{"gene":"COL6A2","run_date":"2026-04-28T17:28:53","timeline":{"discoveries":[{"year":2002,"finding":"COL6A2 nonsense mutations lead to nonsense-mediated mRNA decay; very low levels of undegraded mutant mRNA at the distal triple-helical domain produce abnormal microfibrils that cannot form extensive networks, demonstrating that the C-terminal globular domain is not essential for triple-helix formation but is critical for microfibrillar assembly","method":"Fibroblast mRNA analysis, Northern blot, immunofluorescence of collagen VI matrix deposition in patient and carrier cells","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 — multiple orthogonal methods (mRNA quantification, matrix deposition assay) in patient fibroblasts with carrier controls, moderate evidence","pmids":["12218063"],"is_preprint":false},{"year":2010,"finding":"Recessive COL6A2 C-globular missense mutations impair collagen VI secretion and assembly: E624K (C1 subdomain) alters electrostatic potential near the metal ion-dependent adhesion site causing abnormal fibril morphology, while R876S (C2 subdomain) prevents chain assembly into triple-helical molecules; the minute secreted collagen VI from R876S fibroblasts consists solely of the C2a splice variant, which can assemble into short microfibrils and may functionally compensate for loss of the normal COL6A2 chain when mutations occur in the C2 subdomain","method":"Patient fibroblast analysis, stable transfection with mutant constructs, secretion assays, electron microscopy of microfibrils, Western blot","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1-2 — in vitro functional assays with mutagenesis in fibroblasts and transfected cells, multiple orthogonal readouts","pmids":["20106987"],"is_preprint":false},{"year":2005,"finding":"A homozygous intronic COL6A2 mutation (A→G at -10 of intron 12) activates cryptic splice acceptor sites generating normal mRNA, exon 13-deleted mRNA, and frameshifted transcripts degraded by nonsense-mediated decay; diminished COL6A2 mRNA expression (not dominant-negative protein) is the primary pathogenic mechanism in this UCMD patient","method":"RT-PCR of fibroblast RNA, genomic DNA sequencing, Northern blot analysis","journal":"Human genetics","confidence":"Medium","confidence_rationale":"Tier 2 — multiple molecular methods establishing splice mechanism, single lab","pmids":["16075202"],"is_preprint":false},{"year":2010,"finding":"A deletion within intron 1A of COL6A2 in compound heterozygosity with an exon 28 deletion causes monoallelic transcription of the COL6A2 gene, establishing that deep intronic deletions can silence one allele and contribute to recessive collagen VI myopathy","method":"Custom CGH array, RNA studies showing monoallelic transcription","journal":"BMC medical genetics","confidence":"Medium","confidence_rationale":"Tier 2 — CGH array plus functional RNA monoallelic transcription confirmation, single lab","pmids":["20302629"],"is_preprint":false},{"year":2012,"finding":"Antisense oligonucleotide-mediated exon 3 skipping of mutant COL6A2 mRNA (targeting a SNP cistronic with a dominant mutation) depletes the mutated transcript via nonsense-mediated decay, recovering correct collagen VI secretion and restoring interconnected microfilament network formation in the extracellular matrix","method":"2'-O-methyl phosphorothioate antisense oligonucleotide treatment of patient fibroblasts, collagen VI secretion assay, immunofluorescence of ECM network","journal":"Human gene therapy","confidence":"Medium","confidence_rationale":"Tier 2 — functional rescue in patient cells with defined molecular mechanism, single lab","pmids":["22992134"],"is_preprint":false},{"year":2011,"finding":"Co-overexpression of COL6A2 and DSCAM cooperatively causes congenital heart defects (atrial septal defects, cardiac hypertrophy, ~50% mortality) in mice, while overexpression of either gene alone has little or no effect; transcriptional analysis identifies downstream perturbation of genes involved in adhesion and cardiac hypertrophy; cooperative interaction also observed in H9C2 cardiac cells","method":"Drosophila heart combinatorial screen, mouse cardiac co-overexpression, H9C2 cell line experiments, transcriptional profiling","journal":"PLoS genetics","confidence":"High","confidence_rationale":"Tier 2 — multi-organism genetic epistasis with defined morphological and physiological readouts, replicated across Drosophila, mouse, and cell line","pmids":["22072978"],"is_preprint":false},{"year":1991,"finding":"COL6A1 and COL6A2 form a gene cluster on the distal portion of human chromosome 21q22.3, as determined by pulsed-field gel electrophoresis and somatic cell hybrids","method":"Pulsed-field gel electrophoresis, somatic cell hybrid mapping","journal":"Human genetics","confidence":"Medium","confidence_rationale":"Tier 2 — direct physical mapping experiment, moderate evidence","pmids":["1676701"],"is_preprint":false},{"year":1995,"finding":"COL6A1 and COL6A2 genes are arranged head-to-tail (5'-COL6A1-3' to 5'-COL6A2-3') and separated by ~150 kb on chromosome 21q22.3","method":"Fiber-FISH (fluorescence in situ hybridization)","journal":"Genomics","confidence":"Medium","confidence_rationale":"Tier 2 — direct visualization by high-resolution fiber-FISH","pmids":["8575781"],"is_preprint":false},{"year":2024,"finding":"A homozygous deletion of the canonical polyadenylation signal in the 3'-UTR of COL6A2 (c.*198_*466del) causes switching to alternative last exon usage, resulting in sarcolemma-specific collagen VI deficiency rather than complete absence; RNA sequencing confirmed alternative last exon transcripts as the molecular mechanism","method":"Whole-genome sequencing, RNA sequencing of patient muscle, immunofluorescence for collagen VI localization","journal":"Neurology. Genetics","confidence":"Medium","confidence_rationale":"Tier 2 — orthogonal genomic and transcriptomic methods with protein-level functional consequence, single lab","pmids":["38544966"],"is_preprint":false},{"year":2024,"finding":"miR-3189-3p directly targets the 3'UTR of COL6A2 mRNA (confirmed by luciferase reporter assay and mutagenesis), and PRC2-mediated H3K27me3 epigenetically silences miR-3189, thereby indirectly upregulating COL6A2; COL6A2 overexpression promotes GBM cell proliferation, migration, and EMT","method":"Luciferase reporter assay, mutagenesis, Western blot, functional cell assays (proliferation, migration, EMT markers), ChIP for H3K27me3","journal":"Journal of cellular physiology","confidence":"Medium","confidence_rationale":"Tier 2 — direct target validation by luciferase/mutagenesis plus functional rescue, single lab","pmids":["38860406"],"is_preprint":false},{"year":2025,"finding":"COL6A2 physically interacts with integrin β1 (by co-immunoprecipitation), thereby activating Wnt/β-catenin signaling to induce EMT in clear cell renal cell carcinoma; COL6A2 knockdown inhibited proliferation, migration, and invasion, and rescue with a Wnt/β-catenin activator restored the malignant phenotype","method":"Co-immunoprecipitation, Western blot, integrin blockade, rescue experiments, CCK-8, wound healing, Transwell assays","journal":"Journal of Cancer","confidence":"Medium","confidence_rationale":"Tier 2 — co-IP plus pathway rescue experiments establish integrin β1-Wnt/β-catenin axis, single lab","pmids":["41323784"],"is_preprint":false},{"year":2025,"finding":"COL6A2 silencing in glioblastoma cells restores dendritic cell activation and enhances infiltration and function of effector immune cells, as measured by CyTOF; COL6A2 promotes GBM cell proliferation, invasion, and chemoresistance in functional assays","method":"CyTOF immune profiling, TIMER analysis, functional proliferation/invasion assays, COL6A2 silencing","journal":"Cancer science","confidence":"Medium","confidence_rationale":"Tier 2 — CyTOF provides direct immune cell quantification with functional consequence, single lab","pmids":["41074600"],"is_preprint":false},{"year":2025,"finding":"In mouse embryonic liver cells, HP1 inactivation leads to stabilization of enhancer RNAs and increased enhancer activity at loci regulating Col6a2 (and Col6a1) ECM genes; the RNA exosome complex is recruited to chromatin by HP1, and HP1 directly interacts with the RNA exosome","method":"HP1 triple-knockout mouse liver cells, RNA-seq, chromatin immunoprecipitation, direct interaction assay between HP1 and RNA exosome","journal":"bioRxiv","confidence":"Low","confidence_rationale":"Tier 3 — Col6a2 is one of many ECM genes affected; mechanistic link to Col6a2 specifically is indirect (preprint, single lab)","pmids":[],"is_preprint":true},{"year":2025,"finding":"In Col1a2-/-;Col6a2-/- mice with defective cardiac ECM stiffness, cardiomyocyte maturation is impaired and the ectopic cardiomyocyte differentiation program observed with TGFβ ligand deletion is not reproduced, placing Col6a2 as a component of the ECM stiffness axis that programs cardiomyocyte identity downstream of fibroblast TGFβ signaling","method":"Col1a2-/-;Col6a2-/- double-knockout mouse model, cardiac gene expression profiling, ECM stiffness measurement","journal":"bioRxiv","confidence":"Low","confidence_rationale":"Tier 3 — genetic epistasis in mouse but Col6a2 role is inferred from compound knockout; preprint, single lab","pmids":[],"is_preprint":true},{"year":2025,"finding":"Exosomal miR-128-2-5p from postmenopausal osteoporosis patients inhibits COL6A2 expression in osteoblasts in vitro, reducing osteoblast adhesion via the focal adhesion pathway","method":"Exosome isolation, miRNA overexpression/inhibition in osteoblasts, Western blot, osteoblast adhesion assay, bioinformatics (luciferase validation not explicitly stated)","journal":"Human molecular genetics","confidence":"Low","confidence_rationale":"Tier 3 — single lab, functional adhesion assay but direct miRNA-COL6A2 targeting not validated by mutagenesis","pmids":["39817546"],"is_preprint":false}],"current_model":"COL6A2 encodes the alpha-2 chain of type VI collagen, an extracellular matrix microfibrillar protein whose C-terminal globular domain (particularly the C2 subdomain) is critical for microfibrillar assembly but not triple-helix formation; pathogenic mutations cause collagen VI myopathies (Ullrich CMD, Bethlem myopathy) via nonsense-mediated mRNA decay, dominant-negative interference with secretion/assembly, or splice switching, while the protein also physically interacts with integrin β1 to activate Wnt/β-catenin and EMT signaling in cancer contexts, and cooperates with DSCAM to produce congenital heart defects through adhesion and hypertrophy pathways."},"narrative":{"teleology":[{"year":1991,"claim":"Establishing the genomic organization of COL6A2 resolved that the alpha-1 and alpha-2 chain genes form a tightly linked cluster on chromosome 21q22.3, providing the physical framework for understanding coordinate regulation and disease genetics.","evidence":"Pulsed-field gel electrophoresis, somatic cell hybrid mapping, and fiber-FISH in human cells","pmids":["1676701","8575781"],"confidence":"Medium","gaps":["Functional significance of head-to-tail arrangement not determined","Whether coordinate transcriptional regulation occurs from the shared locus was not tested"]},{"year":2002,"claim":"Demonstrating that COL6A2 nonsense mutations trigger nonsense-mediated mRNA decay and that residual mutant mRNA produces abnormal microfibrils unable to form extensive networks established the C-terminal globular domain as essential for microfibrillar assembly but not triple-helix formation.","evidence":"Northern blot, mRNA quantification, and immunofluorescence of collagen VI matrix deposition in patient and carrier fibroblasts","pmids":["12218063"],"confidence":"High","gaps":["Structural basis for why the C-terminal domain is required for network formation was not resolved","Contribution of individual C-terminal subdomains (C1 vs C2) not dissected"]},{"year":2005,"claim":"Identification of a deep intronic splice mutation generating cryptic transcripts degraded by NMD showed that loss of COL6A2 mRNA quantity, not dominant-negative protein, can be the primary disease mechanism in Ullrich CMD.","evidence":"RT-PCR and Northern blot of patient fibroblast RNA with genomic DNA sequencing","pmids":["16075202"],"confidence":"Medium","gaps":["Quantitative threshold of COL6A2 mRNA needed for functional matrix assembly not defined","Only one patient studied"]},{"year":2010,"claim":"Dissecting recessive C-globular missense mutations showed that the C1 subdomain (E624K) permits chain assembly but disrupts fibril morphology, while the C2 subdomain (R876S) prevents triple-helical molecule assembly altogether; the C2a splice variant can partially compensate, refining the domain-specific roles in collagen VI biogenesis.","evidence":"Patient fibroblast analysis, stable transfection of mutant constructs, secretion assays, electron microscopy of microfibrils","pmids":["20106987"],"confidence":"High","gaps":["Structural mechanism by which C2a variant rescues assembly not resolved","Whether compensatory C2a expression is clinically relevant in vivo not established"]},{"year":2010,"claim":"Discovery that deep intronic deletions can silence one COL6A2 allele expanded the mutational spectrum of collagen VI myopathies beyond coding and canonical splice-site mutations.","evidence":"Custom CGH array with RNA monoallelic transcription confirmation in patient cells","pmids":["20302629"],"confidence":"Medium","gaps":["Mechanism of transcriptional silencing by intronic deletion not characterized","Whether regulatory elements within intron 1A control COL6A2 expression was not tested"]},{"year":2011,"claim":"Demonstrating that COL6A2 and DSCAM must be co-overexpressed to produce congenital heart defects established a genetic interaction linking collagen VI to cardiac adhesion and hypertrophy pathways beyond its structural ECM role.","evidence":"Combinatorial overexpression screen in Drosophila heart, mouse cardiac overexpression, H9C2 cell transcriptional profiling","pmids":["22072978"],"confidence":"High","gaps":["Direct physical interaction between COL6A2 and DSCAM not shown","Whether this cooperativity is relevant to Down syndrome-associated heart defects in humans not confirmed"]},{"year":2012,"claim":"Antisense oligonucleotide-mediated exon skipping selectively degraded the mutant COL6A2 transcript and restored collagen VI secretion and ECM network formation, providing proof-of-concept for allele-specific therapeutic silencing of dominant COL6A2 mutations.","evidence":"2'-O-methyl phosphorothioate antisense oligonucleotide treatment of patient fibroblasts with collagen VI secretion and immunofluorescence readouts","pmids":["22992134"],"confidence":"Medium","gaps":["In vivo efficacy and delivery not tested","Applicability to other dominant COL6A2 mutations not demonstrated"]},{"year":2024,"claim":"A polyadenylation signal deletion in the COL6A2 3'-UTR caused alternative last exon usage and sarcolemma-specific collagen VI deficiency, revealing that post-transcriptional 3'-end processing defects produce tissue-selective rather than global collagen VI loss.","evidence":"Whole-genome sequencing, RNA sequencing of patient muscle, immunofluorescence for collagen VI localization","pmids":["38544966"],"confidence":"Medium","gaps":["Why the deficiency is sarcolemma-specific rather than global is mechanistically unexplained","Single family reported"]},{"year":2024,"claim":"Direct luciferase-validated targeting of COL6A2 by miR-3189-3p, whose expression is epigenetically silenced by PRC2-mediated H3K27me3, linked COL6A2 upregulation to GBM proliferation, migration, and EMT, establishing COL6A2 as a functional effector in glioblastoma malignancy.","evidence":"Luciferase reporter assay with mutagenesis, ChIP for H3K27me3, functional cell assays in GBM cells","pmids":["38860406"],"confidence":"Medium","gaps":["In vivo relevance in GBM animal models not shown","Whether COL6A2 is a driver or passenger in glioblastoma progression not resolved"]},{"year":2025,"claim":"Identification of a physical interaction between COL6A2 and integrin β1 that activates Wnt/β-catenin signaling to drive EMT in renal cell carcinoma defined a specific signaling axis through which extracellular COL6A2 promotes tumor invasion.","evidence":"Co-immunoprecipitation, integrin blockade, Wnt/β-catenin activator rescue experiments in ccRCC cells","pmids":["41323784"],"confidence":"Medium","gaps":["Co-IP not validated by reciprocal IP or structural data","Whether integrin β1 interaction occurs in non-cancer physiological contexts not tested","In vivo tumor model validation absent"]},{"year":2025,"claim":"COL6A2 silencing in GBM cells restored dendritic cell activation and effector immune cell infiltration, revealing an immunosuppressive function of COL6A2 in the tumor microenvironment.","evidence":"CyTOF immune profiling and functional proliferation/invasion assays upon COL6A2 knockdown in glioblastoma cells","pmids":["41074600"],"confidence":"Medium","gaps":["Mechanism by which COL6A2 suppresses dendritic cell activation not identified","In vivo immunological validation not performed"]},{"year":null,"claim":"The structural basis for how the C2 subdomain directs microfibrillar network assembly, the in vivo relevance of integrin β1–Wnt/β-catenin signaling in physiological collagen VI functions, and whether COL6A2's immunomodulatory and cardiac roles represent distinct or overlapping mechanisms remain unresolved.","evidence":"","pmids":[],"confidence":"Low","gaps":["No atomic-resolution structure of the COL6A2 C-terminal domain in the context of the trimer","No in vivo validation of integrin β1-mediated signaling axis","Mechanism of immune evasion mediated by COL6A2 not molecularly defined"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0005198","term_label":"structural molecule activity","supporting_discovery_ids":[0,1]},{"term_id":"GO:0098631","term_label":"cell adhesion mediator activity","supporting_discovery_ids":[5,10]}],"localization":[{"term_id":"GO:0031012","term_label":"extracellular matrix","supporting_discovery_ids":[0,1,4,8]},{"term_id":"GO:0005576","term_label":"extracellular region","supporting_discovery_ids":[0,1,4]}],"pathway":[{"term_id":"R-HSA-1474244","term_label":"Extracellular matrix organization","supporting_discovery_ids":[0,1,4,8]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[10]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[5]}],"complexes":["type VI collagen trimer"],"partners":["COL6A1","DSCAM","ITGB1"],"other_free_text":[]},"mechanistic_narrative":"COL6A2 encodes the alpha-2 chain of type VI collagen, a microfibrillar extracellular matrix protein whose assembly, secretion, and network formation are essential for skeletal muscle integrity, cardiac development, and cell-matrix signaling. The C-terminal globular domain, particularly the C2 subdomain, is dispensable for triple-helix formation but critical for microfibrillar assembly; nonsense, missense, and splice-site mutations in COL6A2 cause collagen VI myopathies (Ullrich congenital muscular dystrophy and Bethlem myopathy) through mechanisms including nonsense-mediated mRNA decay, impaired secretion, and dominant-negative interference with matrix network formation [PMID:12218063, PMID:20106987, PMID:16075202, PMID:38544966]. COL6A2 physically interacts with integrin β1 to activate Wnt/β-catenin signaling and epithelial-mesenchymal transition in carcinoma cells, and its overexpression promotes proliferation, migration, and immune evasion in glioblastoma [PMID:41323784, PMID:38860406, PMID:41074600]. Co-overexpression of COL6A2 with DSCAM cooperatively produces congenital heart defects in mice through perturbation of adhesion and cardiac hypertrophy gene programs [PMID:22072978]."},"prefetch_data":{"uniprot":{"accession":"P12110","full_name":"Collagen alpha-2(VI) chain","aliases":[],"length_aa":1019,"mass_kda":108.6,"function":"Collagen VI acts as a cell-binding protein","subcellular_location":"Secreted, extracellular space, extracellular matrix; Membrane","url":"https://www.uniprot.org/uniprotkb/P12110/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/COL6A2","classification":"Not Classified","n_dependent_lines":0,"n_total_lines":1208,"dependency_fraction":0.0},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/COL6A2","total_profiled":1310},"omim":[{"mim_id":"620728","title":"ULLRICH CONGENITAL MUSCULAR DYSTROPHY 1C; UCMD1C","url":"https://www.omim.org/entry/620728"},{"mim_id":"620727","title":"ULLRICH CONGENITAL MUSCULAR DYSTROPHY 1B; UCMD1B","url":"https://www.omim.org/entry/620727"},{"mim_id":"620726","title":"BETHLEM MYOPATHY 1C; BTHLM1C","url":"https://www.omim.org/entry/620726"},{"mim_id":"620725","title":"BETHLEM MYOPATHY 1B; BTHLM1B","url":"https://www.omim.org/entry/620725"},{"mim_id":"616471","title":"BETHLEM MYOPATHY 2; BTHLM2","url":"https://www.omim.org/entry/616471"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Uncertain","locations":[{"location":"Cytosol","reliability":"Uncertain"},{"location":"Plasma membrane","reliability":"Additional"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in many","driving_tissues":[],"url":"https://www.proteinatlas.org/search/COL6A2"},"hgnc":{"alias_symbol":[],"prev_symbol":[]},"alphafold":{"accession":"P12110","domains":[{"cath_id":"3.40.50.410","chopping":"40-247","consensus_level":"high","plddt":86.123,"start":40,"end":247},{"cath_id":"3.40.50.410","chopping":"607-811","consensus_level":"high","plddt":84.4308,"start":607,"end":811},{"cath_id":"3.40.50.410","chopping":"831-1017","consensus_level":"high","plddt":89.5409,"start":831,"end":1017}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/P12110","model_url":"https://alphafold.ebi.ac.uk/files/AF-P12110-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-P12110-F1-predicted_aligned_error_v6.png","plddt_mean":68.25},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=COL6A2","jax_strain_url":"https://www.jax.org/strain/search?query=COL6A2"},"sequence":{"accession":"P12110","fasta_url":"https://rest.uniprot.org/uniprotkb/P12110.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/P12110/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/P12110"}},"corpus_meta":[{"pmid":"22072978","id":"PMC_22072978","title":"Over-expression of DSCAM and COL6A2 cooperatively generates congenital heart defects.","date":"2011","source":"PLoS genetics","url":"https://pubmed.ncbi.nlm.nih.gov/22072978","citation_count":75,"is_preprint":false},{"pmid":"12218063","id":"PMC_12218063","title":"Effects on collagen VI mRNA stability and microfibrillar assembly of three COL6A2 mutations in two families with Ullrich congenital muscular dystrophy.","date":"2002","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/12218063","citation_count":53,"is_preprint":false},{"pmid":"1676701","id":"PMC_1676701","title":"The COL6A1 and COL6A2 genes exist as a gene cluster and detect highly informative DNA polymorphisms in the telomeric region of human chromosome 21q.","date":"1991","source":"Human genetics","url":"https://pubmed.ncbi.nlm.nih.gov/1676701","citation_count":32,"is_preprint":false},{"pmid":"8575781","id":"PMC_8575781","title":"Head to tail organization of the human COL6A1 and COL6A2 genes by fiber-FISH.","date":"1995","source":"Genomics","url":"https://pubmed.ncbi.nlm.nih.gov/8575781","citation_count":31,"is_preprint":false},{"pmid":"20302629","id":"PMC_20302629","title":"Identification of a deep intronic mutation in the COL6A2 gene by a novel custom oligonucleotide CGH array designed to explore allelic and genetic heterogeneity in collagen VI-related myopathies.","date":"2010","source":"BMC medical genetics","url":"https://pubmed.ncbi.nlm.nih.gov/20302629","citation_count":27,"is_preprint":false},{"pmid":"22992134","id":"PMC_22992134","title":"Antisense-induced messenger depletion corrects a COL6A2 dominant mutation in Ullrich myopathy.","date":"2012","source":"Human gene therapy","url":"https://pubmed.ncbi.nlm.nih.gov/22992134","citation_count":26,"is_preprint":false},{"pmid":"20106987","id":"PMC_20106987","title":"Recessive COL6A2 C-globular missense mutations in Ullrich congenital muscular dystrophy: role of the C2a splice variant.","date":"2010","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/20106987","citation_count":26,"is_preprint":false},{"pmid":"16075202","id":"PMC_16075202","title":"A homozygous COL6A2 intron mutation causes in-frame triple-helical deletion and nonsense-mediated mRNA decay in a patient with Ullrich congenital muscular dystrophy.","date":"2005","source":"Human genetics","url":"https://pubmed.ncbi.nlm.nih.gov/16075202","citation_count":20,"is_preprint":false},{"pmid":"32581558","id":"PMC_32581558","title":"Comprehensive Transcriptomic Analysis and Experimental Validation Identify lncRNA HOXA-AS2/miR-184/COL6A2 as the Critical ceRNA Regulation Involved in Low-Grade Glioma Recurrence.","date":"2020","source":"OncoTargets and therapy","url":"https://pubmed.ncbi.nlm.nih.gov/32581558","citation_count":20,"is_preprint":false},{"pmid":"23138527","id":"PMC_23138527","title":"Identification of COL6A2 mutations in progressive myoclonus epilepsy syndrome.","date":"2012","source":"Human 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pathology","url":"https://pubmed.ncbi.nlm.nih.gov/33625261","citation_count":13,"is_preprint":false},{"pmid":"8807328","id":"PMC_8807328","title":"Identification of a polymorphic CA repeat in the COL6A2 gene on human chromosome 21q22.3.","date":"1996","source":"Human heredity","url":"https://pubmed.ncbi.nlm.nih.gov/8807328","citation_count":10,"is_preprint":false},{"pmid":"30963254","id":"PMC_30963254","title":"A novel COL6A2 mutation causing late-onset limb-girdle muscular dystrophy.","date":"2019","source":"Journal of neurology","url":"https://pubmed.ncbi.nlm.nih.gov/30963254","citation_count":9,"is_preprint":false},{"pmid":"40770761","id":"PMC_40770761","title":"COL6A2 in clear cell renal cell carcinoma: a multifaceted driver of tumor progression, immune evasion, and drug sensitivity.","date":"2025","source":"Journal of translational medicine","url":"https://pubmed.ncbi.nlm.nih.gov/40770761","citation_count":7,"is_preprint":false},{"pmid":"9107679","id":"PMC_9107679","title":"Human COL6A1: genomic characterization of the globular domains, structural and evolutionary comparison with COL6A2.","date":"1997","source":"Mammalian genome : official journal of the International Mammalian Genome Society","url":"https://pubmed.ncbi.nlm.nih.gov/9107679","citation_count":7,"is_preprint":false},{"pmid":"39704340","id":"PMC_39704340","title":"A diagnostic signatures for intervertebral disc degeneration using TNFAIP6 and COL6A2 based on single-cell RNA-seq and bulk RNA-seq analyses.","date":"2024","source":"Annals of medicine","url":"https://pubmed.ncbi.nlm.nih.gov/39704340","citation_count":5,"is_preprint":false},{"pmid":"38860406","id":"PMC_38860406","title":"A novel interplay between PRC2 and miR-3189 regulates epithelial-mesenchymal transition (EMT) via modulating COL6A2 in glioblastoma.","date":"2024","source":"Journal of cellular physiology","url":"https://pubmed.ncbi.nlm.nih.gov/38860406","citation_count":3,"is_preprint":false},{"pmid":"39596604","id":"PMC_39596604","title":"Segregation of the COL6A2 Variant (c.1817-3C>G) in a Consanguineous Saudi Family with Bethlem Myopathy.","date":"2024","source":"Genes","url":"https://pubmed.ncbi.nlm.nih.gov/39596604","citation_count":2,"is_preprint":false},{"pmid":"39135765","id":"PMC_39135765","title":"Bethlem myopathy: A novel homozygous variant of c.385C>T (p.Arg129Cys) in the COL6A2 gene.","date":"2024","source":"Clinical case reports","url":"https://pubmed.ncbi.nlm.nih.gov/39135765","citation_count":2,"is_preprint":false},{"pmid":"38065855","id":"PMC_38065855","title":"Spontaneous mutation in the COL6A2 gene causing Ullrich congenital muscular dystrophy type 1 in a Chinese child: A case report.","date":"2023","source":"Medicine","url":"https://pubmed.ncbi.nlm.nih.gov/38065855","citation_count":1,"is_preprint":false},{"pmid":"39817546","id":"PMC_39817546","title":"Regulatory role of miR-128-2-5p in serum exosomes on COL6A2 expression and postmenopausal osteoporosis.","date":"2025","source":"Human molecular genetics","url":"https://pubmed.ncbi.nlm.nih.gov/39817546","citation_count":1,"is_preprint":false},{"pmid":"38544966","id":"PMC_38544966","title":"Splicing Switching of Alternative Last Exons Due to a Deletion Including Canonical Polyadenylation Site in COL6A2 Gene Causes Recessive UCMD.","date":"2024","source":"Neurology. Genetics","url":"https://pubmed.ncbi.nlm.nih.gov/38544966","citation_count":1,"is_preprint":false},{"pmid":"36292982","id":"PMC_36292982","title":"The Presentation of Two Unrelated Clinical Cases from the Republic of North Ossetia-Alania with the Same Previously Undescribed Variant in the COL6A2 Gene.","date":"2022","source":"International journal of molecular sciences","url":"https://pubmed.ncbi.nlm.nih.gov/36292982","citation_count":1,"is_preprint":false},{"pmid":"32663882","id":"PMC_32663882","title":"A Revisited Diagnosis of Collagen VI Related Muscular Dystrophy in a Patient with a Novel COL6A2 Variant and 21q22.3 Deletion.","date":"2020","source":"Neuropediatrics","url":"https://pubmed.ncbi.nlm.nih.gov/32663882","citation_count":1,"is_preprint":false},{"pmid":"41074600","id":"PMC_41074600","title":"COL6A2: A Key Survival-Related Gene and Restricting Antitumor Immunity in Glioblastoma.","date":"2025","source":"Cancer science","url":"https://pubmed.ncbi.nlm.nih.gov/41074600","citation_count":0,"is_preprint":false},{"pmid":"41154655","id":"PMC_41154655","title":"Landscape Analysis of COL6A1, COL6A2, and COL6A3 Pathogenic Variants in a Large Italian Cohort Presenting with Collagen VI-Related Myopathies: A Nationwide Report.","date":"2025","source":"Biomolecules","url":"https://pubmed.ncbi.nlm.nih.gov/41154655","citation_count":0,"is_preprint":false},{"pmid":"41323784","id":"PMC_41323784","title":"COL6A2 drives clear cell renal cell carcinoma progression via integrin-dependent modulation of Wnt/β-catenin signaling.","date":"2025","source":"Journal of Cancer","url":"https://pubmed.ncbi.nlm.nih.gov/41323784","citation_count":0,"is_preprint":false},{"pmid":null,"id":"bio_10.1101_2025.09.23.25336398","title":"Disentangling osteoarthritis-specific genetic effects from obesity to identify novel therapeutic targets","date":"2025-09-25","source":"bioRxiv","url":"https://doi.org/10.1101/2025.09.23.25336398","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2025.09.22.677845","title":"Cardiomyocyte-expressed TGFβ signals to fibroblasts to program early heart maturation and adult myocyte identity","date":"2025-09-22","source":"bioRxiv","url":"https://doi.org/10.1101/2025.09.22.677845","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2025.02.14.638307","title":"Targeting of the nuclear RNA exosome to chromatin by HP1 affects the transcriptional programs of liver cells","date":"2025-02-19","source":"bioRxiv","url":"https://doi.org/10.1101/2025.02.14.638307","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":16935,"output_tokens":3463,"usd":0.051375},"stage2":{"model":"claude-opus-4-6","input_tokens":6885,"output_tokens":2827,"usd":0.15765},"total_usd":0.209025,"stage1_batch_id":"msgbatch_011kfMfE81o6CTcyhVUqumuW","stage2_batch_id":"msgbatch_01DTputS6WNkH745x1nVSoBo","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2002,\n      \"finding\": \"COL6A2 nonsense mutations lead to nonsense-mediated mRNA decay; very low levels of undegraded mutant mRNA at the distal triple-helical domain produce abnormal microfibrils that cannot form extensive networks, demonstrating that the C-terminal globular domain is not essential for triple-helix formation but is critical for microfibrillar assembly\",\n      \"method\": \"Fibroblast mRNA analysis, Northern blot, immunofluorescence of collagen VI matrix deposition in patient and carrier cells\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods (mRNA quantification, matrix deposition assay) in patient fibroblasts with carrier controls, moderate evidence\",\n      \"pmids\": [\"12218063\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"Recessive COL6A2 C-globular missense mutations impair collagen VI secretion and assembly: E624K (C1 subdomain) alters electrostatic potential near the metal ion-dependent adhesion site causing abnormal fibril morphology, while R876S (C2 subdomain) prevents chain assembly into triple-helical molecules; the minute secreted collagen VI from R876S fibroblasts consists solely of the C2a splice variant, which can assemble into short microfibrils and may functionally compensate for loss of the normal COL6A2 chain when mutations occur in the C2 subdomain\",\n      \"method\": \"Patient fibroblast analysis, stable transfection with mutant constructs, secretion assays, electron microscopy of microfibrils, Western blot\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — in vitro functional assays with mutagenesis in fibroblasts and transfected cells, multiple orthogonal readouts\",\n      \"pmids\": [\"20106987\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"A homozygous intronic COL6A2 mutation (A→G at -10 of intron 12) activates cryptic splice acceptor sites generating normal mRNA, exon 13-deleted mRNA, and frameshifted transcripts degraded by nonsense-mediated decay; diminished COL6A2 mRNA expression (not dominant-negative protein) is the primary pathogenic mechanism in this UCMD patient\",\n      \"method\": \"RT-PCR of fibroblast RNA, genomic DNA sequencing, Northern blot analysis\",\n      \"journal\": \"Human genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — multiple molecular methods establishing splice mechanism, single lab\",\n      \"pmids\": [\"16075202\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"A deletion within intron 1A of COL6A2 in compound heterozygosity with an exon 28 deletion causes monoallelic transcription of the COL6A2 gene, establishing that deep intronic deletions can silence one allele and contribute to recessive collagen VI myopathy\",\n      \"method\": \"Custom CGH array, RNA studies showing monoallelic transcription\",\n      \"journal\": \"BMC medical genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — CGH array plus functional RNA monoallelic transcription confirmation, single lab\",\n      \"pmids\": [\"20302629\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Antisense oligonucleotide-mediated exon 3 skipping of mutant COL6A2 mRNA (targeting a SNP cistronic with a dominant mutation) depletes the mutated transcript via nonsense-mediated decay, recovering correct collagen VI secretion and restoring interconnected microfilament network formation in the extracellular matrix\",\n      \"method\": \"2'-O-methyl phosphorothioate antisense oligonucleotide treatment of patient fibroblasts, collagen VI secretion assay, immunofluorescence of ECM network\",\n      \"journal\": \"Human gene therapy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — functional rescue in patient cells with defined molecular mechanism, single lab\",\n      \"pmids\": [\"22992134\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"Co-overexpression of COL6A2 and DSCAM cooperatively causes congenital heart defects (atrial septal defects, cardiac hypertrophy, ~50% mortality) in mice, while overexpression of either gene alone has little or no effect; transcriptional analysis identifies downstream perturbation of genes involved in adhesion and cardiac hypertrophy; cooperative interaction also observed in H9C2 cardiac cells\",\n      \"method\": \"Drosophila heart combinatorial screen, mouse cardiac co-overexpression, H9C2 cell line experiments, transcriptional profiling\",\n      \"journal\": \"PLoS genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multi-organism genetic epistasis with defined morphological and physiological readouts, replicated across Drosophila, mouse, and cell line\",\n      \"pmids\": [\"22072978\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1991,\n      \"finding\": \"COL6A1 and COL6A2 form a gene cluster on the distal portion of human chromosome 21q22.3, as determined by pulsed-field gel electrophoresis and somatic cell hybrids\",\n      \"method\": \"Pulsed-field gel electrophoresis, somatic cell hybrid mapping\",\n      \"journal\": \"Human genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — direct physical mapping experiment, moderate evidence\",\n      \"pmids\": [\"1676701\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1995,\n      \"finding\": \"COL6A1 and COL6A2 genes are arranged head-to-tail (5'-COL6A1-3' to 5'-COL6A2-3') and separated by ~150 kb on chromosome 21q22.3\",\n      \"method\": \"Fiber-FISH (fluorescence in situ hybridization)\",\n      \"journal\": \"Genomics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — direct visualization by high-resolution fiber-FISH\",\n      \"pmids\": [\"8575781\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"A homozygous deletion of the canonical polyadenylation signal in the 3'-UTR of COL6A2 (c.*198_*466del) causes switching to alternative last exon usage, resulting in sarcolemma-specific collagen VI deficiency rather than complete absence; RNA sequencing confirmed alternative last exon transcripts as the molecular mechanism\",\n      \"method\": \"Whole-genome sequencing, RNA sequencing of patient muscle, immunofluorescence for collagen VI localization\",\n      \"journal\": \"Neurology. Genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — orthogonal genomic and transcriptomic methods with protein-level functional consequence, single lab\",\n      \"pmids\": [\"38544966\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"miR-3189-3p directly targets the 3'UTR of COL6A2 mRNA (confirmed by luciferase reporter assay and mutagenesis), and PRC2-mediated H3K27me3 epigenetically silences miR-3189, thereby indirectly upregulating COL6A2; COL6A2 overexpression promotes GBM cell proliferation, migration, and EMT\",\n      \"method\": \"Luciferase reporter assay, mutagenesis, Western blot, functional cell assays (proliferation, migration, EMT markers), ChIP for H3K27me3\",\n      \"journal\": \"Journal of cellular physiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — direct target validation by luciferase/mutagenesis plus functional rescue, single lab\",\n      \"pmids\": [\"38860406\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"COL6A2 physically interacts with integrin β1 (by co-immunoprecipitation), thereby activating Wnt/β-catenin signaling to induce EMT in clear cell renal cell carcinoma; COL6A2 knockdown inhibited proliferation, migration, and invasion, and rescue with a Wnt/β-catenin activator restored the malignant phenotype\",\n      \"method\": \"Co-immunoprecipitation, Western blot, integrin blockade, rescue experiments, CCK-8, wound healing, Transwell assays\",\n      \"journal\": \"Journal of Cancer\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — co-IP plus pathway rescue experiments establish integrin β1-Wnt/β-catenin axis, single lab\",\n      \"pmids\": [\"41323784\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"COL6A2 silencing in glioblastoma cells restores dendritic cell activation and enhances infiltration and function of effector immune cells, as measured by CyTOF; COL6A2 promotes GBM cell proliferation, invasion, and chemoresistance in functional assays\",\n      \"method\": \"CyTOF immune profiling, TIMER analysis, functional proliferation/invasion assays, COL6A2 silencing\",\n      \"journal\": \"Cancer science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — CyTOF provides direct immune cell quantification with functional consequence, single lab\",\n      \"pmids\": [\"41074600\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"In mouse embryonic liver cells, HP1 inactivation leads to stabilization of enhancer RNAs and increased enhancer activity at loci regulating Col6a2 (and Col6a1) ECM genes; the RNA exosome complex is recruited to chromatin by HP1, and HP1 directly interacts with the RNA exosome\",\n      \"method\": \"HP1 triple-knockout mouse liver cells, RNA-seq, chromatin immunoprecipitation, direct interaction assay between HP1 and RNA exosome\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 — Col6a2 is one of many ECM genes affected; mechanistic link to Col6a2 specifically is indirect (preprint, single lab)\",\n      \"pmids\": [],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"In Col1a2-/-;Col6a2-/- mice with defective cardiac ECM stiffness, cardiomyocyte maturation is impaired and the ectopic cardiomyocyte differentiation program observed with TGFβ ligand deletion is not reproduced, placing Col6a2 as a component of the ECM stiffness axis that programs cardiomyocyte identity downstream of fibroblast TGFβ signaling\",\n      \"method\": \"Col1a2-/-;Col6a2-/- double-knockout mouse model, cardiac gene expression profiling, ECM stiffness measurement\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 — genetic epistasis in mouse but Col6a2 role is inferred from compound knockout; preprint, single lab\",\n      \"pmids\": [],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Exosomal miR-128-2-5p from postmenopausal osteoporosis patients inhibits COL6A2 expression in osteoblasts in vitro, reducing osteoblast adhesion via the focal adhesion pathway\",\n      \"method\": \"Exosome isolation, miRNA overexpression/inhibition in osteoblasts, Western blot, osteoblast adhesion assay, bioinformatics (luciferase validation not explicitly stated)\",\n      \"journal\": \"Human molecular genetics\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 — single lab, functional adhesion assay but direct miRNA-COL6A2 targeting not validated by mutagenesis\",\n      \"pmids\": [\"39817546\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"COL6A2 encodes the alpha-2 chain of type VI collagen, an extracellular matrix microfibrillar protein whose C-terminal globular domain (particularly the C2 subdomain) is critical for microfibrillar assembly but not triple-helix formation; pathogenic mutations cause collagen VI myopathies (Ullrich CMD, Bethlem myopathy) via nonsense-mediated mRNA decay, dominant-negative interference with secretion/assembly, or splice switching, while the protein also physically interacts with integrin β1 to activate Wnt/β-catenin and EMT signaling in cancer contexts, and cooperates with DSCAM to produce congenital heart defects through adhesion and hypertrophy pathways.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"COL6A2 encodes the alpha-2 chain of type VI collagen, a microfibrillar extracellular matrix protein whose assembly, secretion, and network formation are essential for skeletal muscle integrity, cardiac development, and cell-matrix signaling. The C-terminal globular domain, particularly the C2 subdomain, is dispensable for triple-helix formation but critical for microfibrillar assembly; nonsense, missense, and splice-site mutations in COL6A2 cause collagen VI myopathies (Ullrich congenital muscular dystrophy and Bethlem myopathy) through mechanisms including nonsense-mediated mRNA decay, impaired secretion, and dominant-negative interference with matrix network formation [PMID:12218063, PMID:20106987, PMID:16075202, PMID:38544966]. COL6A2 physically interacts with integrin β1 to activate Wnt/β-catenin signaling and epithelial-mesenchymal transition in carcinoma cells, and its overexpression promotes proliferation, migration, and immune evasion in glioblastoma [PMID:41323784, PMID:38860406, PMID:41074600]. Co-overexpression of COL6A2 with DSCAM cooperatively produces congenital heart defects in mice through perturbation of adhesion and cardiac hypertrophy gene programs [PMID:22072978].\",\n  \"teleology\": [\n    {\n      \"year\": 1991,\n      \"claim\": \"Establishing the genomic organization of COL6A2 resolved that the alpha-1 and alpha-2 chain genes form a tightly linked cluster on chromosome 21q22.3, providing the physical framework for understanding coordinate regulation and disease genetics.\",\n      \"evidence\": \"Pulsed-field gel electrophoresis, somatic cell hybrid mapping, and fiber-FISH in human cells\",\n      \"pmids\": [\"1676701\", \"8575781\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Functional significance of head-to-tail arrangement not determined\", \"Whether coordinate transcriptional regulation occurs from the shared locus was not tested\"]\n    },\n    {\n      \"year\": 2002,\n      \"claim\": \"Demonstrating that COL6A2 nonsense mutations trigger nonsense-mediated mRNA decay and that residual mutant mRNA produces abnormal microfibrils unable to form extensive networks established the C-terminal globular domain as essential for microfibrillar assembly but not triple-helix formation.\",\n      \"evidence\": \"Northern blot, mRNA quantification, and immunofluorescence of collagen VI matrix deposition in patient and carrier fibroblasts\",\n      \"pmids\": [\"12218063\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis for why the C-terminal domain is required for network formation was not resolved\", \"Contribution of individual C-terminal subdomains (C1 vs C2) not dissected\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Identification of a deep intronic splice mutation generating cryptic transcripts degraded by NMD showed that loss of COL6A2 mRNA quantity, not dominant-negative protein, can be the primary disease mechanism in Ullrich CMD.\",\n      \"evidence\": \"RT-PCR and Northern blot of patient fibroblast RNA with genomic DNA sequencing\",\n      \"pmids\": [\"16075202\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Quantitative threshold of COL6A2 mRNA needed for functional matrix assembly not defined\", \"Only one patient studied\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Dissecting recessive C-globular missense mutations showed that the C1 subdomain (E624K) permits chain assembly but disrupts fibril morphology, while the C2 subdomain (R876S) prevents triple-helical molecule assembly altogether; the C2a splice variant can partially compensate, refining the domain-specific roles in collagen VI biogenesis.\",\n      \"evidence\": \"Patient fibroblast analysis, stable transfection of mutant constructs, secretion assays, electron microscopy of microfibrils\",\n      \"pmids\": [\"20106987\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural mechanism by which C2a variant rescues assembly not resolved\", \"Whether compensatory C2a expression is clinically relevant in vivo not established\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Discovery that deep intronic deletions can silence one COL6A2 allele expanded the mutational spectrum of collagen VI myopathies beyond coding and canonical splice-site mutations.\",\n      \"evidence\": \"Custom CGH array with RNA monoallelic transcription confirmation in patient cells\",\n      \"pmids\": [\"20302629\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism of transcriptional silencing by intronic deletion not characterized\", \"Whether regulatory elements within intron 1A control COL6A2 expression was not tested\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Demonstrating that COL6A2 and DSCAM must be co-overexpressed to produce congenital heart defects established a genetic interaction linking collagen VI to cardiac adhesion and hypertrophy pathways beyond its structural ECM role.\",\n      \"evidence\": \"Combinatorial overexpression screen in Drosophila heart, mouse cardiac overexpression, H9C2 cell transcriptional profiling\",\n      \"pmids\": [\"22072978\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct physical interaction between COL6A2 and DSCAM not shown\", \"Whether this cooperativity is relevant to Down syndrome-associated heart defects in humans not confirmed\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Antisense oligonucleotide-mediated exon skipping selectively degraded the mutant COL6A2 transcript and restored collagen VI secretion and ECM network formation, providing proof-of-concept for allele-specific therapeutic silencing of dominant COL6A2 mutations.\",\n      \"evidence\": \"2'-O-methyl phosphorothioate antisense oligonucleotide treatment of patient fibroblasts with collagen VI secretion and immunofluorescence readouts\",\n      \"pmids\": [\"22992134\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"In vivo efficacy and delivery not tested\", \"Applicability to other dominant COL6A2 mutations not demonstrated\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"A polyadenylation signal deletion in the COL6A2 3'-UTR caused alternative last exon usage and sarcolemma-specific collagen VI deficiency, revealing that post-transcriptional 3'-end processing defects produce tissue-selective rather than global collagen VI loss.\",\n      \"evidence\": \"Whole-genome sequencing, RNA sequencing of patient muscle, immunofluorescence for collagen VI localization\",\n      \"pmids\": [\"38544966\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Why the deficiency is sarcolemma-specific rather than global is mechanistically unexplained\", \"Single family reported\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Direct luciferase-validated targeting of COL6A2 by miR-3189-3p, whose expression is epigenetically silenced by PRC2-mediated H3K27me3, linked COL6A2 upregulation to GBM proliferation, migration, and EMT, establishing COL6A2 as a functional effector in glioblastoma malignancy.\",\n      \"evidence\": \"Luciferase reporter assay with mutagenesis, ChIP for H3K27me3, functional cell assays in GBM cells\",\n      \"pmids\": [\"38860406\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"In vivo relevance in GBM animal models not shown\", \"Whether COL6A2 is a driver or passenger in glioblastoma progression not resolved\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Identification of a physical interaction between COL6A2 and integrin β1 that activates Wnt/β-catenin signaling to drive EMT in renal cell carcinoma defined a specific signaling axis through which extracellular COL6A2 promotes tumor invasion.\",\n      \"evidence\": \"Co-immunoprecipitation, integrin blockade, Wnt/β-catenin activator rescue experiments in ccRCC cells\",\n      \"pmids\": [\"41323784\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Co-IP not validated by reciprocal IP or structural data\", \"Whether integrin β1 interaction occurs in non-cancer physiological contexts not tested\", \"In vivo tumor model validation absent\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"COL6A2 silencing in GBM cells restored dendritic cell activation and effector immune cell infiltration, revealing an immunosuppressive function of COL6A2 in the tumor microenvironment.\",\n      \"evidence\": \"CyTOF immune profiling and functional proliferation/invasion assays upon COL6A2 knockdown in glioblastoma cells\",\n      \"pmids\": [\"41074600\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism by which COL6A2 suppresses dendritic cell activation not identified\", \"In vivo immunological validation not performed\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The structural basis for how the C2 subdomain directs microfibrillar network assembly, the in vivo relevance of integrin β1–Wnt/β-catenin signaling in physiological collagen VI functions, and whether COL6A2's immunomodulatory and cardiac roles represent distinct or overlapping mechanisms remain unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No atomic-resolution structure of the COL6A2 C-terminal domain in the context of the trimer\", \"No in vivo validation of integrin β1-mediated signaling axis\", \"Mechanism of immune evasion mediated by COL6A2 not molecularly defined\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0005198\", \"supporting_discovery_ids\": [0, 1]},\n      {\"term_id\": \"GO:0098631\", \"supporting_discovery_ids\": [5, 10]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0031012\", \"supporting_discovery_ids\": [0, 1, 4, 8]},\n      {\"term_id\": \"GO:0005576\", \"supporting_discovery_ids\": [0, 1, 4]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1474244\", \"supporting_discovery_ids\": [0, 1, 4, 8]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [10]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [5]}\n    ],\n    \"complexes\": [\"type VI collagen trimer\"],\n    \"partners\": [\"COL6A1\", \"DSCAM\", \"ITGB1\"],\n    \"other_free_text\": []\n  }\n}\n```"}