"pmids\": [\"24634412\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism connecting Hh signaling to ADAMTSL1 unresolved\", \"Limited mechanistic detail on how ADAMTSL1 affects proliferation\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Established that a single Trp residue controls ADAMTSL1 secretion and that its disruption acts dominant-negatively, providing a disease-relevant mechanism.\",\n      \"evidence\": \"WT vs p.Trp42Arg secretion assays, co-transfection dominant-negative test, and three-generation pedigree cosegregation\",\n      \"pmids\": [\"28722276\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Disease phenotype caused by the variant not detailed mechanistically\", \"Downstream ECM consequence of retained protein not defined\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Connected ADAMTSL1 variants to a tissue-specific skeletal phenotype, implicating it in mandibular condylar cartilage growth.\",\n      \"evidence\": \"Whole-exome sequencing, cosegregation in Thai families, and in situ expression in mouse condyle\",\n      \"pmids\": [\"30714143\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Proposed aggrecan-cleavage mechanism not experimentally confirmed\", \"Functional consequence of the variants untested\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Identified ADAMTSL1 as a marker of a Schwann cell subtype specialized for large-caliber motor axons and relevant to ALS.\",\n      \"evidence\": \"Single-nucleus RNA-seq of mouse nerve, immunostaining validation, comparison to SOD1G93A and human ALS tissue\",\n      \"pmids\": [\"35115729\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"ADAMTSL1 used as a marker, not functionally manipulated\", \"Causal role of ADAMTSL1 in the SC subtype unestablished\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Demonstrated the physiological importance of the ADAMTSL1-marked Schwann cell population for motor axon maintenance and its reversibility.\",\n      \"evidence\": \"Inducible Pmp2-CreERT2/iDTR ablation with behavioral, electrophysiological, and EM ultrastructural readouts\",\n      \"pmids\": [\"39880678\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"ADAMTSL1 is a co-marker of the ablated cells, not the manipulated molecule\", \"Direct contribution of ADAMTSL1 protein to axon support not isolated\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"Whether mammalian ADAMTSL1 has a defined ECM ligand, receptor, or biochemical activity that mediates its roles in neural guidance and connective tissue regulation remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No direct mammalian binding partner or substrate identified\", \"No structural model beyond rotary-shadowing morphology\", \"Functional link between glycosylation/cleavage and downstream phenotypes unestablished\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [],\n    \"localization\": [\n      {\"term_id\": \"GO:0005576\", \"supporting_discovery_ids\": [0]},\n      {\"term_id\": \"GO:0031012\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"pathway\": [],\n    \"complexes\": [],\n    \"partners\": [\"B3GLCT\", \"MMP10\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"faith_supported":5,"faith_total":5,"faith_pct":100.0}}