{"gene":"COL6A3","run_date":"2026-06-09T22:57:19","timeline":{"discoveries":[{"year":2002,"finding":"The C5 domain of the COL6A3 α3(VI) chain is synthesized and incorporated into newly formed collagen VI fibrils but is cleaved off immediately after secretion and is absent from the mature pericellular type VI collagen matrix in adult articular cartilage, as shown by confocal laser-scanning microscopy and immunoelectron microscopy with a specific anti-C5 antiserum.","method":"Confocal laser-scanning microscopy, immunoelectron microscopy, double-labeling immunostaining","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct localization with two orthogonal microscopy methods tied to functional processing event, single lab","pmids":["11785962"],"is_preprint":false},{"year":2002,"finding":"Homozygous loss-of-function mutations in COL6A3 (splice-site 6930+5A>G causing exon 29 skipping, and nonsense R2342X) cause Ullrich congenital muscular dystrophy with partial or complete absence of collagen VI in muscle and fibroblasts, establishing COL6A3 as a causal gene for this muscular dystrophy.","method":"Microsatellite linkage mapping, Sanger sequencing of COL6A3 mutations, muscle biopsy immunostaining for collagen VI","journal":"American journal of human genetics","confidence":"High","confidence_rationale":"Tier 2 / Strong — three independent families with distinct mutations, linkage confirmed, protein absence verified in tissue; replicated across labs in subsequent studies","pmids":["11992252"],"is_preprint":false},{"year":1998,"finding":"A missense mutation (Gly→Glu) in the von Willebrand factor type A (vWFA/N2) domain of COL6A3 segregates with autosomal dominant Bethlem myopathy in a large pedigree, demonstrating that mutations in the N-terminal globular domain (as well as the triple-helical domain) of COL6A3 can cause Bethlem myopathy.","method":"Linkage analysis, Sanger sequencing, segregation analysis in 31 family members, exclusion from 338 control chromosomes","journal":"Human molecular genetics","confidence":"High","confidence_rationale":"Tier 2 / Strong — mutation segregates perfectly in large pedigree, absent in controls, replicated by subsequent reports of triple-helix mutations","pmids":["9536084"],"is_preprint":false},{"year":1999,"finding":"A de novo Gly→Arg substitution in the triple-helical coding region of COL6A3 disrupts triple helix structure and causes autosomal dominant Bethlem myopathy, confirming that glycine substitutions in the triple helix of α3(VI) collagen are pathogenic.","method":"Clinical description, Sanger sequencing, bioinformatic domain analysis","journal":"Neuromuscular disorders","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — de novo mutation with confirmed segregation, single lab but consistent with mechanistic model established by prior studies","pmids":["10399756"],"is_preprint":false},{"year":2013,"finding":"Mice expressing a non-functional α3(VI) collagen chain (Col6a3 mutant) lack extracellular collagen VI microfibrils, show decreased muscle mass and contractile force, and display ultrastructurally abnormal collagen fibrils in tendon but not cornea, indicating a tissue-specific role of COL6A3 in collagen I fibrillogenesis. The C-terminal cleavage product of α3(VI) is not required for normal growth and development.","method":"Transgenic mouse model, electron microscopy, muscle contractile force measurements, immunofluorescence, histopathology","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — in vivo knockout model with multiple orthogonal functional readouts (ultrastructure, force, fibrillogenesis) in a single rigorous study","pmids":["23564457"],"is_preprint":false},{"year":2014,"finding":"Heterozygous deletion of exon 16 in the Col6a3 gene produces a mutant α3(VI) protein that exerts a dominant-negative effect on collagen VI microfibrillar assembly in fibroblasts, recapitulating dominant Ullrich congenital muscular dystrophy; mutant mice develop myopathy with mitochondrial and sarcoplasmic reticulum ultrastructural alterations and compromised muscle contractile function.","method":"Targeted gene deletion (mouse model), biosynthetic pulse-chase studies, electron microscopy, muscle contractile function assays","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — reconstitution-level biosynthetic assays demonstrating dominant-negative mechanism, multiple orthogonal phenotypic readouts","pmids":["24563484"],"is_preprint":false},{"year":2015,"finding":"Recessive compound heterozygous mutations in COL6A3, with at least one allele affecting exon 41, cause early-onset isolated dystonia (DYT27) with underlying neurodevelopmental deficits (axonal outgrowth deficits) in zebrafish; Col6a3 is expressed in neurons of the adult mouse brain, placing COL6A3 in a neuronal extracellular matrix pathway distinct from its role in muscle.","method":"Whole-exome sequencing, zebrafish morpholino knockdown with in-frame deletions, axonal outgrowth assay, mouse brain in situ hybridization/RT-PCR","journal":"American journal of human genetics","confidence":"High","confidence_rationale":"Tier 2 / Strong — human genetics in multiple pedigrees plus functional zebrafish model with exon-specific phenotype and neuronal expression confirmed by in situ","pmids":["26004199"],"is_preprint":false},{"year":2008,"finding":"The t(1;2)(p13;q37) chromosomal translocation generates a COL6A3-CSF1 fusion transcript in tenosynovial giant cell tumors; in-frame fusion products were detected by RT-PCR, with CSF1 breakpoints downstream of exon 5 so the fusion does not encode the CSF1 receptor-binding amino-terminal domain.","method":"Cytogenetics, RT-PCR, sequence analysis of breakpoints","journal":"Genes, chromosomes & cancer","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — RT-PCR detection confirmed in 3/6 cases with sequencing; mechanistic consequence of fusion remains unclear per the authors","pmids":["17918257"],"is_preprint":false},{"year":2011,"finding":"COL6A3 undergoes tumor-specific alternative splicing in pancreatic ductal adenocarcinoma, with consistent inclusion of exons 3, 4, and 6 in tumor tissue but not adjacent normal tissue; exon 4 inclusion is exclusively tumor-specific, suggesting cancer-specific isoforms contribute to desmoplastic stroma.","method":"RT-PCR with isoform-specific primers, Western blot, immunohistochemistry in paired PDA vs. normal tissues and animal models","journal":"Surgery","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — multiple orthogonal detection methods across 18 paired samples and two animal models, single lab","pmids":["21719059"],"is_preprint":false},{"year":2014,"finding":"siRNA allele-specifically targeting a COL6A3 exon-16 skipping mutation in UCMD patient fibroblasts selectively suppresses mutant transcript expression without affecting the wild-type allele, and treatment considerably improves collagen VI matrix quantity and quality as assessed by confocal microscopy.","method":"siRNA allele-specific silencing, quantitative RT-PCR, reporter construct in HEK293T, confocal microscopy of collagen VI matrix","journal":"Molecular therapy. Nucleic acids","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — allele-specific silencing with reporter validation plus patient cell functional readout, single lab","pmids":["24518369"],"is_preprint":false},{"year":2017,"finding":"Gapmer antisense oligonucleotides targeting a heterozygous 18-nt deletion mutation in COL6A3 exon 15 selectively suppress mutant transcripts at the mRNA level (more effectively than pre-mRNA targeting) via RNase H recruitment, resulting in increased deposition of collagen VI protein into the extracellular matrix in patient-derived cells.","method":"Gapmer AON transfection, RT-PCR/qPCR of allele-specific transcripts, Western blot of collagen VI matrix deposition","journal":"Molecular therapy. Nucleic acids","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — mechanism of RNase H-mediated cleavage demonstrated with functional protein rescue, single lab","pmids":["28918041"],"is_preprint":false},{"year":2018,"finding":"COL6A3 knockdown in human adipocytes increases triglyceride content, lipolysis, insulin-induced Akt phosphorylation, and adipogenic gene expression, and abrogates TNF-α- and LPS-induced MCP1 (CCL2) mRNA expression and secretion; matrix metalloproteinase-11 treatment reduces COL6A3 protein and simultaneously suppresses MCP1 induction, placing COL6A3 upstream of inflammatory MCP1 signaling in adipocytes.","method":"Stable shRNA knockdown in immortalized human preadipocytes, MTT/lipolysis/insulin signaling assays, MMP-11 treatment, co-culture with THP1 macrophages, RT-PCR/ELISA","journal":"Obesity (Silver Spring, Md.)","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal functional assays in stable KD lines plus MMP-11 pharmacologic validation, single lab","pmids":["27312141"],"is_preprint":false},{"year":2014,"finding":"PPARG knockdown in developing human adipocytes increases COL6A3 mRNA ~1.5-fold, and COL6A3 mRNA is ~2.8-fold higher in small (less mature) compared to large adipocytes, demonstrating that PPARγ-mediated adipocyte differentiation negatively regulates COL6A3 expression.","method":"PPARG siRNA knockdown in primary human adipocytes (euglycemic clamp-phenotyped subjects), adipocyte size fractionation from surgical biopsies, RT-qPCR","journal":"Obesity (Silver Spring, Md.)","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional knockdown plus cell-biological fractionation, single lab, mechanistic link to PPARγ pathway established","pmids":["24719315"],"is_preprint":false},{"year":2015,"finding":"Leptin treatment causes a dose-dependent decrease in COL6A3 expression in human adipose tissue, while insulin and glucose have no effect, demonstrating a direct paracrine regulatory pathway by which leptin modulates extracellular matrix composition through COL6A3.","method":"In vitro leptin/insulin/glucose treatment of adipose tissue explants, RT-qPCR, comparison across depot and obesity status","journal":"Endocrinology","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — dose-response in multiple conditions with dose-dependent effect confirmed, single lab, single method for the mechanistic claim","pmids":["25337653"],"is_preprint":false},{"year":2018,"finding":"COL6A3-derived endotrophin (ETP, cleaved from the C5 domain) induces JNK-dependent hepatocyte apoptosis and activates non-parenchymal liver cells to promote hepatic inflammation and fibrosis; neutralizing anti-ETP antibodies suppress these pathological consequences in chronic liver disease models.","method":"Recombinant ETP treatment of hepatocytes, JNK pathway analysis, neutralizing antibody treatment in chronic liver disease mouse models, co-culture experiments","journal":"The Journal of pathology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vitro mechanism (JNK activation) plus in vivo antibody rescue, single lab with multiple readouts","pmids":["30246318"],"is_preprint":false},{"year":2020,"finding":"Two homozygous COL6A3 mutations (p.Val86Ala and p.Arg689Cys) identified in Peters' anomaly patients cause abnormal intracellular retention of mutant COL6A3 protein and reduce cellular resistance to oxidative stress through an enhanced endoplasmic reticulum stress response.","method":"Patient exome/panel sequencing, immunofluorescence for protein localization, ER stress markers, oxidative stress assays in cell lines expressing mutant protein","journal":"Frontiers in cell and developmental biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional assays of ER retention and oxidative stress with mutant protein, single lab with multiple readouts","pmids":["33304895"],"is_preprint":false},{"year":2020,"finding":"COL6A3 overexpression in bone marrow mesenchymal stem cells (BMSCs) promotes mitophagy (colocalization of mitochondria and lysosomes, restored mitochondrial membrane potential), enhances osteogenic and adipogenic differentiation, and reduces LPS-induced inflammatory mediator expression (iNOS, COX-2); blockade of mitophagy with Mdivi-1 abolishes these COL6A3-mediated effects.","method":"Lentiviral COL6A3 overexpression, Western blot, TUNEL apoptosis, JC-1 staining, immunofluorescence colocalization, mitophagy inhibitor (Mdivi-1) rescue experiment","journal":"Molecular biology reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — pharmacological rescue experiment (Mdivi-1) placing COL6A3 upstream of mitophagy, multiple orthogonal assays, single lab","pmids":["38270688"],"is_preprint":false},{"year":2023,"finding":"Experimental knockdown of COL6A3 induces transcriptional changes overlapping with the majority of experimental senescence models, with cell-cycle arrest linked to modulation of DREAM complex-targeted genes, identifying COL6A3 as a functional inducer of cellular senescence.","method":"COL6A3 siRNA knockdown, RNA-seq transcriptome comparison across 10 senescence models, DREAM complex gene-set analysis","journal":"Cell reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional KD with transcriptomic integration across 10 models, pathway placement via DREAM complex, single lab","pmids":["37938972"],"is_preprint":false},{"year":2020,"finding":"PRRX1 transcription factor directly transactivates the human COL6A3 promoter (reporter assay), and PRRX1 knockdown reduces COL6A3 mRNA in human and mouse adipose cells; TGF-β1 upregulates Col6a3 mRNA while TNF-α decreases PRRX1-mediated transactivation, placing PRRX1 as a transcriptional regulator of COL6A3 in adipose tissue.","method":"PRRX1 knockdown and overexpression, COL6A3 promoter-reporter luciferase assay, qRT-PCR in human/mouse adipose cells, TGF-β1 and TNF-α treatment","journal":"Scientific reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — promoter reporter plus KD/OE in two cell types with cytokine modulation, single lab","pmids":["33214660"],"is_preprint":false},{"year":2024,"finding":"A damaging COL6A3 variant introduced by CRISPR-Cas9 into iPSC-derived neocartilage organoids results in significantly lower binding between pericellular matrix proteins COL6A3 and fibronectin, provokes an osteoarthritic chondrocyte state, and abolishes the characteristic inflammatory signaling response (PTGS2, PECAM1, ADAMTS5) to hyperphysiological mechanical loading; the lncRNA MIR31HG is identified as a key epigenetic regulator of this loading response.","method":"CRISPR-Cas9 genome editing of iPSC-derived neocartilage organoids, multi-omics (mRNA and lncRNA), protein binding assay, mechanical loading","journal":"Advanced science","confidence":"High","confidence_rationale":"Tier 1 / Strong — CRISPR reconstitution in organoid model, multi-omics plus direct protein binding assay, multiple orthogonal readouts in single study","pmids":["39021299"],"is_preprint":false},{"year":2026,"finding":"A damaging COL6A3 variant in iPSC-derived chondrocytes reduces pericellular matrix (PCM) elastic modulus, reduces expression of key matrix proteins, causes heightened osmotically-induced calcium signaling (consistent with reduced PCM stiffness), reduces anabolic response to TRPV4 activation, disrupts circadian rhythms (increased BMAL1, phase shift), and exacerbates catabolic response to IL-1, demonstrating that COL6A3 regulates chondrocyte mechanotransduction via PCM mechanical properties.","method":"CRISPR-edited iPSC-derived chondrocytes, atomic force microscopy of PCM modulus, calcium imaging, TRPV4 activation assays, RNA-seq, circadian rhythm analysis, IL-1 stimulation","journal":"Stem cell research & therapy","confidence":"High","confidence_rationale":"Tier 1 / Strong — CRISPR reconstitution with direct biomechanical measurement (AFM) and multiple functional readouts in a rigorous single study","pmids":["41692747"],"is_preprint":false},{"year":2025,"finding":"ETP-specific knockout mice (ETPKO), generated by inserting lox2272 sites into the Col6a3 locus to selectively ablate ETP while preserving Col6a3 expression, show that ETP depletion significantly attenuates kidney fibrosis progression in ischemia-reperfusion injury, establishing endotrophin as a key driver of fibrosis independently of the full COL6A3 protein.","method":"Cre-lox ETP-specific knockout mouse generation, genomic sequencing confirmation, mCherry reporter, renal ischemia-reperfusion injury model, fibrosis quantification","journal":"bioRxiv (preprint)","confidence":"Medium","confidence_rationale":"Tier 1-2 / Moderate — novel ETP-specific KO with in vivo disease model; strong mechanistic specificity but preprint, single lab","pmids":[],"is_preprint":true},{"year":2025,"finding":"Integrative Mendelian randomization and colocalization identified COL6A3-derived endotrophin as mediating the effect of obesity (BMI) on coronary artery disease risk; body fat reduction decreases plasma endotrophin levels, implicating ETP as a tractable circulating mediator linking adiposity to cardiovascular disease.","method":"Two-step proteome-wide Mendelian randomization, Bayesian colocalization, single-cell RNA sequencing, epigenomics, clinical intervention (fat loss) studies","journal":"Nature genetics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic causal inference with colocalization plus intervention data, multiple methods; no direct in vitro/in vivo functional experiment on ETP mechanism per se","pmids":["39856218"],"is_preprint":false},{"year":2025,"finding":"COL6A3 exon 4 inclusion is identified as one of a 5-ASE signature specifically associated with TGFβ-induced myofibroblast differentiation in primary skin fibroblasts, validated by ddPCR and AS-PCR and retrieved in multiple independent RNA-seq datasets of TGFβ-stimulated lung and skin fibroblasts.","method":"RNA-seq, ddPCR, AS-PCR in primary skin fibroblasts, validation in public lung/skin fibroblast datasets","journal":"bioRxiv (preprint)","confidence":"Low","confidence_rationale":"Tier 3 / Weak — preprint, single-method per validation assay, no functional consequence of the COL6A3 exon 4 inclusion specifically demonstrated","pmids":[],"is_preprint":true}],"current_model":"COL6A3 encodes the α3 chain of type VI collagen, which is required for extracellular collagen VI microfibril assembly; the C5 (endotrophin) domain is cleaved from assembled fibrils immediately after secretion and acts as a bioactive signaling peptide that drives fibrosis, TGF-β-like EMT, and cardiometabolic disease; loss-of-function mutations in COL6A3 cause a spectrum of collagen VI-related myopathies (Ullrich CMDs/Bethlem myopathy) through dominant-negative or haploinsufficient disruption of microfibrillar assembly, while tissue-specific recessive mutations affecting exon 41 impair neuronal extracellular matrix function to cause isolated dystonia (DYT27); in chondrocytes, COL6A3 constitutes the pericellular matrix and directly regulates mechanotransduction through its influence on PCM elastic modulus and TRPV4 signaling; in adipose tissue COL6A3 expression is regulated by PPARγ, leptin (negatively), and the transcription factor PRRX1, and modulates inflammatory MCP1 signaling upstream of the PI3K/Akt pathway."},"narrative":{"mechanistic_narrative":"COL6A3 encodes the α3 chain of type VI collagen, an extracellular matrix component required for assembly of collagen VI microfibrils that organize the pericellular and interstitial matrix; loss of functional α3(VI) in vivo abolishes collagen VI microfibrils and produces decreased muscle mass, reduced contractile force, and tissue-specific defects in collagen I fibrillogenesis [PMID:23564457]. Homozygous loss-of-function mutations cause Ullrich congenital muscular dystrophy with absence of collagen VI from muscle and fibroblasts [PMID:11992252], while glycine substitutions in the triple-helical domain and mutations in the N-terminal von Willebrand factor type A domain cause Bethlem myopathy [PMID:9536084, PMID:10399756]; in-frame mutant chains act through a dominant-negative effect on microfibrillar assembly [PMID:24563484]. Recessive mutations affecting exon 41 instead impair a neuronal extracellular matrix function, producing isolated dystonia (DYT27) with axonal outgrowth deficits, distinct from the muscle disease [PMID:26004199]. The C-terminal C5 domain of α3(VI) is cleaved immediately after secretion and is absent from the mature matrix [PMID:11785962]; this cleaved product, endotrophin, functions as a bioactive peptide that activates JNK-dependent hepatocyte apoptosis and drives inflammation and fibrosis, effects suppressed by neutralizing antibodies or by ETP-specific ablation [PMID:30246318], and links adiposity to coronary artery disease risk [PMID:39856218]. In chondrocytes, COL6A3 binds fibronectin within the pericellular matrix and sets PCM elastic modulus, thereby governing mechanotransduction through osmotic calcium signaling and TRPV4-dependent anabolic responses, with damaging variants provoking an osteoarthritic state [PMID:39021299, PMID:41692747]. In adipocytes, COL6A3 expression is driven by the transcription factor PRRX1 and negatively regulated by PPARγ-mediated differentiation and leptin, and COL6A3 acts upstream of inflammatory MCP1/CCL2 signaling and insulin/Akt responses [PMID:27312141, PMID:24719315, PMID:25337653, PMID:33214660].","teleology":[{"year":1998,"claim":"Established that mutations in the N-terminal globular vWFA domain of α3(VI), not only the triple helix, are pathogenic, broadening the mutational basis of Bethlem myopathy.","evidence":"Linkage and segregation of a Gly→Glu vWFA missense mutation in a large pedigree, excluded in controls","pmids":["9536084"],"confidence":"High","gaps":["Did not establish how the vWFA mutation perturbs microfibril assembly biochemically","No tissue-level collagen VI quantification"]},{"year":1999,"claim":"Confirmed that glycine substitutions disrupting the α3(VI) triple helix cause dominant Bethlem myopathy, anchoring the triple-helix structural mechanism.","evidence":"Sanger sequencing and domain analysis of a de novo Gly→Arg substitution","pmids":["10399756"],"confidence":"Medium","gaps":["Single family","No functional assembly assay of the mutant chain"]},{"year":2002,"claim":"Demonstrated that the C5 domain is incorporated into nascent fibrils but cleaved off immediately after secretion, defining COL6A3 as the source of a secreted, post-assembly processing product later recognized as endotrophin.","evidence":"Confocal and immunoelectron microscopy with anti-C5 antiserum in articular cartilage","pmids":["11785962"],"confidence":"Medium","gaps":["Did not identify the protease responsible for cleavage","Function of the cleaved C5 fragment not addressed"]},{"year":2002,"claim":"Established COL6A3 as a causal gene for Ullrich congenital muscular dystrophy via recessive loss-of-function alleles, tying disease to collagen VI absence.","evidence":"Linkage mapping, mutation sequencing, and muscle/fibroblast collagen VI immunostaining across three families","pmids":["11992252"],"confidence":"High","gaps":["Did not resolve the molecular consequence on microfibril architecture","Genotype–phenotype severity correlation not established"]},{"year":2013,"claim":"Showed in vivo that functional α3(VI) is required for collagen VI microfibril formation, muscle force, and tissue-specific collagen I fibrillogenesis, and that the C-terminal cleavage product is dispensable for normal development.","evidence":"Col6a3 mutant mouse with EM, contractile force, and fibrillogenesis readouts","pmids":["23564457"],"confidence":"High","gaps":["Did not test pathological roles of the cleaved product under disease/stress","Mechanism of tendon-specific (not corneal) fibril defect unresolved"]},{"year":2014,"claim":"Defined the dominant-negative mechanism by which in-frame mutant α3(VI) chains poison microfibrillar assembly, explaining dominant UCMD.","evidence":"Exon-16-deletion mouse with biosynthetic pulse-chase, EM, and contractile assays","pmids":["24563484"],"confidence":"High","gaps":["Did not quantify the stoichiometric threshold of mutant incorporation needed for dominance"]},{"year":2014,"claim":"Introduced allele-specific silencing as a strategy to rescue collagen VI matrix in UCMD by selectively knocking down the dominant-negative mutant transcript.","evidence":"Allele-specific siRNA in patient fibroblasts with reporter validation and confocal matrix readout","pmids":["24518369"],"confidence":"Medium","gaps":["No in vivo efficacy","Single mutation context"]},{"year":2014,"claim":"Identified PPARγ-driven adipocyte differentiation as a negative regulator of COL6A3, embedding the gene in adipose ECM remodeling.","evidence":"PPARG siRNA knockdown and adipocyte size fractionation with RT-qPCR","pmids":["24719315"],"confidence":"Medium","gaps":["Indirect regulation; no direct promoter binding shown","Single lab"]},{"year":2015,"claim":"Established leptin as a direct paracrine repressor of COL6A3 in adipose tissue, distinguishing it from glucose/insulin inputs.","evidence":"Dose-response leptin/insulin/glucose treatment of adipose explants with RT-qPCR","pmids":["25337653"],"confidence":"Medium","gaps":["Mechanism of leptin-to-COL6A3 transcriptional repression not defined","Single method for the mechanistic claim"]},{"year":2015,"claim":"Revealed a tissue-specific neuronal function for COL6A3 distinct from muscle, with exon-41-dependent recessive mutations causing isolated dystonia (DYT27).","evidence":"Whole-exome sequencing in pedigrees, zebrafish axonal outgrowth assay, and mouse brain expression","pmids":["26004199"],"confidence":"High","gaps":["Molecular role of exon 41 in neuronal ECM unresolved","No mammalian neuronal phenotype model"]},{"year":2017,"claim":"Extended allele-specific suppression with gapmer antisense oligonucleotides acting at the mRNA level via RNase H, restoring collagen VI deposition.","evidence":"Gapmer AON transfection in patient cells with allele-specific qPCR and matrix Western blot","pmids":["28918041"],"confidence":"Medium","gaps":["No in vivo delivery","Mutation-specific design limits generalizability"]},{"year":2018,"claim":"Placed COL6A3 upstream of inflammatory MCP1/CCL2 signaling and metabolic regulation in adipocytes, linking the matrix protein to insulin sensitivity and lipid handling.","evidence":"Stable shRNA knockdown in human adipocytes with lipolysis/insulin assays, MMP-11 treatment, and macrophage co-culture","pmids":["27312141"],"confidence":"Medium","gaps":["Whether the effect requires intact matrix versus the cleaved fragment not separated","Single lab"]},{"year":2018,"claim":"Defined endotrophin (cleaved C5) as a bioactive driver of hepatocyte apoptosis, inflammation, and fibrosis amenable to antibody neutralization, giving the post-secretion fragment a pathological function.","evidence":"Recombinant ETP treatment with JNK analysis and neutralizing antibody rescue in chronic liver disease models","pmids":["30246318"],"confidence":"Medium","gaps":["ETP receptor/binding partner not identified","Single lab"]},{"year":2020,"claim":"Identified COL6A3 mutations causing intracellular retention and heightened ER/oxidative stress in Peters' anomaly, adding a proteostatic disease mechanism.","evidence":"Patient sequencing with mutant protein localization and ER/oxidative stress assays in cell lines","pmids":["33304895"],"confidence":"Medium","gaps":["No animal model of the ocular phenotype","Causal chain from ER stress to malformation not established"]},{"year":2020,"claim":"Established PRRX1 as a direct transcriptional activator of COL6A3 integrating TGF-β and TNF-α inputs in adipose tissue.","evidence":"Promoter-reporter luciferase plus PRRX1 knockdown/overexpression and cytokine treatment in adipose cells","pmids":["33214660"],"confidence":"Medium","gaps":["In vivo relevance of PRRX1–COL6A3 axis not tested","Single lab"]},{"year":2020,"claim":"Linked COL6A3 to mitophagy-dependent differentiation and anti-inflammatory effects in mesenchymal stem cells.","evidence":"Lentiviral overexpression with mitophagy markers and Mdivi-1 inhibitor rescue","pmids":["38270688"],"confidence":"Medium","gaps":["Mechanism connecting an ECM protein to intracellular mitophagy unexplained","Overexpression-only, single lab"]},{"year":2023,"claim":"Identified COL6A3 as a functional inducer of cellular senescence acting through DREAM-complex-targeted cell-cycle genes.","evidence":"COL6A3 siRNA knockdown with RNA-seq comparison across 10 senescence models and DREAM gene-set analysis","pmids":["37938972"],"confidence":"Medium","gaps":["Direct molecular link between COL6A3 and DREAM regulation not defined","Correlative transcriptomics"]},{"year":2024,"claim":"Showed via CRISPR organoid reconstitution that COL6A3 binds fibronectin in the pericellular matrix and is required for the inflammatory response to mechanical loading, with MIR31HG as an epigenetic regulator.","evidence":"CRISPR-edited iPSC neocartilage organoids with protein binding assay, mechanical loading, and multi-omics","pmids":["39021299"],"confidence":"High","gaps":["Mechanistic role of MIR31HG downstream of COL6A3 not resolved","Loading-response signaling intermediates not fully mapped"]},{"year":2025,"claim":"Demonstrated that COL6A3 sets PCM elastic modulus to control chondrocyte mechanotransduction, calcium/TRPV4 signaling, circadian rhythm, and IL-1 catabolic responses.","evidence":"CRISPR-edited iPSC chondrocytes with AFM modulus measurement, calcium imaging, TRPV4 assays, RNA-seq, and IL-1 stimulation","pmids":["41692747"],"confidence":"High","gaps":["How reduced PCM stiffness mechanistically couples to TRPV4 not fully defined","In vivo cartilage phenotype not tested"]},{"year":2025,"claim":"Provided ETP-specific genetic ablation showing endotrophin drives fibrosis independently of full-length COL6A3.","evidence":"Cre-lox ETP-specific knockout mice in renal ischemia-reperfusion model (preprint)","pmids":[],"confidence":"Medium","gaps":["Preprint, single lab","ETP downstream receptor/signaling in kidney not identified"]},{"year":2025,"claim":"Used genetic causal inference to position circulating endotrophin as a mediator linking obesity to coronary artery disease, suggesting therapeutic tractability.","evidence":"Two-step Mendelian randomization, colocalization, single-cell RNA-seq, and fat-loss intervention","pmids":["39856218"],"confidence":"Medium","gaps":["No direct in vitro/in vivo ETP cardiovascular mechanism","Causal estimate, not experimental"]},{"year":null,"claim":"The protease(s) that cleave the C5/endotrophin domain and the receptor through which endotrophin signals remain unidentified, leaving the central bioactive axis mechanistically incomplete.","evidence":"No timeline discovery identifies the ETP-cleaving enzyme or ETP receptor","pmids":[],"confidence":"Medium","gaps":["ETP receptor unknown","ETP-generating protease unknown","Direct molecular link between matrix loss and intracellular phenotypes (mitophagy, senescence) unresolved"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0005198","term_label":"structural molecule activity","supporting_discovery_ids":[4,5,1]},{"term_id":"GO:0048018","term_label":"receptor ligand activity","supporting_discovery_ids":[14,21,22]}],"localization":[{"term_id":"GO:0031012","term_label":"extracellular matrix","supporting_discovery_ids":[0,4,19]},{"term_id":"GO:0005576","term_label":"extracellular region","supporting_discovery_ids":[0,10]},{"term_id":"GO:0005783","term_label":"endoplasmic reticulum","supporting_discovery_ids":[15]}],"pathway":[{"term_id":"R-HSA-1474244","term_label":"Extracellular matrix organization","supporting_discovery_ids":[4,5,19]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[1,2,6]}],"complexes":["collagen VI microfibril"],"partners":["CSF1","FN1"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"P12111","full_name":"Collagen alpha-3(VI) chain","aliases":[],"length_aa":3177,"mass_kda":343.7,"function":"Collagen VI acts as a cell-binding protein","subcellular_location":"Secreted, extracellular space, extracellular matrix","url":"https://www.uniprot.org/uniprotkb/P12111/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/COL6A3","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/COL6A3","total_profiled":1310},"omim":[{"mim_id":"620728","title":"ULLRICH CONGENITAL MUSCULAR DYSTROPHY 1C; UCMD1C","url":"https://www.omim.org/entry/620728"},{"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"},{"mim_id":"616411","title":"DYSTONIA 27; DYT27","url":"https://www.omim.org/entry/616411"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Endoplasmic reticulum","reliability":"Approved"},{"location":"Vesicles","reliability":"Additional"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"smooth muscle","ntpm":391.7}],"url":"https://www.proteinatlas.org/search/COL6A3"},"hgnc":{"alias_symbol":[],"prev_symbol":[]},"alphafold":{"accession":"P12111","domains":[],"viewer_url":"https://alphafold.ebi.ac.uk/entry/P12111","model_url":"https://alphafold.ebi.ac.uk/files/AF-P12111-5-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-P12111-5-F1-predicted_aligned_error_v6.png","plddt_mean":84.38},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=COL6A3","jax_strain_url":"https://www.jax.org/strain/search?query=COL6A3"},"sequence":{"accession":"P12111","fasta_url":"https://rest.uniprot.org/uniprotkb/P12111.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/P12111/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/P12111"}},"corpus_meta":[{"pmid":"11992252","id":"PMC_11992252","title":"Mutations in COL6A3 cause severe and mild phenotypes of Ullrich congenital muscular dystrophy.","date":"2002","source":"American journal of human genetics","url":"https://pubmed.ncbi.nlm.nih.gov/11992252","citation_count":126,"is_preprint":false},{"pmid":"29143985","id":"PMC_29143985","title":"Silencing of COL1A2, COL6A3, and THBS2 inhibits gastric cancer cell proliferation, migration, and invasion while promoting apoptosis through the PI3k-Akt signaling pathway.","date":"2018","source":"Journal of cellular biochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/29143985","citation_count":104,"is_preprint":false},{"pmid":"17918257","id":"PMC_17918257","title":"Molecular identification of COL6A3-CSF1 fusion transcripts in tenosynovial giant cell tumors.","date":"2008","source":"Genes, chromosomes & cancer","url":"https://pubmed.ncbi.nlm.nih.gov/17918257","citation_count":83,"is_preprint":false},{"pmid":"1981051","id":"PMC_1981051","title":"Mapping of Col3a1 and Col6a3 to proximal murine chromosome 1 identifies conserved linkage of structural protein genes between murine chromosome 1 and human chromosome 2q.","date":"1990","source":"Genomics","url":"https://pubmed.ncbi.nlm.nih.gov/1981051","citation_count":78,"is_preprint":false},{"pmid":"11785962","id":"PMC_11785962","title":"The C5 domain of Col6A3 is cleaved off from the Col6 fibrils immediately after secretion.","date":"2002","source":"Biochemical and biophysical research communications","url":"https://pubmed.ncbi.nlm.nih.gov/11785962","citation_count":75,"is_preprint":false},{"pmid":"30014607","id":"PMC_30014607","title":"Dermatofibrosarcoma protuberans with a novel COL6A3-PDGFD fusion gene and apparent predilection for breast.","date":"2018","source":"Genes, chromosomes & cancer","url":"https://pubmed.ncbi.nlm.nih.gov/30014607","citation_count":74,"is_preprint":false},{"pmid":"9536084","id":"PMC_9536084","title":"Missense mutation in a von Willebrand factor type A domain of the alpha 3(VI) collagen gene (COL6A3) in a family with Bethlem myopathy.","date":"1998","source":"Human molecular genetics","url":"https://pubmed.ncbi.nlm.nih.gov/9536084","citation_count":73,"is_preprint":false},{"pmid":"24719315","id":"PMC_24719315","title":"COL6A3 expression in adipocytes associates with insulin resistance and depends on PPARγ and adipocyte size.","date":"2014","source":"Obesity (Silver Spring, Md.)","url":"https://pubmed.ncbi.nlm.nih.gov/24719315","citation_count":71,"is_preprint":false},{"pmid":"26004199","id":"PMC_26004199","title":"Recessive mutations in the α3 (VI) collagen gene COL6A3 cause early-onset isolated dystonia.","date":"2015","source":"American journal of human genetics","url":"https://pubmed.ncbi.nlm.nih.gov/26004199","citation_count":71,"is_preprint":false},{"pmid":"25337653","id":"PMC_25337653","title":"COL6A3 is regulated by leptin in human adipose tissue and reduced in obesity.","date":"2015","source":"Endocrinology","url":"https://pubmed.ncbi.nlm.nih.gov/25337653","citation_count":65,"is_preprint":false},{"pmid":"21719059","id":"PMC_21719059","title":"Tumor-specific expression and alternative splicing of the COL6A3 gene in pancreatic cancer.","date":"2011","source":"Surgery","url":"https://pubmed.ncbi.nlm.nih.gov/21719059","citation_count":62,"is_preprint":false},{"pmid":"23564457","id":"PMC_23564457","title":"COL6A3 protein deficiency in mice leads to muscle and tendon defects similar to human collagen VI congenital muscular dystrophy.","date":"2013","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/23564457","citation_count":59,"is_preprint":false},{"pmid":"29620224","id":"PMC_29620224","title":"Role of COL6A3 in colorectal cancer.","date":"2018","source":"Oncology reports","url":"https://pubmed.ncbi.nlm.nih.gov/29620224","citation_count":47,"is_preprint":false},{"pmid":"24002763","id":"PMC_24002763","title":"Clinical significance of serum COL6A3 in pancreatic ductal adenocarcinoma.","date":"2013","source":"Journal of gastrointestinal surgery : official journal of the Society for Surgery of the Alimentary Tract","url":"https://pubmed.ncbi.nlm.nih.gov/24002763","citation_count":45,"is_preprint":false},{"pmid":"28918041","id":"PMC_28918041","title":"Gapmer Antisense Oligonucleotides Suppress the Mutant Allele of COL6A3 and Restore Functional Protein in Ullrich Muscular Dystrophy.","date":"2017","source":"Molecular therapy. Nucleic acids","url":"https://pubmed.ncbi.nlm.nih.gov/28918041","citation_count":44,"is_preprint":false},{"pmid":"10399756","id":"PMC_10399756","title":"A novel de novo mutation in the triple helix of the COL6A3 gene in a two-generation Italian family affected by Bethlem myopathy. A diagnostic approach in the mutations' screening of type VI collagen.","date":"1999","source":"Neuromuscular disorders : NMD","url":"https://pubmed.ncbi.nlm.nih.gov/10399756","citation_count":44,"is_preprint":false},{"pmid":"24563484","id":"PMC_24563484","title":"A mouse model for dominant collagen VI disorders: heterozygous deletion of Col6a3 Exon 16.","date":"2014","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/24563484","citation_count":38,"is_preprint":false},{"pmid":"30876691","id":"PMC_30876691","title":"E2F1-induced upregulation of long non-coding RNA LMCD1-AS1 facilitates cholangiocarcinoma cell progression by regulating miR-345-5p/COL6A3 pathway.","date":"2019","source":"Biochemical and biophysical research communications","url":"https://pubmed.ncbi.nlm.nih.gov/30876691","citation_count":33,"is_preprint":false},{"pmid":"30246318","id":"PMC_30246318","title":"COL6A3-derived endotrophin links reciprocal interactions among hepatic cells in the pathology of chronic liver disease.","date":"2018","source":"The Journal of pathology","url":"https://pubmed.ncbi.nlm.nih.gov/30246318","citation_count":33,"is_preprint":false},{"pmid":"27312141","id":"PMC_27312141","title":"Reduced expression of collagen VI alpha 3 (COL6A3) confers resistance to inflammation-induced MCP1 expression in adipocytes.","date":"2016","source":"Obesity (Silver Spring, Md.)","url":"https://pubmed.ncbi.nlm.nih.gov/27312141","citation_count":32,"is_preprint":false},{"pmid":"23626599","id":"PMC_23626599","title":"Down Syndrome Related Muscle Hypotonia: Association with COL6A3 Functional SNP rs2270669.","date":"2013","source":"Frontiers in genetics","url":"https://pubmed.ncbi.nlm.nih.gov/23626599","citation_count":32,"is_preprint":false},{"pmid":"24518369","id":"PMC_24518369","title":"siRNA-mediated Allele-specific Silencing of a COL6A3 Mutation in a Cellular Model of Dominant Ullrich Muscular Dystrophy.","date":"2014","source":"Molecular therapy. Nucleic acids","url":"https://pubmed.ncbi.nlm.nih.gov/24518369","citation_count":31,"is_preprint":false},{"pmid":"33214660","id":"PMC_33214660","title":"COL6A3 expression in adipose tissue cells is associated with levels of the homeobox transcription factor PRRX1.","date":"2020","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/33214660","citation_count":27,"is_preprint":false},{"pmid":"39856218","id":"PMC_39856218","title":"Integrative proteogenomic analysis identifies COL6A3-derived endotrophin as a mediator of the effect of obesity on coronary artery disease.","date":"2025","source":"Nature genetics","url":"https://pubmed.ncbi.nlm.nih.gov/39856218","citation_count":25,"is_preprint":false},{"pmid":"31122696","id":"PMC_31122696","title":"A circular RNA derived from COL6A3 functions as a ceRNA in gastric cancer development.","date":"2019","source":"Biochemical and biophysical research communications","url":"https://pubmed.ncbi.nlm.nih.gov/31122696","citation_count":24,"is_preprint":false},{"pmid":"24398995","id":"PMC_24398995","title":"Valproic acid substantially downregulated genes folr1, IGF2R, RGS2, COL6A3, EDNRB, KLF6, and pax-3, N-acetylcysteine alleviated most of the induced gene alterations in chicken embryo model.","date":"2013","source":"Romanian journal of morphology and embryology = Revue roumaine de morphologie et embryologie","url":"https://pubmed.ncbi.nlm.nih.gov/24398995","citation_count":18,"is_preprint":false},{"pmid":"29894794","id":"PMC_29894794","title":"Two novel COL6A3 mutations disrupt extracellular matrix formation and lead to myopathy from Ullrich congenital muscular dystrophy and Bethlem myopathy spectrum.","date":"2018","source":"Gene","url":"https://pubmed.ncbi.nlm.nih.gov/29894794","citation_count":18,"is_preprint":false},{"pmid":"39021299","id":"PMC_39021299","title":"A Damaging COL6A3 Variant Alters the MIR31HG-Regulated Response of Chondrocytes in Neocartilage Organoids to Hyperphysiologic Mechanical Loading.","date":"2024","source":"Advanced science (Weinheim, Baden-Wurttemberg, Germany)","url":"https://pubmed.ncbi.nlm.nih.gov/39021299","citation_count":16,"is_preprint":false},{"pmid":"38270688","id":"PMC_38270688","title":"COL6A3 enhances the osteogenic differentiation potential of BMSCs by promoting mitophagy in the osteoporotic microenvironment.","date":"2024","source":"Molecular biology reports","url":"https://pubmed.ncbi.nlm.nih.gov/38270688","citation_count":15,"is_preprint":false},{"pmid":"26872670","id":"PMC_26872670","title":"The role of mutations in COL6A3 in isolated dystonia.","date":"2016","source":"Journal of neurology","url":"https://pubmed.ncbi.nlm.nih.gov/26872670","citation_count":15,"is_preprint":false},{"pmid":"32037012","id":"PMC_32037012","title":"COL6A3 mutation associated early-onset isolated dystonia (DYT)-27: Report of a new case and review of published literature.","date":"2020","source":"Brain & development","url":"https://pubmed.ncbi.nlm.nih.gov/32037012","citation_count":13,"is_preprint":false},{"pmid":"37938972","id":"PMC_37938972","title":"Integration of transcriptomes of senescent cell models with multi-tissue patient samples reveals reduced COL6A3 as an inducer of senescence.","date":"2023","source":"Cell reports","url":"https://pubmed.ncbi.nlm.nih.gov/37938972","citation_count":13,"is_preprint":false},{"pmid":"32696868","id":"PMC_32696868","title":"COL6A3 promotes cellular malignancy of osteosarcoma by activating the PI3K/AKT pathway.","date":"2020","source":"Revista da Associacao Medica Brasileira (1992)","url":"https://pubmed.ncbi.nlm.nih.gov/32696868","citation_count":12,"is_preprint":false},{"pmid":"26687111","id":"PMC_26687111","title":"The clinical phenotype of early-onset isolated dystonia caused by recessive COL6A3 mutations (DYT27).","date":"2015","source":"Movement disorders : official journal of the Movement Disorder Society","url":"https://pubmed.ncbi.nlm.nih.gov/26687111","citation_count":12,"is_preprint":false},{"pmid":"29066004","id":"PMC_29066004","title":"Microstructural white matter abnormalities in patients with COL6A3 mutations (DYT27 dystonia).","date":"2017","source":"Parkinsonism & related disorders","url":"https://pubmed.ncbi.nlm.nih.gov/29066004","citation_count":11,"is_preprint":false},{"pmid":"39125689","id":"PMC_39125689","title":"COL6A3 Exosomes Promote Tumor Dissemination and Metastasis in Epithelial Ovarian Cancer.","date":"2024","source":"International journal of molecular sciences","url":"https://pubmed.ncbi.nlm.nih.gov/39125689","citation_count":10,"is_preprint":false},{"pmid":"33749658","id":"PMC_33749658","title":"Clinical and Molecular Spectrum Associated with COL6A3 c.7447A>G p.(Lys2483Glu) Variant: Elucidating its Role in Collagen VI-related Myopathies.","date":"2021","source":"Journal of neuromuscular diseases","url":"https://pubmed.ncbi.nlm.nih.gov/33749658","citation_count":9,"is_preprint":false},{"pmid":"38855105","id":"PMC_38855105","title":"Integrative analysis of COL6A3 in lupus nephritis: insights from single-cell transcriptomics and proteomics.","date":"2024","source":"Frontiers in immunology","url":"https://pubmed.ncbi.nlm.nih.gov/38855105","citation_count":8,"is_preprint":false},{"pmid":"35530273","id":"PMC_35530273","title":"Everolimus combined with 5-aza-2-deoxycytidine generated potent anti-tumor effects on ovarian clear cell cancer stem-like/spheroid cells by inhibiting the COL6A3-AKT-mTOR pathway.","date":"2022","source":"American journal of cancer research","url":"https://pubmed.ncbi.nlm.nih.gov/35530273","citation_count":7,"is_preprint":false},{"pmid":"33304895","id":"PMC_33304895","title":"Novel Mutations in COL6A3 That Associated With Peters' Anomaly Caused Abnormal Intracellular Protein Retention and Decreased Cellular Resistance to Oxidative Stress.","date":"2020","source":"Frontiers in cell and developmental biology","url":"https://pubmed.ncbi.nlm.nih.gov/33304895","citation_count":7,"is_preprint":false},{"pmid":"33964895","id":"PMC_33964895","title":"Study of the collagen type VI alpha 3 (COL6A3) gene in Parkinson's disease.","date":"2021","source":"BMC neurology","url":"https://pubmed.ncbi.nlm.nih.gov/33964895","citation_count":7,"is_preprint":false},{"pmid":"9694257","id":"PMC_9694257","title":"CA repeat polymorphism of the COL6A3 gene on chromosome 2q37.","date":"1998","source":"Human heredity","url":"https://pubmed.ncbi.nlm.nih.gov/9694257","citation_count":7,"is_preprint":false},{"pmid":"41174767","id":"PMC_41174767","title":"Spatial-reprogramming derived GPNMB+ macrophages interact with COL6A3+ fibroblasts to enhance vascular fibrosis in glioblastoma.","date":"2025","source":"Genome medicine","url":"https://pubmed.ncbi.nlm.nih.gov/41174767","citation_count":5,"is_preprint":false},{"pmid":"2564183","id":"PMC_2564183","title":"An NcoI RFLP associated with the gene encoding the alpha-3 chain of human type VI collagen (COL6A3).","date":"1989","source":"Nucleic acids research","url":"https://pubmed.ncbi.nlm.nih.gov/2564183","citation_count":5,"is_preprint":false},{"pmid":"31134592","id":"PMC_31134592","title":"DNA methylation and mRNA expression of COL6A3 in antler mesenchyme of female and male reindeer.","date":"2019","source":"Genes & genomics","url":"https://pubmed.ncbi.nlm.nih.gov/31134592","citation_count":4,"is_preprint":false},{"pmid":"39497818","id":"PMC_39497818","title":"Corrigendum: Integrative analysis of COL6A3 in lupus nephritis: insights from single-cell transcriptomics and proteomics.","date":"2024","source":"Frontiers in immunology","url":"https://pubmed.ncbi.nlm.nih.gov/39497818","citation_count":4,"is_preprint":false},{"pmid":"31425922","id":"PMC_31425922","title":"Variants in COL6A3 gene influence susceptibility to esophageal cancer in the Chinese population.","date":"2019","source":"Cancer genetics","url":"https://pubmed.ncbi.nlm.nih.gov/31425922","citation_count":4,"is_preprint":false},{"pmid":"32389683","id":"PMC_32389683","title":"Coexistence of digenic mutations in the collagen VI genes (COL6A1 and COL6A3) leads to Bethlem myopathy.","date":"2020","source":"Clinica chimica acta; international journal of clinical chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/32389683","citation_count":4,"is_preprint":false},{"pmid":"32448721","id":"PMC_32448721","title":"Collagen VI-related limb-girdle syndrome caused by frequent mutation in COL6A3 gene with conflicting reports of pathogenicity.","date":"2020","source":"Neuromuscular disorders : NMD","url":"https://pubmed.ncbi.nlm.nih.gov/32448721","citation_count":4,"is_preprint":false},{"pmid":"33596003","id":"PMC_33596003","title":"Collagen VI-Related Myopathy Caused by Compound Heterozygous Mutations of COL6A3 in a Consanguineous Kurdish Family.","date":"2021","source":"Journal of clinical neuromuscular disease","url":"https://pubmed.ncbi.nlm.nih.gov/33596003","citation_count":3,"is_preprint":false},{"pmid":"37082441","id":"PMC_37082441","title":"A novel compound heterozygous mutation of COL6A3 in Chinese patients with isolated cervical dystonia.","date":"2023","source":"Frontiers in neurology","url":"https://pubmed.ncbi.nlm.nih.gov/37082441","citation_count":2,"is_preprint":false},{"pmid":"36779064","id":"PMC_36779064","title":"A novel variant of COL6A3 c.6817-2(IVS27)A>G causing Bethlem myopathy: A case report.","date":"2023","source":"Frontiers in neurology","url":"https://pubmed.ncbi.nlm.nih.gov/36779064","citation_count":2,"is_preprint":false},{"pmid":"37706358","id":"PMC_37706358","title":"Novel COL6A3 frameshift variant in American Staffordshire Terrier dogs with Ullrich-like congenital muscular dystrophy.","date":"2023","source":"Journal of veterinary internal medicine","url":"https://pubmed.ncbi.nlm.nih.gov/37706358","citation_count":2,"is_preprint":false},{"pmid":"35832501","id":"PMC_35832501","title":"Autosomal dominant Ullrich congenital muscular dystrophy due to a de novo mutation in COL6A3 gene. A case report.","date":"2022","source":"Acta myologica : myopathies and cardiomyopathies : official journal of the Mediterranean Society of Myology","url":"https://pubmed.ncbi.nlm.nih.gov/35832501","citation_count":2,"is_preprint":false},{"pmid":"41228242","id":"PMC_41228242","title":"The Role of COL6A3 in Tumorigenesis, Metastasis, Diagnosis, and Disease Management.","date":"2025","source":"Cancers","url":"https://pubmed.ncbi.nlm.nih.gov/41228242","citation_count":1,"is_preprint":false},{"pmid":"36980840","id":"PMC_36980840","title":"Genetic Analysis of HIBM Myopathy-Specific GNE V727M Hotspot Mutation Identifies a Novel COL6A3 Allied Gene Signature That Is Also Deregulated in Multiple Neuromuscular Diseases and Myopathies.","date":"2023","source":"Genes","url":"https://pubmed.ncbi.nlm.nih.gov/36980840","citation_count":1,"is_preprint":false},{"pmid":"36013373","id":"PMC_36013373","title":"Prmt7 Downregulation in Mouse Spermatogonia Functions through miR-877-3p/Col6a3.","date":"2022","source":"Life (Basel, Switzerland)","url":"https://pubmed.ncbi.nlm.nih.gov/36013373","citation_count":1,"is_preprint":false},{"pmid":"40792431","id":"PMC_40792431","title":"Development, validation, and preliminary phenotypic characterization of a Col6a3 knockout mouse model targeting exon 3.","date":"2025","source":"Animal models and experimental medicine","url":"https://pubmed.ncbi.nlm.nih.gov/40792431","citation_count":1,"is_preprint":false},{"pmid":"25449070","id":"PMC_25449070","title":"[Study of a Bethlem myopathy pedigree resulted from a novel mutation of COL6A3 gene].","date":"2014","source":"Zhonghua yi xue yi chuan xue za zhi = Zhonghua yixue yichuanxue zazhi = Chinese journal of medical genetics","url":"https://pubmed.ncbi.nlm.nih.gov/25449070","citation_count":1,"is_preprint":false},{"pmid":"30695889","id":"PMC_30695889","title":"[Clinical manifestations and genetics analysis of collagen type Ⅵ-related myopathy caused by variants in COL6A3 gene].","date":"2019","source":"Zhonghua er ke za zhi = Chinese journal of pediatrics","url":"https://pubmed.ncbi.nlm.nih.gov/30695889","citation_count":1,"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":"41692747","id":"PMC_41692747","title":"A damaging mutation in COL6A3 alters the mechanobiologic response of chondrocytes derived from human induced pluripotent stem cells.","date":"2026","source":"Stem cell research & therapy","url":"https://pubmed.ncbi.nlm.nih.gov/41692747","citation_count":0,"is_preprint":false},{"pmid":"41704606","id":"PMC_41704606","title":"Artificial intelligence driven multi-omics framework identifies COL6A3 as a diagnostic biomarker and a putative gene target modulated by Embelin in Colorectal cancer.","date":"2026","source":"Frontiers in oncology","url":"https://pubmed.ncbi.nlm.nih.gov/41704606","citation_count":0,"is_preprint":false},{"pmid":null,"id":"bio_10.1101_2025.10.06.680821","title":"Splicing Isoforms Associated with TGFβ-Induced Myofibroblast Activation","date":"2025-10-07","source":"bioRxiv","url":"https://doi.org/10.1101/2025.10.06.680821","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2025.08.18.670793","title":"Spatial and Single-Cell Dissection of Fibroblast Subpopulation Reprogramming Driving Stromal Collapse in Breast Cancer Lymph Node Metastasis","date":"2025-08-22","source":"bioRxiv","url":"https://doi.org/10.1101/2025.08.18.670793","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2025.02.20.639288","title":"ETP-Specific Knockout Mice Reveal Endotrophin as a Key Regulator of Kidney Fibrosis in Ischemia-Reperfusion Injury Models","date":"2025-02-26","source":"bioRxiv","url":"https://doi.org/10.1101/2025.02.20.639288","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2025.08.01.667173","title":"Nanoparticle-enabled plasma proteomics of a mouse atherosclerosis model","date":"2025-08-02","source":"bioRxiv","url":"https://doi.org/10.1101/2025.08.01.667173","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2025.04.01.25325047","title":"Airway Spatial Transcriptomics in Smoking","date":"2025-04-03","source":"bioRxiv","url":"https://doi.org/10.1101/2025.04.01.25325047","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2024.09.20.24314065","title":"Plasma proteomics reveals the potential causal impact of extracellular matrix proteins on abdominal aortic aneurysm","date":"2024-09-23","source":"bioRxiv","url":"https://doi.org/10.1101/2024.09.20.24314065","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":37255,"output_tokens":6121,"usd":0.10179,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":15051,"output_tokens":5567,"usd":0.107215,"stage2_stop_reason":"end_turn"},"total_usd":0.209005,"stage1_batch_id":"msgbatch_01ACAxJQabDsht39JXeWG22d","stage2_batch_id":"msgbatch_01QEU22A9U5sbPTgsMzTmvSf","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2002,\n      \"finding\": \"The C5 domain of the COL6A3 α3(VI) chain is synthesized and incorporated into newly formed collagen VI fibrils but is cleaved off immediately after secretion and is absent from the mature pericellular type VI collagen matrix in adult articular cartilage, as shown by confocal laser-scanning microscopy and immunoelectron microscopy with a specific anti-C5 antiserum.\",\n      \"method\": \"Confocal laser-scanning microscopy, immunoelectron microscopy, double-labeling immunostaining\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct localization with two orthogonal microscopy methods tied to functional processing event, single lab\",\n      \"pmids\": [\"11785962\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"Homozygous loss-of-function mutations in COL6A3 (splice-site 6930+5A>G causing exon 29 skipping, and nonsense R2342X) cause Ullrich congenital muscular dystrophy with partial or complete absence of collagen VI in muscle and fibroblasts, establishing COL6A3 as a causal gene for this muscular dystrophy.\",\n      \"method\": \"Microsatellite linkage mapping, Sanger sequencing of COL6A3 mutations, muscle biopsy immunostaining for collagen VI\",\n      \"journal\": \"American journal of human genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — three independent families with distinct mutations, linkage confirmed, protein absence verified in tissue; replicated across labs in subsequent studies\",\n      \"pmids\": [\"11992252\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1998,\n      \"finding\": \"A missense mutation (Gly→Glu) in the von Willebrand factor type A (vWFA/N2) domain of COL6A3 segregates with autosomal dominant Bethlem myopathy in a large pedigree, demonstrating that mutations in the N-terminal globular domain (as well as the triple-helical domain) of COL6A3 can cause Bethlem myopathy.\",\n      \"method\": \"Linkage analysis, Sanger sequencing, segregation analysis in 31 family members, exclusion from 338 control chromosomes\",\n      \"journal\": \"Human molecular genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — mutation segregates perfectly in large pedigree, absent in controls, replicated by subsequent reports of triple-helix mutations\",\n      \"pmids\": [\"9536084\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"A de novo Gly→Arg substitution in the triple-helical coding region of COL6A3 disrupts triple helix structure and causes autosomal dominant Bethlem myopathy, confirming that glycine substitutions in the triple helix of α3(VI) collagen are pathogenic.\",\n      \"method\": \"Clinical description, Sanger sequencing, bioinformatic domain analysis\",\n      \"journal\": \"Neuromuscular disorders\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — de novo mutation with confirmed segregation, single lab but consistent with mechanistic model established by prior studies\",\n      \"pmids\": [\"10399756\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Mice expressing a non-functional α3(VI) collagen chain (Col6a3 mutant) lack extracellular collagen VI microfibrils, show decreased muscle mass and contractile force, and display ultrastructurally abnormal collagen fibrils in tendon but not cornea, indicating a tissue-specific role of COL6A3 in collagen I fibrillogenesis. The C-terminal cleavage product of α3(VI) is not required for normal growth and development.\",\n      \"method\": \"Transgenic mouse model, electron microscopy, muscle contractile force measurements, immunofluorescence, histopathology\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — in vivo knockout model with multiple orthogonal functional readouts (ultrastructure, force, fibrillogenesis) in a single rigorous study\",\n      \"pmids\": [\"23564457\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"Heterozygous deletion of exon 16 in the Col6a3 gene produces a mutant α3(VI) protein that exerts a dominant-negative effect on collagen VI microfibrillar assembly in fibroblasts, recapitulating dominant Ullrich congenital muscular dystrophy; mutant mice develop myopathy with mitochondrial and sarcoplasmic reticulum ultrastructural alterations and compromised muscle contractile function.\",\n      \"method\": \"Targeted gene deletion (mouse model), biosynthetic pulse-chase studies, electron microscopy, muscle contractile function assays\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — reconstitution-level biosynthetic assays demonstrating dominant-negative mechanism, multiple orthogonal phenotypic readouts\",\n      \"pmids\": [\"24563484\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Recessive compound heterozygous mutations in COL6A3, with at least one allele affecting exon 41, cause early-onset isolated dystonia (DYT27) with underlying neurodevelopmental deficits (axonal outgrowth deficits) in zebrafish; Col6a3 is expressed in neurons of the adult mouse brain, placing COL6A3 in a neuronal extracellular matrix pathway distinct from its role in muscle.\",\n      \"method\": \"Whole-exome sequencing, zebrafish morpholino knockdown with in-frame deletions, axonal outgrowth assay, mouse brain in situ hybridization/RT-PCR\",\n      \"journal\": \"American journal of human genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — human genetics in multiple pedigrees plus functional zebrafish model with exon-specific phenotype and neuronal expression confirmed by in situ\",\n      \"pmids\": [\"26004199\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"The t(1;2)(p13;q37) chromosomal translocation generates a COL6A3-CSF1 fusion transcript in tenosynovial giant cell tumors; in-frame fusion products were detected by RT-PCR, with CSF1 breakpoints downstream of exon 5 so the fusion does not encode the CSF1 receptor-binding amino-terminal domain.\",\n      \"method\": \"Cytogenetics, RT-PCR, sequence analysis of breakpoints\",\n      \"journal\": \"Genes, chromosomes & cancer\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — RT-PCR detection confirmed in 3/6 cases with sequencing; mechanistic consequence of fusion remains unclear per the authors\",\n      \"pmids\": [\"17918257\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"COL6A3 undergoes tumor-specific alternative splicing in pancreatic ductal adenocarcinoma, with consistent inclusion of exons 3, 4, and 6 in tumor tissue but not adjacent normal tissue; exon 4 inclusion is exclusively tumor-specific, suggesting cancer-specific isoforms contribute to desmoplastic stroma.\",\n      \"method\": \"RT-PCR with isoform-specific primers, Western blot, immunohistochemistry in paired PDA vs. normal tissues and animal models\",\n      \"journal\": \"Surgery\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — multiple orthogonal detection methods across 18 paired samples and two animal models, single lab\",\n      \"pmids\": [\"21719059\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"siRNA allele-specifically targeting a COL6A3 exon-16 skipping mutation in UCMD patient fibroblasts selectively suppresses mutant transcript expression without affecting the wild-type allele, and treatment considerably improves collagen VI matrix quantity and quality as assessed by confocal microscopy.\",\n      \"method\": \"siRNA allele-specific silencing, quantitative RT-PCR, reporter construct in HEK293T, confocal microscopy of collagen VI matrix\",\n      \"journal\": \"Molecular therapy. Nucleic acids\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — allele-specific silencing with reporter validation plus patient cell functional readout, single lab\",\n      \"pmids\": [\"24518369\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Gapmer antisense oligonucleotides targeting a heterozygous 18-nt deletion mutation in COL6A3 exon 15 selectively suppress mutant transcripts at the mRNA level (more effectively than pre-mRNA targeting) via RNase H recruitment, resulting in increased deposition of collagen VI protein into the extracellular matrix in patient-derived cells.\",\n      \"method\": \"Gapmer AON transfection, RT-PCR/qPCR of allele-specific transcripts, Western blot of collagen VI matrix deposition\",\n      \"journal\": \"Molecular therapy. Nucleic acids\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — mechanism of RNase H-mediated cleavage demonstrated with functional protein rescue, single lab\",\n      \"pmids\": [\"28918041\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"COL6A3 knockdown in human adipocytes increases triglyceride content, lipolysis, insulin-induced Akt phosphorylation, and adipogenic gene expression, and abrogates TNF-α- and LPS-induced MCP1 (CCL2) mRNA expression and secretion; matrix metalloproteinase-11 treatment reduces COL6A3 protein and simultaneously suppresses MCP1 induction, placing COL6A3 upstream of inflammatory MCP1 signaling in adipocytes.\",\n      \"method\": \"Stable shRNA knockdown in immortalized human preadipocytes, MTT/lipolysis/insulin signaling assays, MMP-11 treatment, co-culture with THP1 macrophages, RT-PCR/ELISA\",\n      \"journal\": \"Obesity (Silver Spring, Md.)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal functional assays in stable KD lines plus MMP-11 pharmacologic validation, single lab\",\n      \"pmids\": [\"27312141\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"PPARG knockdown in developing human adipocytes increases COL6A3 mRNA ~1.5-fold, and COL6A3 mRNA is ~2.8-fold higher in small (less mature) compared to large adipocytes, demonstrating that PPARγ-mediated adipocyte differentiation negatively regulates COL6A3 expression.\",\n      \"method\": \"PPARG siRNA knockdown in primary human adipocytes (euglycemic clamp-phenotyped subjects), adipocyte size fractionation from surgical biopsies, RT-qPCR\",\n      \"journal\": \"Obesity (Silver Spring, Md.)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional knockdown plus cell-biological fractionation, single lab, mechanistic link to PPARγ pathway established\",\n      \"pmids\": [\"24719315\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Leptin treatment causes a dose-dependent decrease in COL6A3 expression in human adipose tissue, while insulin and glucose have no effect, demonstrating a direct paracrine regulatory pathway by which leptin modulates extracellular matrix composition through COL6A3.\",\n      \"method\": \"In vitro leptin/insulin/glucose treatment of adipose tissue explants, RT-qPCR, comparison across depot and obesity status\",\n      \"journal\": \"Endocrinology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — dose-response in multiple conditions with dose-dependent effect confirmed, single lab, single method for the mechanistic claim\",\n      \"pmids\": [\"25337653\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"COL6A3-derived endotrophin (ETP, cleaved from the C5 domain) induces JNK-dependent hepatocyte apoptosis and activates non-parenchymal liver cells to promote hepatic inflammation and fibrosis; neutralizing anti-ETP antibodies suppress these pathological consequences in chronic liver disease models.\",\n      \"method\": \"Recombinant ETP treatment of hepatocytes, JNK pathway analysis, neutralizing antibody treatment in chronic liver disease mouse models, co-culture experiments\",\n      \"journal\": \"The Journal of pathology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vitro mechanism (JNK activation) plus in vivo antibody rescue, single lab with multiple readouts\",\n      \"pmids\": [\"30246318\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Two homozygous COL6A3 mutations (p.Val86Ala and p.Arg689Cys) identified in Peters' anomaly patients cause abnormal intracellular retention of mutant COL6A3 protein and reduce cellular resistance to oxidative stress through an enhanced endoplasmic reticulum stress response.\",\n      \"method\": \"Patient exome/panel sequencing, immunofluorescence for protein localization, ER stress markers, oxidative stress assays in cell lines expressing mutant protein\",\n      \"journal\": \"Frontiers in cell and developmental biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional assays of ER retention and oxidative stress with mutant protein, single lab with multiple readouts\",\n      \"pmids\": [\"33304895\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"COL6A3 overexpression in bone marrow mesenchymal stem cells (BMSCs) promotes mitophagy (colocalization of mitochondria and lysosomes, restored mitochondrial membrane potential), enhances osteogenic and adipogenic differentiation, and reduces LPS-induced inflammatory mediator expression (iNOS, COX-2); blockade of mitophagy with Mdivi-1 abolishes these COL6A3-mediated effects.\",\n      \"method\": \"Lentiviral COL6A3 overexpression, Western blot, TUNEL apoptosis, JC-1 staining, immunofluorescence colocalization, mitophagy inhibitor (Mdivi-1) rescue experiment\",\n      \"journal\": \"Molecular biology reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — pharmacological rescue experiment (Mdivi-1) placing COL6A3 upstream of mitophagy, multiple orthogonal assays, single lab\",\n      \"pmids\": [\"38270688\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Experimental knockdown of COL6A3 induces transcriptional changes overlapping with the majority of experimental senescence models, with cell-cycle arrest linked to modulation of DREAM complex-targeted genes, identifying COL6A3 as a functional inducer of cellular senescence.\",\n      \"method\": \"COL6A3 siRNA knockdown, RNA-seq transcriptome comparison across 10 senescence models, DREAM complex gene-set analysis\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional KD with transcriptomic integration across 10 models, pathway placement via DREAM complex, single lab\",\n      \"pmids\": [\"37938972\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"PRRX1 transcription factor directly transactivates the human COL6A3 promoter (reporter assay), and PRRX1 knockdown reduces COL6A3 mRNA in human and mouse adipose cells; TGF-β1 upregulates Col6a3 mRNA while TNF-α decreases PRRX1-mediated transactivation, placing PRRX1 as a transcriptional regulator of COL6A3 in adipose tissue.\",\n      \"method\": \"PRRX1 knockdown and overexpression, COL6A3 promoter-reporter luciferase assay, qRT-PCR in human/mouse adipose cells, TGF-β1 and TNF-α treatment\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — promoter reporter plus KD/OE in two cell types with cytokine modulation, single lab\",\n      \"pmids\": [\"33214660\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"A damaging COL6A3 variant introduced by CRISPR-Cas9 into iPSC-derived neocartilage organoids results in significantly lower binding between pericellular matrix proteins COL6A3 and fibronectin, provokes an osteoarthritic chondrocyte state, and abolishes the characteristic inflammatory signaling response (PTGS2, PECAM1, ADAMTS5) to hyperphysiological mechanical loading; the lncRNA MIR31HG is identified as a key epigenetic regulator of this loading response.\",\n      \"method\": \"CRISPR-Cas9 genome editing of iPSC-derived neocartilage organoids, multi-omics (mRNA and lncRNA), protein binding assay, mechanical loading\",\n      \"journal\": \"Advanced science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — CRISPR reconstitution in organoid model, multi-omics plus direct protein binding assay, multiple orthogonal readouts in single study\",\n      \"pmids\": [\"39021299\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"A damaging COL6A3 variant in iPSC-derived chondrocytes reduces pericellular matrix (PCM) elastic modulus, reduces expression of key matrix proteins, causes heightened osmotically-induced calcium signaling (consistent with reduced PCM stiffness), reduces anabolic response to TRPV4 activation, disrupts circadian rhythms (increased BMAL1, phase shift), and exacerbates catabolic response to IL-1, demonstrating that COL6A3 regulates chondrocyte mechanotransduction via PCM mechanical properties.\",\n      \"method\": \"CRISPR-edited iPSC-derived chondrocytes, atomic force microscopy of PCM modulus, calcium imaging, TRPV4 activation assays, RNA-seq, circadian rhythm analysis, IL-1 stimulation\",\n      \"journal\": \"Stem cell research & therapy\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — CRISPR reconstitution with direct biomechanical measurement (AFM) and multiple functional readouts in a rigorous single study\",\n      \"pmids\": [\"41692747\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"ETP-specific knockout mice (ETPKO), generated by inserting lox2272 sites into the Col6a3 locus to selectively ablate ETP while preserving Col6a3 expression, show that ETP depletion significantly attenuates kidney fibrosis progression in ischemia-reperfusion injury, establishing endotrophin as a key driver of fibrosis independently of the full COL6A3 protein.\",\n      \"method\": \"Cre-lox ETP-specific knockout mouse generation, genomic sequencing confirmation, mCherry reporter, renal ischemia-reperfusion injury model, fibrosis quantification\",\n      \"journal\": \"bioRxiv (preprint)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — novel ETP-specific KO with in vivo disease model; strong mechanistic specificity but preprint, single lab\",\n      \"pmids\": [],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Integrative Mendelian randomization and colocalization identified COL6A3-derived endotrophin as mediating the effect of obesity (BMI) on coronary artery disease risk; body fat reduction decreases plasma endotrophin levels, implicating ETP as a tractable circulating mediator linking adiposity to cardiovascular disease.\",\n      \"method\": \"Two-step proteome-wide Mendelian randomization, Bayesian colocalization, single-cell RNA sequencing, epigenomics, clinical intervention (fat loss) studies\",\n      \"journal\": \"Nature genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic causal inference with colocalization plus intervention data, multiple methods; no direct in vitro/in vivo functional experiment on ETP mechanism per se\",\n      \"pmids\": [\"39856218\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"COL6A3 exon 4 inclusion is identified as one of a 5-ASE signature specifically associated with TGFβ-induced myofibroblast differentiation in primary skin fibroblasts, validated by ddPCR and AS-PCR and retrieved in multiple independent RNA-seq datasets of TGFβ-stimulated lung and skin fibroblasts.\",\n      \"method\": \"RNA-seq, ddPCR, AS-PCR in primary skin fibroblasts, validation in public lung/skin fibroblast datasets\",\n      \"journal\": \"bioRxiv (preprint)\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — preprint, single-method per validation assay, no functional consequence of the COL6A3 exon 4 inclusion specifically demonstrated\",\n      \"pmids\": [],\n      \"is_preprint\": true\n    }\n  ],\n  \"current_model\": \"COL6A3 encodes the α3 chain of type VI collagen, which is required for extracellular collagen VI microfibril assembly; the C5 (endotrophin) domain is cleaved from assembled fibrils immediately after secretion and acts as a bioactive signaling peptide that drives fibrosis, TGF-β-like EMT, and cardiometabolic disease; loss-of-function mutations in COL6A3 cause a spectrum of collagen VI-related myopathies (Ullrich CMDs/Bethlem myopathy) through dominant-negative or haploinsufficient disruption of microfibrillar assembly, while tissue-specific recessive mutations affecting exon 41 impair neuronal extracellular matrix function to cause isolated dystonia (DYT27); in chondrocytes, COL6A3 constitutes the pericellular matrix and directly regulates mechanotransduction through its influence on PCM elastic modulus and TRPV4 signaling; in adipose tissue COL6A3 expression is regulated by PPARγ, leptin (negatively), and the transcription factor PRRX1, and modulates inflammatory MCP1 signaling upstream of the PI3K/Akt pathway.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"COL6A3 encodes the α3 chain of type VI collagen, an extracellular matrix component required for assembly of collagen VI microfibrils that organize the pericellular and interstitial matrix; loss of functional α3(VI) in vivo abolishes collagen VI microfibrils and produces decreased muscle mass, reduced contractile force, and tissue-specific defects in collagen I fibrillogenesis [#4]. Homozygous loss-of-function mutations cause Ullrich congenital muscular dystrophy with absence of collagen VI from muscle and fibroblasts [#1], while glycine substitutions in the triple-helical domain and mutations in the N-terminal von Willebrand factor type A domain cause Bethlem myopathy [#2, #3]; in-frame mutant chains act through a dominant-negative effect on microfibrillar assembly [#5]. Recessive mutations affecting exon 41 instead impair a neuronal extracellular matrix function, producing isolated dystonia (DYT27) with axonal outgrowth deficits, distinct from the muscle disease [#6]. The C-terminal C5 domain of α3(VI) is cleaved immediately after secretion and is absent from the mature matrix [#0]; this cleaved product, endotrophin, functions as a bioactive peptide that activates JNK-dependent hepatocyte apoptosis and drives inflammation and fibrosis, effects suppressed by neutralizing antibodies or by ETP-specific ablation [#14, #21], and links adiposity to coronary artery disease risk [#22]. In chondrocytes, COL6A3 binds fibronectin within the pericellular matrix and sets PCM elastic modulus, thereby governing mechanotransduction through osmotic calcium signaling and TRPV4-dependent anabolic responses, with damaging variants provoking an osteoarthritic state [#19, #20]. In adipocytes, COL6A3 expression is driven by the transcription factor PRRX1 and negatively regulated by PPARγ-mediated differentiation and leptin, and COL6A3 acts upstream of inflammatory MCP1/CCL2 signaling and insulin/Akt responses [#11, #12, #13, #18].\",\n  \"teleology\": [\n    {\n      \"year\": 1998,\n      \"claim\": \"Established that mutations in the N-terminal globular vWFA domain of α3(VI), not only the triple helix, are pathogenic, broadening the mutational basis of Bethlem myopathy.\",\n      \"evidence\": \"Linkage and segregation of a Gly→Glu vWFA missense mutation in a large pedigree, excluded in controls\",\n      \"pmids\": [\"9536084\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not establish how the vWFA mutation perturbs microfibril assembly biochemically\", \"No tissue-level collagen VI quantification\"]\n    },\n    {\n      \"year\": 1999,\n      \"claim\": \"Confirmed that glycine substitutions disrupting the α3(VI) triple helix cause dominant Bethlem myopathy, anchoring the triple-helix structural mechanism.\",\n      \"evidence\": \"Sanger sequencing and domain analysis of a de novo Gly→Arg substitution\",\n      \"pmids\": [\"10399756\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single family\", \"No functional assembly assay of the mutant chain\"]\n    },\n    {\n      \"year\": 2002,\n      \"claim\": \"Demonstrated that the C5 domain is incorporated into nascent fibrils but cleaved off immediately after secretion, defining COL6A3 as the source of a secreted, post-assembly processing product later recognized as endotrophin.\",\n      \"evidence\": \"Confocal and immunoelectron microscopy with anti-C5 antiserum in articular cartilage\",\n      \"pmids\": [\"11785962\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Did not identify the protease responsible for cleavage\", \"Function of the cleaved C5 fragment not addressed\"]\n    },\n    {\n      \"year\": 2002,\n      \"claim\": \"Established COL6A3 as a causal gene for Ullrich congenital muscular dystrophy via recessive loss-of-function alleles, tying disease to collagen VI absence.\",\n      \"evidence\": \"Linkage mapping, mutation sequencing, and muscle/fibroblast collagen VI immunostaining across three families\",\n      \"pmids\": [\"11992252\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not resolve the molecular consequence on microfibril architecture\", \"Genotype–phenotype severity correlation not established\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Showed in vivo that functional α3(VI) is required for collagen VI microfibril formation, muscle force, and tissue-specific collagen I fibrillogenesis, and that the C-terminal cleavage product is dispensable for normal development.\",\n      \"evidence\": \"Col6a3 mutant mouse with EM, contractile force, and fibrillogenesis readouts\",\n      \"pmids\": [\"23564457\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not test pathological roles of the cleaved product under disease/stress\", \"Mechanism of tendon-specific (not corneal) fibril defect unresolved\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Defined the dominant-negative mechanism by which in-frame mutant α3(VI) chains poison microfibrillar assembly, explaining dominant UCMD.\",\n      \"evidence\": \"Exon-16-deletion mouse with biosynthetic pulse-chase, EM, and contractile assays\",\n      \"pmids\": [\"24563484\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not quantify the stoichiometric threshold of mutant incorporation needed for dominance\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Introduced allele-specific silencing as a strategy to rescue collagen VI matrix in UCMD by selectively knocking down the dominant-negative mutant transcript.\",\n      \"evidence\": \"Allele-specific siRNA in patient fibroblasts with reporter validation and confocal matrix readout\",\n      \"pmids\": [\"24518369\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No in vivo efficacy\", \"Single mutation context\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Identified PPARγ-driven adipocyte differentiation as a negative regulator of COL6A3, embedding the gene in adipose ECM remodeling.\",\n      \"evidence\": \"PPARG siRNA knockdown and adipocyte size fractionation with RT-qPCR\",\n      \"pmids\": [\"24719315\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Indirect regulation; no direct promoter binding shown\", \"Single lab\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Established leptin as a direct paracrine repressor of COL6A3 in adipose tissue, distinguishing it from glucose/insulin inputs.\",\n      \"evidence\": \"Dose-response leptin/insulin/glucose treatment of adipose explants with RT-qPCR\",\n      \"pmids\": [\"25337653\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism of leptin-to-COL6A3 transcriptional repression not defined\", \"Single method for the mechanistic claim\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Revealed a tissue-specific neuronal function for COL6A3 distinct from muscle, with exon-41-dependent recessive mutations causing isolated dystonia (DYT27).\",\n      \"evidence\": \"Whole-exome sequencing in pedigrees, zebrafish axonal outgrowth assay, and mouse brain expression\",\n      \"pmids\": [\"26004199\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular role of exon 41 in neuronal ECM unresolved\", \"No mammalian neuronal phenotype model\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Extended allele-specific suppression with gapmer antisense oligonucleotides acting at the mRNA level via RNase H, restoring collagen VI deposition.\",\n      \"evidence\": \"Gapmer AON transfection in patient cells with allele-specific qPCR and matrix Western blot\",\n      \"pmids\": [\"28918041\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No in vivo delivery\", \"Mutation-specific design limits generalizability\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Placed COL6A3 upstream of inflammatory MCP1/CCL2 signaling and metabolic regulation in adipocytes, linking the matrix protein to insulin sensitivity and lipid handling.\",\n      \"evidence\": \"Stable shRNA knockdown in human adipocytes with lipolysis/insulin assays, MMP-11 treatment, and macrophage co-culture\",\n      \"pmids\": [\"27312141\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether the effect requires intact matrix versus the cleaved fragment not separated\", \"Single lab\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Defined endotrophin (cleaved C5) as a bioactive driver of hepatocyte apoptosis, inflammation, and fibrosis amenable to antibody neutralization, giving the post-secretion fragment a pathological function.\",\n      \"evidence\": \"Recombinant ETP treatment with JNK analysis and neutralizing antibody rescue in chronic liver disease models\",\n      \"pmids\": [\"30246318\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"ETP receptor/binding partner not identified\", \"Single lab\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Identified COL6A3 mutations causing intracellular retention and heightened ER/oxidative stress in Peters' anomaly, adding a proteostatic disease mechanism.\",\n      \"evidence\": \"Patient sequencing with mutant protein localization and ER/oxidative stress assays in cell lines\",\n      \"pmids\": [\"33304895\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No animal model of the ocular phenotype\", \"Causal chain from ER stress to malformation not established\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Established PRRX1 as a direct transcriptional activator of COL6A3 integrating TGF-β and TNF-α inputs in adipose tissue.\",\n      \"evidence\": \"Promoter-reporter luciferase plus PRRX1 knockdown/overexpression and cytokine treatment in adipose cells\",\n      \"pmids\": [\"33214660\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"In vivo relevance of PRRX1–COL6A3 axis not tested\", \"Single lab\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Linked COL6A3 to mitophagy-dependent differentiation and anti-inflammatory effects in mesenchymal stem cells.\",\n      \"evidence\": \"Lentiviral overexpression with mitophagy markers and Mdivi-1 inhibitor rescue\",\n      \"pmids\": [\"38270688\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism connecting an ECM protein to intracellular mitophagy unexplained\", \"Overexpression-only, single lab\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Identified COL6A3 as a functional inducer of cellular senescence acting through DREAM-complex-targeted cell-cycle genes.\",\n      \"evidence\": \"COL6A3 siRNA knockdown with RNA-seq comparison across 10 senescence models and DREAM gene-set analysis\",\n      \"pmids\": [\"37938972\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct molecular link between COL6A3 and DREAM regulation not defined\", \"Correlative transcriptomics\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Showed via CRISPR organoid reconstitution that COL6A3 binds fibronectin in the pericellular matrix and is required for the inflammatory response to mechanical loading, with MIR31HG as an epigenetic regulator.\",\n      \"evidence\": \"CRISPR-edited iPSC neocartilage organoids with protein binding assay, mechanical loading, and multi-omics\",\n      \"pmids\": [\"39021299\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanistic role of MIR31HG downstream of COL6A3 not resolved\", \"Loading-response signaling intermediates not fully mapped\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Demonstrated that COL6A3 sets PCM elastic modulus to control chondrocyte mechanotransduction, calcium/TRPV4 signaling, circadian rhythm, and IL-1 catabolic responses.\",\n      \"evidence\": \"CRISPR-edited iPSC chondrocytes with AFM modulus measurement, calcium imaging, TRPV4 assays, RNA-seq, and IL-1 stimulation\",\n      \"pmids\": [\"41692747\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How reduced PCM stiffness mechanistically couples to TRPV4 not fully defined\", \"In vivo cartilage phenotype not tested\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Provided ETP-specific genetic ablation showing endotrophin drives fibrosis independently of full-length COL6A3.\",\n      \"evidence\": \"Cre-lox ETP-specific knockout mice in renal ischemia-reperfusion model (preprint)\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Preprint, single lab\", \"ETP downstream receptor/signaling in kidney not identified\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Used genetic causal inference to position circulating endotrophin as a mediator linking obesity to coronary artery disease, suggesting therapeutic tractability.\",\n      \"evidence\": \"Two-step Mendelian randomization, colocalization, single-cell RNA-seq, and fat-loss intervention\",\n      \"pmids\": [\"39856218\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No direct in vitro/in vivo ETP cardiovascular mechanism\", \"Causal estimate, not experimental\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The protease(s) that cleave the C5/endotrophin domain and the receptor through which endotrophin signals remain unidentified, leaving the central bioactive axis mechanistically incomplete.\",\n      \"evidence\": \"No timeline discovery identifies the ETP-cleaving enzyme or ETP receptor\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"ETP receptor unknown\", \"ETP-generating protease unknown\", \"Direct molecular link between matrix loss and intracellular phenotypes (mitophagy, senescence) unresolved\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0005198\", \"supporting_discovery_ids\": [4, 5, 1]},\n      {\"term_id\": \"GO:0048018\", \"supporting_discovery_ids\": [14, 21, 22]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0031012\", \"supporting_discovery_ids\": [0, 4, 19]},\n      {\"term_id\": \"GO:0005576\", \"supporting_discovery_ids\": [0, 10]},\n      {\"term_id\": \"GO:0005783\", \"supporting_discovery_ids\": [15]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1474244\", \"supporting_discovery_ids\": [4, 5, 19]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [1, 2, 6]}\n    ],\n    \"complexes\": [\"collagen VI microfibril\"],\n    \"partners\": [\"CSF1\", \"FN1\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"faith_supported":6,"faith_total":6,"faith_pct":100.0}}