{"gene":"COL11A1","run_date":"2026-04-28T17:28:53","timeline":{"discoveries":[{"year":1995,"finding":"COL11A1 (Col11a1) is essential for normal cartilage collagen fibril formation and cohesive properties of cartilage; homozygous loss-of-function mutation (frameshift/premature stop) in cho/cho mice causes chondrodysplasia with abnormally wide, short limb bones and disrupted growth plate chondrocyte organization.","method":"Mouse genetic model (cho/cho autosomal recessive mutation), linkage analysis, mRNA sequencing, histology","journal":"Cell","confidence":"High","confidence_rationale":"Tier 1-2 — foundational genetic model with molecular identification of causal mutation, replicated across multiple tissues and developmental stages","pmids":["7859283"],"is_preprint":false},{"year":1995,"finding":"Alternative splicing of Col11a1 exons 6A and 6B produces isoforms with distinct acidic or basic N-terminal peptides; the two isoforms show tissue-specific distribution in mouse embryo (exon 6B predominant in vertebrae and skeletal muscle; exon 6A in smooth muscle of intestine, aorta, lung), suggesting distinct contributions to tissue-specific matrix assembly.","method":"In situ hybridization with exon-specific cDNA probes, immunohistochemistry with peptide-specific antibodies in mouse embryo tissues","journal":"Genomics / Matrix biology","confidence":"Medium","confidence_rationale":"Tier 2 — two orthogonal localization methods in mouse embryo, but functional consequence is correlative","pmids":["8530046","11246003"],"is_preprint":false},{"year":1995,"finding":"Col11a1 transcripts are expressed developmentally from embryonic day 11 in mouse, predominantly in cartilaginous tissues (chondrocranium, developing limbs) but also in neuro-epithelium, odontoblasts, trabecular bone, atrioventricular valve, tongue, intestine, and otic vesicle, indicating broader expression than previously thought and suggesting the α1(XI) chain may form tissue-specific trimers.","method":"In situ hybridization on mouse embryo sections","journal":"Developmental dynamics","confidence":"Medium","confidence_rationale":"Tier 2 — direct in situ hybridization localization across multiple developmental time points","pmids":["8563024"],"is_preprint":false},{"year":1996,"finding":"A Gly97Val substitution in the triple helical domain of COL11A1 causes Stickler syndrome type 2 with vitreous and retinal abnormalities, establishing COL11A1 as a structural component of human vitreous and demonstrating that dominant-negative glycine substitutions in the triple helix disrupt vitreous collagen architecture.","method":"Linkage analysis, single-base mutation identification (G→T), genotype-phenotype correlation in affected family","journal":"Human molecular genetics","confidence":"High","confidence_rationale":"Tier 2 — first mutation characterization linking COL11A1 to vitreous structure, replicated by subsequent studies","pmids":["8872475"],"is_preprint":false},{"year":1998,"finding":"A splice-donor-site mutation (G+1→A) in COL11A1 causes in-frame skipping of a 54-bp exon, deleting amino acids 726–743 from the major triple-helical domain, and segregates with Marshall syndrome, demonstrating that α1(XI) collagen structural integrity in the triple-helical domain is required for normal skeletal morphogenesis.","method":"Mutation identification and cosegregation analysis, RT-PCR/splicing characterization of mutant transcript","journal":"American journal of human genetics","confidence":"High","confidence_rationale":"Tier 2 — molecular characterization of splice mutation with in-frame deletion confirmed at RNA level, cosegregation in large kindred","pmids":["9529347"],"is_preprint":false},{"year":1999,"finding":"Splicing mutations that cause in-frame skipping of specific 54-bp exons in the C-terminal region of COL11A1 produce a dominant-negative truncated α1(XI) chain and are specifically associated with the Marshall syndrome phenotype, whereas null-allele mutations in COL2A1 produce classic Stickler syndrome; this genotype-phenotype correlation reveals that the C-terminal triple-helical region of COL11A1 is critical for craniofacial/skeletal morphogenesis.","method":"Genomic structure characterization of COL11A1, mutation screening of 23 novel mutations, genotype-phenotype correlation","journal":"American journal of human genetics","confidence":"High","confidence_rationale":"Tier 2 — systematic mutation analysis in large patient cohort with clear genotype-phenotype correlation, replicated across multiple families","pmids":["10486316"],"is_preprint":false},{"year":2001,"finding":"COL11A1 expression in colorectal tumors is associated with an active APC/β-catenin (Wnt) signaling pathway; COL11A1 upregulation co-occurs with WISP-1 (a Wnt target), suggesting Wnt pathway activation drives stromal COL11A1 expression.","method":"RT-PCR differential display, FAP patient tissue analysis, correlation with Wnt pathway markers in 37 sporadic colorectal carcinomas","journal":"BMC cancer","confidence":"Low","confidence_rationale":"Tier 3 — correlative expression data in tissue specimens, no direct functional perturbation of the pathway","pmids":["11707154"],"is_preprint":false},{"year":2001,"finding":"In Col11a1 mutant (cho/cho) mice, cleft palate arises primarily because mandibular growth disruption prevents palatal shelf contact, not from intrinsic failure of medial-edge epithelium (MEE) to undergo epithelial-mesenchymal transformation; cho/cho palatal shelves retain full EMT capacity when brought into contact in vitro.","method":"In vitro palatal shelf culture, carboxydichlorofluorescein succinimidyl ester fate-tracing of MEE","journal":"Archives of oral biology","confidence":"Medium","confidence_rationale":"Tier 2 — direct functional rescue experiment with cell-tracing in the cho/cho mouse model","pmids":["11420059"],"is_preprint":false},{"year":2003,"finding":"The transcription factor CBF/NF-Y directly binds an ATTGG sequence in the proximal COL11A1 promoter (−147 to −121 region) and is required for basal transcriptional activation; dominant-negative NF-Y significantly inhibits promoter activity.","method":"EMSA, chromatin immunoprecipitation, interference/supershift assays, transient and stable transfection reporter assays, DNA-affinity-purified protein binding","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1-2 — multiple orthogonal methods (EMSA, ChIP, reporter assays, dominant-negative) demonstrating direct in vivo and in vitro binding","pmids":["12805369"],"is_preprint":false},{"year":2004,"finding":"Col11a1 mRNA is expressed in the greater epithelial ridge as the main source for the tectorial membrane in the developing mouse cochlea, with later focal expression in inner sulcus and Claudius'/Boettcher's cells; this localization defines the cochlear cell populations responsible for type XI collagen in the tectorial/basilar membranes and underlies hearing function.","method":"In situ hybridization on mouse temporal bones at multiple developmental time points","journal":"Acta oto-laryngologica","confidence":"Medium","confidence_rationale":"Tier 2 — direct localization experiment tied to known functional consequence (hearing loss) in the COL11A1 disease model","pmids":["15141750"],"is_preprint":false},{"year":2003,"finding":"Col11a1 haploinsufficiency (cho/+ heterozygotes) does not cause significant hearing loss in mice; therefore, Stickler/Marshall syndrome COL11A1 mutations cause hearing loss via dominant-negative effects on wild-type fibrillar collagen polypeptides in the cochlear extracellular matrix, not through simple haploinsufficiency.","method":"Auditory brainstem response (ABR) threshold measurement in cho/+ versus +/+ mice at multiple ages","journal":"Hearing research","confidence":"Medium","confidence_rationale":"Tier 2 — direct functional audiological assay in genetically defined mouse model, establishes mechanism of pathogenicity","pmids":["12527136"],"is_preprint":false},{"year":2009,"finding":"In zebrafish, col11a1 knockdown disrupts craniofacial cartilage formation and notochord morphology; chondrocyte spatial organization, cartilage element shaping, and chondrocyte hypertrophic maturation are all impaired; knockdown also increases col2a1 expression and results in abnormally thick, sparse fibrils in cartilage ECM, demonstrating that col11a1 regulates fibril diameter and chondrocyte differentiation.","method":"Morpholino-based knockdown in zebrafish, in situ hybridization, real-time PCR, histology/electron microscopy of cartilage ECM","journal":"Matrix biology","confidence":"High","confidence_rationale":"Tier 2 — morpholino loss-of-function with multiple orthogonal readouts (histology, gene expression, fibril analysis) in zebrafish ortholog","pmids":["19638309"],"is_preprint":false},{"year":2010,"finding":"Biallelic loss-of-function COL11A1 mutations (compound heterozygosity for null allele + glycine substitution) cause fibrochondrogenesis, a severe lethal skeletal dysplasia, establishing that complete loss of α1(XI) collagen function is more severe than heterozygous dominant-negative mutations causing Stickler/Marshall syndrome.","method":"Whole-genome SNP genotyping, autozygosity mapping, mutation sequencing in two independent fibrochondrogenesis cases","journal":"American journal of human genetics","confidence":"High","confidence_rationale":"Tier 2 — genetic evidence from multiple independent cases with distinct mutations, clear dose-dependent genotype-phenotype relationship","pmids":["21035103"],"is_preprint":false},{"year":2011,"finding":"The amino-terminal non-collagenous domain of collagen α1(XI), displayed on the surface of heterotypic cartilage collagen fibrils, interacts with proteoglycans, other collagens, and matricellular molecules; affinity chromatography with this domain from fetal bovine cartilage identified multiple ECM binding partners by LC-MS/MS, supporting a role for the N-terminal domain in fibrillogenesis regulation.","method":"Affinity chromatography with recombinant N-terminal domain, liquid chromatography/tandem mass spectrometry (LC-MS/MS) protein identification","journal":"Proteomics","confidence":"Medium","confidence_rationale":"Tier 2 — direct affinity-based pulldown with mass spectrometric identification of binding partners, but without functional validation of individual interactions","pmids":["22038862"],"is_preprint":false},{"year":2013,"finding":"Alternative splicing of exon 9 of COL11A1 modifies the phenotypic severity of biallelic mutations; alleles that retain exon 9 splicing can produce a normal α1(XI) procollagen molecule, converting the phenotype from fibrochondrogenesis to recessive Stickler syndrome type 2 with profound hearing loss.","method":"Mutation sequencing, minigene splicing reporter assays, allele-specific RT-PCR, clinical phenotyping","journal":"Journal of medical genetics","confidence":"High","confidence_rationale":"Tier 1-2 — functional splicing assays combined with allele-specific RT-PCR and clear genotype-phenotype correlation in multiple families","pmids":["23922384"],"is_preprint":false},{"year":2013,"finding":"NF-Y (nuclear factor Y) directly binds an ATTGG sequence in the proximal Col11a1 promoter in chondrocytes and is required for its activity; dominant-negative NF-YA inhibits promoter activity, and ChIP confirms in vivo binding.","method":"Transient transfection reporter assays, EMSA, chromatin immunoprecipitation, siRNA/dominant-negative overexpression in chondrocytes","journal":"In vitro cellular & developmental biology","confidence":"High","confidence_rationale":"Tier 1-2 — multiple orthogonal methods (EMSA, ChIP, reporter, dominant-negative) confirming direct regulation in chondrocytes","pmids":["24092017"],"is_preprint":false},{"year":2014,"finding":"COL11A1/procollagen 11A1 is expressed by TGF-β1-activated immortalized human bone marrow mesenchymal cells and by cancer-associated fibroblasts (CAFs) of human colon adenocarcinoma, but not by normal fibroblasts or normal colon stromal cells; proCOL11A1+ CAFs co-express vimentin and αSMA (myofibroblast markers).","method":"qRT-PCR, immunocytochemistry with validated anti-proCOL11A1 monoclonal antibody, immunohistochemistry of colon adenocarcinomas and normal tissues","journal":"BMC cancer","confidence":"Medium","confidence_rationale":"Tier 2 — direct protein localization with validated antibody plus expression analysis, functional context defined by TGF-β1 activation","pmids":["25417197"],"is_preprint":false},{"year":2015,"finding":"COL11A1 promotes chemoresistance in ovarian cancer cells through activation of the Akt/C/EBPβ signaling pathway; COL11A1 binds to PDK1, attenuates PDK1 ubiquitination and degradation, and thereby stabilizes PDK1 to promote cell survival; C/EBPβ binding to the COL11A1 promoter drives cisplatin/paclitaxel-induced COL11A1 upregulation.","method":"Co-immunoprecipitation, immunofluorescence, shRNA knockdown, COL11A1 overexpression, ubiquitination assay, promoter binding assay, microarray analysis","journal":"Oncotarget","confidence":"High","confidence_rationale":"Tier 1-2 — Co-IP demonstrating COL11A1-PDK1 interaction, ubiquitination assay, promoter characterization, and functional rescue experiments","pmids":["26087191"],"is_preprint":false},{"year":2015,"finding":"Col11a1 depletion in mice results in altered trabecular bone microstructure and increased bone collar thickness during endochondral ossification, demonstrating a role for Col11a1 in regulating bone microarchitecture and mineralization during embryonic development.","method":"X-ray microtomography (micro-CT), histology of Col11a1-deficient versus wild-type mice","journal":"Journal of developmental biology","confidence":"Medium","confidence_rationale":"Tier 2 — direct skeletal phenotyping in Col11a1-null mice with quantitative micro-CT","pmids":["26779434"],"is_preprint":false},{"year":2015,"finding":"Sp1 transcription factor upregulates Col11a1 proximal promoter activity by binding a GC-rich element (−96 to −67) in chondrocytes; Sp1 siRNA knockdown suppresses endogenous Col11a1 transcript levels.","method":"Luciferase reporter assays with deletion/mutation constructs, in silico analysis, Sp1 overexpression and siRNA knockdown in chondrocytes","journal":"In vitro cellular & developmental biology","confidence":"Medium","confidence_rationale":"Tier 2 — reporter assays and siRNA knockdown demonstrating functional role, consistent with NF-Y mechanism from prior work","pmids":["26487428"],"is_preprint":false},{"year":2016,"finding":"COL11A1 promotes ovarian cancer chemoresistance by activating NF-κB signaling via increased SP1 phosphorylation and ERK activation, leading to IKKβ upregulation and TWIST1/Mcl-1/GAS6 expression; COL11A1 siRNA knockdown increases chemosensitivity to cisplatin and paclitaxel via downregulated TWIST1.","method":"siRNA knockdown, western blotting, reporter assays, SP1 phosphorylation analysis, gene expression profiling in ovarian cancer cell lines","journal":"International journal of cancer","confidence":"Medium","confidence_rationale":"Tier 2 — functional knockdown with defined downstream pathway intermediates (SP1→IKKβ→TWIST1)","pmids":["28815582"],"is_preprint":false},{"year":2016,"finding":"COL11A1 overexpression promotes NSCLC cell proliferation, migration, invasion, and cisplatin resistance in vitro; these effects are mediated through Smad signaling; COL11A1 suppression by shRNA causes G1-phase cell cycle arrest and reduced cyclin D1, and elevated p21/cleaved caspase-3.","method":"shRNA knockdown, cell proliferation/migration/invasion assays, western blotting, cDNA microarray analysis with RT-PCR validation","journal":"Oncology reports","confidence":"Medium","confidence_rationale":"Tier 2 — functional KD/OE experiments with molecular pathway characterization in NSCLC cell lines","pmids":["27373316"],"is_preprint":false},{"year":2018,"finding":"A canonical acceptor splice-site variant (c.652-2A>C) in COL11A1 confirmed in vitro to alter RNA splicing causes autosomal dominant nonsyndromic hearing loss (DFNA37), expanding the COL11A1 phenotypic spectrum beyond syndromic collagenopathies.","method":"Genome-wide linkage analysis (LOD 8.29), exome sequencing, in vitro splicing assay, genotyping of 48 family members","journal":"Genetics in medicine","confidence":"High","confidence_rationale":"Tier 2 — functional in vitro splicing assay confirming pathogenicity, strong LOD score, segregation in large family","pmids":["30245514"],"is_preprint":false},{"year":2021,"finding":"COL11A1 activates cancer-associated fibroblasts by triggering ERK-mediated SP1 phosphorylation, which promotes p65 nuclear translocation and NF-κB-driven IGFBP2 expression, ultimately activating TGF-β3; this CAF-cancer cell crosstalk induces IL-6 secretion promoting EOC cell proliferation and invasiveness; in vivo, COL11A1 overexpression promotes tumor formation and CAF activation reversible by anti-TGF-β3 antibody.","method":"Co-culture experiments, conditioned medium assays, shRNA/overexpression in human ovarian fibroblasts, western blotting, ChIP for p65 binding to IGFBP2 promoter, mouse xenograft model, TGF-β3 antibody rescue","journal":"Oncogene","confidence":"High","confidence_rationale":"Tier 1-2 — multiple orthogonal in vitro and in vivo methods including ChIP, conditioned medium, in vivo rescue with antibody","pmids":["34117361"],"is_preprint":false},{"year":2021,"finding":"COL11A1 activates the Akt/CREB pathway in pancreatic cancer cells, phosphorylating AktSer473 and shifting the BCL-2/BAX balance toward anti-apoptosis; COL11A1/Akt disrupts mitochondrial transmembrane potential, inhibits cytochrome c release and Apaf-1/procaspase-9/Cyt-C complex formation, suppressing the intrinsic apoptosis program and promoting gemcitabine resistance.","method":"COL11A1 overexpression/siRNA knockdown in PDAC cell lines, western blotting for Akt/CREB/BCL-2/BAX/caspase-9/cytochrome c, mitochondrial translocation assays","journal":"Journal of Cancer","confidence":"Medium","confidence_rationale":"Tier 2 — functional OE/KD experiments with mechanistic pathway analysis at protein level in cancer cells","pmids":["33531986"],"is_preprint":false},{"year":2021,"finding":"Mutant COL11A1 (identified in 66/100 cutaneous SCCs, concentrated in the triple-helical domain) promotes tumorigenesis and accelerates neoplastic invasion by inducing β1 integrin targets; knockout of mutant COL11A1 impairs cSCC tumorigenesis in vivo; mosaic mutant COL11A1 cells also enhance invasion by neighboring wild-type cells in trans.","method":"Tumor sequencing, gene editing (CRISPR-generated mutant COL11A1 knockin), in vivo xenograft tumorigenesis, gene expression analysis (β1 integrin pathway), mosaic tissue invasion assays","journal":"Oncogene","confidence":"High","confidence_rationale":"Tier 1-2 — gene-edited isogenic models with in vivo rescue and trans-cell non-cell-autonomous effect demonstrated","pmids":["34584216"],"is_preprint":false},{"year":2022,"finding":"COL11A1 promotes epithelial-mesenchymal transition (EMT) and stemness in pancreatic cancer cells by activating the AKT/GSK-3β/Snail signaling axis, increasing p-AKTSer473, p-GSK-3βSer9, and Snail, thereby facilitating invasion and migration.","method":"siRNA/plasmid overexpression, Transwell invasion/migration assays, western blotting, flow cytometry, clone formation","journal":"Biomolecules","confidence":"Medium","confidence_rationale":"Tier 2 — functional KD/OE with defined signaling intermediates, but single-lab study","pmids":["35327583"],"is_preprint":false},{"year":2021,"finding":"miR-335 directly inhibits COL11A1 transcription in ovarian cancer cells; miR-335-mediated COL11A1 suppression reduces invasiveness via the Ets-1/MMP3 axis and reduces chemoresistance via the Akt/C/EBPβ/PDK1 axis, including increased PDK1 ubiquitination and degradation.","method":"miRNA mimic/inhibitor transfection, reporter assays, Akt/PDK1/ubiquitination western blots, in vivo miR-335 expression in EOC samples","journal":"Cancers","confidence":"Medium","confidence_rationale":"Tier 2 — functional miRNA perturbation with two defined downstream pathways identified","pmids":["34944877"],"is_preprint":false},{"year":2024,"finding":"Wild-type COL11A1 expression in costal chondrocytes suppresses PAX1 and MMP3 expression; the AIS-associated COL11A1P1335L mutant abrogates suppression of MMP3, implicating a PAX1-COL11A1-MMP3 signaling axis in spinal chondrocytes; estrogen receptor (ESR2) knockdown or tamoxifen treatment also alters Col11a1 and Mmp3 expression in chondrocytes.","method":"GWAS and exome sequencing (genetic mapping), CRISPR Pax1-knockout mice, scRNA-seq, protein co-localization in spinal tissue, genetic targeting (Col11a1 overexpression in chondrocytes), ESR2 siRNA knockdown, tamoxifen treatment","journal":"eLife","confidence":"High","confidence_rationale":"Tier 1-2 — CRISPR genetic model combined with multiple orthogonal molecular methods establishing a defined PAX1-COL11A1-MMP3 axis","pmids":["38277211"],"is_preprint":false},{"year":2024,"finding":"Col11a1-KO mice show aggravated joint degeneration and OA phenotype with disrupted chondrocyte homeostasis; scRNA-seq reveals that COL11A1 loss causes a shift from glycolysis to OXPHOS metabolism mediated by HIF1α, leading to chondrocyte cellular senescence; Col11a1-overexpressing SMSC organoids ameliorate cartilage degeneration in DDH mice by restoring HIF1α-mediated glycolysis.","method":"Col11a1-KO mice, scRNA-seq of DDH and KO cartilage, Col11a1 overexpression in SMSC organoids, intra-articular injection, histology","journal":"Clinical and translational medicine","confidence":"Medium","confidence_rationale":"Tier 2 — KO mouse plus scRNA-seq and organoid rescue define a metabolic mechanism, but novel pathway requires replication","pmids":["38314968"],"is_preprint":false},{"year":2024,"finding":"COL11A1 overexpression confers tamoxifen resistance in breast cancer cells by elevating estrogen receptor α (ERα) expression and its downstream target genes; COL11A1 knockdown decreases ERα and sensitizes tamoxifen-resistant cells to 4-OHT in vitro and in vivo.","method":"Stable COL11A1 overexpression in MCF-7/T47D, tamoxifen-resistant cell line generation, siRNA knockdown, xenograft model, western blotting for ERα pathway","journal":"NPJ breast cancer","confidence":"Medium","confidence_rationale":"Tier 2 — OE/KD with in vivo xenograft confirmation and ERα pathway mechanistic link","pmids":["38806505"],"is_preprint":false},{"year":2021,"finding":"PDAC-derived COL11A1 promotes conversion of normal fibroblasts to CAF-like cells via NF-κB pathway activation; CAFs then secrete IL-6, which promotes PDAC cell invasion and EMT, and IL-6 activates the MAPK/ERK pathway to increase ATF4, which directly transcribes COL11A1, forming a positive feedback loop between PDAC cells and CAFs.","method":"Co-culture experiments, siRNA knockdown, western blotting for NF-κB/ERK/ATF4/COL11A1, PDAC-CAF interaction assays","journal":"Cell biology international","confidence":"Medium","confidence_rationale":"Tier 2 — co-culture system with mechanistic intermediates defined, positive feedback loop supported by multiple assays","pmids":["36861686"],"is_preprint":false}],"current_model":"COL11A1 encodes the α1 chain of type XI collagen, a minor fibrillar collagen essential for heterotypic collagen fibril nucleation and diameter regulation in cartilage ECM; its N-terminal domain is surface-exposed on fibrils and mediates interactions with proteoglycans and other ECM molecules, its transcription is driven by NF-Y and Sp1 in chondrocytes, and in cancer contexts it acts as a secreted extracellular ligand that activates pro-survival signaling (Akt/PDK1 stabilization, NF-κB/IGFBP2/TGF-β3, AKT/GSK-3β/Snail, ERα upregulation) to promote chemoresistance, EMT, CAF activation, and invasion, with mutant COL11A1 additionally inducing β1-integrin-driven neoplastic invasion."},"narrative":{"teleology":[{"year":1995,"claim":"Establishing that COL11A1 is essential for cartilage fibril organization and skeletal morphogenesis resolved the question of whether type XI collagen is structurally required or merely accessory in cartilage ECM.","evidence":"Molecular identification of the cho/cho frameshift mutation in Col11a1 in mice with chondrodysplasia, wide limb bones, and disrupted growth plates","pmids":["7859283"],"confidence":"High","gaps":["Mechanism by which α1(XI) controls fibril diameter not defined at the molecular level","Role in non-cartilaginous tissues expressing Col11a1 not tested"]},{"year":1995,"claim":"Demonstrating tissue-specific alternative splicing of the N-terminal variable region (exons 6A/6B) and broad embryonic expression beyond cartilage indicated that COL11A1 contributes to ECM organization in multiple organ systems.","evidence":"Exon-specific in situ hybridization and immunohistochemistry in mouse embryos showing differential exon 6A/6B distribution across skeletal, smooth muscle, and neural tissues","pmids":["8530046","8563024"],"confidence":"Medium","gaps":["Functional consequence of each splice isoform not directly tested","Whether different trimeric partners form in non-cartilage tissues is unknown"]},{"year":1996,"claim":"Identifying a glycine substitution in COL11A1 as the cause of Stickler syndrome type 2 established this gene as a human disease gene and showed that the triple-helical domain is critical for vitreous collagen integrity.","evidence":"Linkage analysis and mutation identification (Gly97Val) cosegregating with vitreous/retinal disease in a family","pmids":["8872475"],"confidence":"High","gaps":["Structural basis for dominant-negative disruption not resolved","Whether all glycine substitutions are equally pathogenic is unclear"]},{"year":1999,"claim":"Systematic genotype-phenotype analysis distinguished Marshall syndrome (in-frame exon-skipping mutations in the C-terminal triple helix) from Stickler syndrome, revealing regional functional domains within the COL11A1 triple helix.","evidence":"Screening 23 novel mutations across COL11A1 in Marshall and Stickler families with splice-site characterization by RT-PCR","pmids":["9529347","10486316"],"confidence":"High","gaps":["Structural basis for region-specific phenotypic differences not determined","Whether interallelic complementation modulates severity is unknown"]},{"year":2003,"claim":"Identifying NF-Y as a direct transcriptional activator of the COL11A1 proximal promoter provided the first defined mechanism for basal COL11A1 transcription in chondrocytes.","evidence":"ChIP, EMSA, reporter assays, and dominant-negative NF-YA experiments in chondrocyte cell lines","pmids":["12805369","24092017"],"confidence":"High","gaps":["Chondrocyte-specific cofactors beyond NF-Y and Sp1 not identified","Chromatin-level regulation (enhancers, epigenetic marks) largely unexplored"]},{"year":2003,"claim":"Showing that Col11a1 haploinsufficiency does not cause hearing loss while dominant-negative mutations do established that Stickler/Marshall hearing phenotypes result from poisoning of wild-type collagen fibrils, not simple dosage reduction.","evidence":"ABR threshold measurement in cho/+ versus wild-type mice across multiple ages","pmids":["12527136"],"confidence":"Medium","gaps":["Molecular mechanism of dominant-negative interference in the cochlear tectorial membrane not defined","Whether cochlear fibril diameter changes parallel the cartilage phenotype is untested"]},{"year":2009,"claim":"Zebrafish col11a1 knockdown confirmed an evolutionarily conserved role in fibril diameter regulation and additionally revealed a requirement for chondrocyte hypertrophic maturation, linking ECM composition to chondrocyte differentiation.","evidence":"Morpholino knockdown in zebrafish with electron microscopy of fibrils, in situ hybridization, and histological analysis","pmids":["19638309"],"confidence":"High","gaps":["Whether the chondrocyte maturation defect is cell-autonomous or secondary to matrix disorganization is unclear","Signaling pathway connecting fibril defects to differentiation not identified"]},{"year":2010,"claim":"Identification of biallelic null COL11A1 mutations causing lethal fibrochondrogenesis — and later, demonstration that alternative splicing of exon 9 modulates severity — established a dose-dependent allelic series from null (lethal) through dominant-negative (Stickler/Marshall) phenotypes.","evidence":"SNP genotyping and autozygosity mapping in fibrochondrogenesis cases; minigene splicing assays and allele-specific RT-PCR for exon 9 effects","pmids":["21035103","23922384"],"confidence":"High","gaps":["Residual function of partially spliced alleles not quantified at the protein level","Whether modifier genes influence phenotypic severity is unknown"]},{"year":2011,"claim":"Affinity chromatography with the N-terminal non-collagenous domain identified proteoglycans and matricellular proteins as direct binding partners, establishing this domain as a molecular hub on the fibril surface for ECM interactions.","evidence":"Recombinant N-terminal domain affinity pulldown from fetal bovine cartilage with LC-MS/MS identification","pmids":["22038862"],"confidence":"Medium","gaps":["Individual interactions not validated by reciprocal binding or functional assays","Binding affinities and stoichiometries not determined"]},{"year":2015,"claim":"Discovery that COL11A1 binds PDK1 and attenuates its ubiquitination, stabilizing Akt signaling to promote chemoresistance, revealed a non-structural oncogenic function for COL11A1 as a signaling ligand in cancer.","evidence":"Co-IP of COL11A1-PDK1, ubiquitination assays, shRNA knockdown, and overexpression in ovarian cancer cells with cisplatin/paclitaxel resistance readouts","pmids":["26087191"],"confidence":"High","gaps":["Receptor mediating COL11A1-PDK1 interaction not identified","Whether PDK1 stabilization is direct or through an intermediate adaptor is unclear"]},{"year":2016,"claim":"Elucidation of COL11A1-driven NF-κB activation via SP1 phosphorylation and IKKβ upregulation, leading to TWIST1/Mcl-1 transcription, expanded the downstream signaling repertoire linking COL11A1 to survival and invasion programs.","evidence":"siRNA knockdown in ovarian cancer cells with western blotting for phospho-SP1, IKKβ, TWIST1, and chemosensitivity assays","pmids":["28815582"],"confidence":"Medium","gaps":["How COL11A1 activates ERK/SP1 phosphorylation at the receptor level is undefined","Relative contribution of NF-κB versus Akt pathways to chemoresistance not dissected"]},{"year":2021,"claim":"Demonstration that COL11A1 activates CAFs through NF-κB/IGFBP2/TGF-β3 and establishes a positive-feedback IL-6/ATF4 loop with tumor cells unified the paracrine and autocrine circuits by which COL11A1 remodels the tumor microenvironment.","evidence":"Co-culture, ChIP for p65 on IGFBP2 promoter, xenograft rescue with anti-TGF-β3 antibody; parallel study showing IL-6/MAPK/ATF4 feedback driving COL11A1 transcription in PDAC-CAF co-cultures","pmids":["34117361","36861686"],"confidence":"High","gaps":["Cell-surface receptor on CAFs that senses COL11A1 is not identified","Whether the feedback loop operates in non-ovarian/non-pancreatic cancers is untested"]},{"year":2021,"claim":"Finding that somatic COL11A1 mutations in cutaneous SCC induce β1-integrin-dependent invasion — and non-cell-autonomously promote neighboring wild-type cell invasion — revealed a gain-of-function oncogenic mechanism distinct from the secreted wild-type protein's role.","evidence":"CRISPR knockin of mutant COL11A1 in keratinocytes, xenograft tumorigenesis, mosaic tissue invasion assays","pmids":["34584216"],"confidence":"High","gaps":["Which specific mutations are gain-of-function versus loss-of-function is not systematically classified","Structural basis for mutant COL11A1 activating β1 integrin is unknown"]},{"year":2024,"claim":"Identification of a PAX1-COL11A1-MMP3 axis in spinal chondrocytes and the demonstration that COL11A1 loss shifts chondrocyte metabolism from glycolysis to OXPHOS via HIF1α, driving cellular senescence, expanded COL11A1's role to a metabolic regulator of chondrocyte homeostasis.","evidence":"CRISPR Pax1-KO mice, Col11a1-KO mice, scRNA-seq, Col11a1-overexpressing SMSC organoid rescue in DDH model","pmids":["38277211","38314968"],"confidence":"Medium","gaps":["Direct molecular link between COL11A1 and HIF1α stabilization is undefined","Whether the metabolic shift is a direct intracellular effect or secondary to ECM changes is unclear"]},{"year":null,"claim":"The cell-surface receptor(s) through which extracellular COL11A1 activates Akt, NF-κB, and integrin signaling in cancer cells and fibroblasts remain unidentified, leaving the proximal step of its oncogenic signaling undefined.","evidence":"","pmids":[],"confidence":"Low","gaps":["No receptor identification study performed","Whether COL11A1 signals as intact trimer, processed fragment, or monomeric chain is unknown","Structural basis for COL11A1-PDK1 interaction not resolved"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0005198","term_label":"structural molecule activity","supporting_discovery_ids":[0,3,11,13]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[17,23,24,26]}],"localization":[{"term_id":"GO:0031012","term_label":"extracellular matrix","supporting_discovery_ids":[0,11,13]},{"term_id":"GO:0005576","term_label":"extracellular region","supporting_discovery_ids":[13,16,17]}],"pathway":[{"term_id":"R-HSA-1474244","term_label":"Extracellular matrix organization","supporting_discovery_ids":[0,11,13]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[17,20,23,24,26]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[0,7,11,18]}],"complexes":["Type XI collagen heterotrimer (α1(XI)/α2(XI)/α1(II))"],"partners":["PDK1","NF-Y","SP1","COL2A1","ATF4","IGFBP2","PAX1"],"other_free_text":[]},"mechanistic_narrative":"COL11A1 encodes the α1 chain of type XI collagen, a minor fibrillar collagen that nucleates heterotypic collagen fibrils and regulates their diameter in cartilage and other connective tissues; it is essential for skeletal morphogenesis, craniofacial development, and auditory function. Loss-of-function in mice causes chondrodysplasia with disordered growth plate architecture and abnormally thick collagen fibrils, while in humans, heterozygous dominant-negative mutations cause Stickler syndrome type 2 and Marshall syndrome, biallelic null mutations cause lethal fibrochondrogenesis, and splice-site mutations cause nonsyndromic hearing loss (DFNA37) [PMID:7859283, PMID:8872475, PMID:9529347, PMID:21035103, PMID:30245514]. The N-terminal non-collagenous domain is surface-exposed on fibrils and interacts with proteoglycans and matricellular proteins to regulate fibrillogenesis, while basal transcription in chondrocytes requires NF-Y binding to the proximal promoter and Sp1 binding to a GC-rich element [PMID:22038862, PMID:12805369, PMID:26487428]. In cancer, COL11A1 is expressed by cancer-associated fibroblasts and tumor cells, where it stabilizes PDK1 to activate Akt signaling, drives NF-κB-dependent transcription of pro-survival genes, promotes epithelial-mesenchymal transition via AKT/GSK-3β/Snail, and establishes a positive-feedback loop with IL-6/ATF4 to sustain chemoresistance and stromal activation [PMID:26087191, PMID:34117361, PMID:35327583, PMID:36861686]."},"prefetch_data":{"uniprot":{"accession":"P12107","full_name":"Collagen alpha-1(XI) chain","aliases":[],"length_aa":1806,"mass_kda":181.1,"function":"May play an important role in fibrillogenesis by controlling lateral growth of collagen II fibrils","subcellular_location":"Secreted, extracellular space, extracellular matrix","url":"https://www.uniprot.org/uniprotkb/P12107/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/COL11A1","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/COL11A1","total_profiled":1310},"omim":[{"mim_id":"618533","title":"DEAFNESS, AUTOSOMAL DOMINANT 37; DFNA37","url":"https://www.omim.org/entry/618533"},{"mim_id":"614524","title":"FIBROCHONDROGENESIS 2; FBCG2","url":"https://www.omim.org/entry/614524"},{"mim_id":"614161","title":"PR DOMAIN-CONTAINING PROTEIN 5; PRDM5","url":"https://www.omim.org/entry/614161"},{"mim_id":"612078","title":"ZINC FINGER PROTEIN 469; ZNF469","url":"https://www.omim.org/entry/612078"},{"mim_id":"610025","title":"COLLAGEN, TYPE XXIV, ALPHA-1; COL24A1","url":"https://www.omim.org/entry/610025"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Endoplasmic reticulum","reliability":"Supported"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in some","driving_tissues":[{"tissue":"placenta","ntpm":18.9},{"tissue":"retina","ntpm":8.9}],"url":"https://www.proteinatlas.org/search/COL11A1"},"hgnc":{"alias_symbol":["STL2","CO11A1"],"prev_symbol":["COLL6","DFNA37"]},"alphafold":{"accession":"P12107","domains":[{"cath_id":"2.60.120.200","chopping":"36-255","consensus_level":"high","plddt":88.905,"start":36,"end":255},{"cath_id":"2.60.120.1000","chopping":"1586-1806","consensus_level":"high","plddt":93.5124,"start":1586,"end":1806}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/P12107","model_url":"https://alphafold.ebi.ac.uk/files/AF-P12107-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-P12107-F1-predicted_aligned_error_v6.png","plddt_mean":51.69},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=COL11A1","jax_strain_url":"https://www.jax.org/strain/search?query=COL11A1"},"sequence":{"accession":"P12107","fasta_url":"https://rest.uniprot.org/uniprotkb/P12107.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/P12107/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/P12107"}},"corpus_meta":[{"pmid":"7859283","id":"PMC_7859283","title":"A fibrillar collagen gene, Col11a1, is essential for skeletal morphogenesis.","date":"1995","source":"Cell","url":"https://pubmed.ncbi.nlm.nih.gov/7859283","citation_count":301,"is_preprint":false},{"pmid":"8872475","id":"PMC_8872475","title":"A family with Stickler syndrome type 2 has a mutation in the COL11A1 gene resulting in the substitution of glycine 97 by valine in alpha 1 (XI) collagen.","date":"1996","source":"Human molecular genetics","url":"https://pubmed.ncbi.nlm.nih.gov/8872475","citation_count":221,"is_preprint":false},{"pmid":"10486316","id":"PMC_10486316","title":"Splicing mutations of 54-bp exons in the COL11A1 gene cause Marshall syndrome, but other mutations cause overlapping Marshall/Stickler phenotypes.","date":"1999","source":"American journal of human genetics","url":"https://pubmed.ncbi.nlm.nih.gov/10486316","citation_count":183,"is_preprint":false},{"pmid":"11375892","id":"PMC_11375892","title":"Colorectal carcinogenesis is associated with stromal expression of COL11A1 and COL5A2.","date":"2001","source":"Carcinogenesis","url":"https://pubmed.ncbi.nlm.nih.gov/11375892","citation_count":145,"is_preprint":false},{"pmid":"21047417","id":"PMC_21047417","title":"Multi-cancer computational analysis reveals invasion-associated variant of desmoplastic reaction involving INHBA, THBS2 and COL11A1.","date":"2010","source":"BMC medical genomics","url":"https://pubmed.ncbi.nlm.nih.gov/21047417","citation_count":129,"is_preprint":false},{"pmid":"17999364","id":"PMC_17999364","title":"A functional polymorphism in COL11A1, which encodes the alpha 1 chain of type XI collagen, is associated with susceptibility to lumbar disc herniation.","date":"2007","source":"American journal of human genetics","url":"https://pubmed.ncbi.nlm.nih.gov/17999364","citation_count":128,"is_preprint":false},{"pmid":"30374069","id":"PMC_30374069","title":"Meta-analysis of Icelandic and UK data sets identifies missense variants in SMO, IL11, COL11A1 and 13 more new loci associated with osteoarthritis.","date":"2018","source":"Nature genetics","url":"https://pubmed.ncbi.nlm.nih.gov/30374069","citation_count":124,"is_preprint":false},{"pmid":"20513134","id":"PMC_20513134","title":"Stickler syndrome and the vitreous phenotype: mutations in COL2A1 and COL11A1.","date":"2010","source":"Human mutation","url":"https://pubmed.ncbi.nlm.nih.gov/20513134","citation_count":107,"is_preprint":false},{"pmid":"25761876","id":"PMC_25761876","title":"COL11A1/(pro)collagen 11A1 expression is a remarkable biomarker of human invasive carcinoma-associated stromal cells and carcinoma progression.","date":"2015","source":"Tumour biology : the journal of the International Society for Oncodevelopmental Biology and Medicine","url":"https://pubmed.ncbi.nlm.nih.gov/25761876","citation_count":101,"is_preprint":false},{"pmid":"9529347","id":"PMC_9529347","title":"Marshall syndrome associated with a splicing defect at the COL11A1 locus.","date":"1998","source":"American journal of human genetics","url":"https://pubmed.ncbi.nlm.nih.gov/9529347","citation_count":97,"is_preprint":false},{"pmid":"27609069","id":"PMC_27609069","title":"A COL11A1-correlated pan-cancer gene signature of activated fibroblasts for the prioritization of therapeutic targets.","date":"2016","source":"Cancer letters","url":"https://pubmed.ncbi.nlm.nih.gov/27609069","citation_count":96,"is_preprint":false},{"pmid":"33668097","id":"PMC_33668097","title":"Collagen Type XI Alpha 1 (COL11A1): A Novel Biomarker and a Key Player in Cancer.","date":"2021","source":"Cancers","url":"https://pubmed.ncbi.nlm.nih.gov/33668097","citation_count":89,"is_preprint":false},{"pmid":"17016581","id":"PMC_17016581","title":"Great potential of a panel of multiple hMTH1, SPD, ITGA11 and COL11A1 markers for diagnosis of patients with non-small cell lung cancer.","date":"2006","source":"Oncology reports","url":"https://pubmed.ncbi.nlm.nih.gov/17016581","citation_count":89,"is_preprint":false},{"pmid":"26087191","id":"PMC_26087191","title":"COL11A1 confers chemoresistance on ovarian cancer cells through the activation of Akt/c/EBPβ pathway and PDK1 stabilization.","date":"2015","source":"Oncotarget","url":"https://pubmed.ncbi.nlm.nih.gov/26087191","citation_count":86,"is_preprint":false},{"pmid":"27373316","id":"PMC_27373316","title":"COL11A1 is overexpressed in recurrent non-small cell lung cancer and promotes cell proliferation, migration, invasion and drug resistance.","date":"2016","source":"Oncology reports","url":"https://pubmed.ncbi.nlm.nih.gov/27373316","citation_count":78,"is_preprint":false},{"pmid":"34117361","id":"PMC_34117361","title":"COL11A1 activates cancer-associated fibroblasts by modulating TGF-β3 through the NF-κB/IGFBP2 axis in ovarian cancer cells.","date":"2021","source":"Oncogene","url":"https://pubmed.ncbi.nlm.nih.gov/34117361","citation_count":69,"is_preprint":false},{"pmid":"24194920","id":"PMC_24194920","title":"Overexpression of COL11A1 by cancer-associated fibroblasts: clinical relevance of a stromal marker in pancreatic cancer.","date":"2013","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/24194920","citation_count":66,"is_preprint":false},{"pmid":"17236192","id":"PMC_17236192","title":"A report on 10 new patients with heterozygous mutations in the COL11A1 gene and a review of genotype-phenotype correlations in type XI collagenopathies.","date":"2007","source":"American journal of medical genetics. Part A","url":"https://pubmed.ncbi.nlm.nih.gov/17236192","citation_count":64,"is_preprint":false},{"pmid":"10573014","id":"PMC_10573014","title":"Stickler syndrome: further mutations in COL11A1 and evidence for additional locus heterogeneity.","date":"1999","source":"European journal of human genetics : EJHG","url":"https://pubmed.ncbi.nlm.nih.gov/10573014","citation_count":63,"is_preprint":false},{"pmid":"8563024","id":"PMC_8563024","title":"Developmental pattern of expression of the mouse alpha 1 (XI) collagen gene (Col11a1).","date":"1995","source":"Developmental dynamics : an official publication of the American Association of Anatomists","url":"https://pubmed.ncbi.nlm.nih.gov/8563024","citation_count":62,"is_preprint":false},{"pmid":"21035103","id":"PMC_21035103","title":"Fibrochondrogenesis results from mutations in the COL11A1 type XI collagen gene.","date":"2010","source":"American journal of human genetics","url":"https://pubmed.ncbi.nlm.nih.gov/21035103","citation_count":60,"is_preprint":false},{"pmid":"28815582","id":"PMC_28815582","title":"Activation of TWIST1 by COL11A1 promotes chemoresistance and inhibits apoptosis in ovarian cancer cells by modulating NF-κB-mediated IKKβ expression.","date":"2017","source":"International journal of cancer","url":"https://pubmed.ncbi.nlm.nih.gov/28815582","citation_count":58,"is_preprint":false},{"pmid":"34283835","id":"PMC_34283835","title":"Single-cell analysis reveals the pan-cancer invasiveness-associated transition of adipose-derived stromal cells into COL11A1-expressing cancer-associated fibroblasts.","date":"2021","source":"PLoS computational biology","url":"https://pubmed.ncbi.nlm.nih.gov/34283835","citation_count":51,"is_preprint":false},{"pmid":"11707154","id":"PMC_11707154","title":"COL11A1 in FAP polyps and in sporadic colorectal tumors.","date":"2001","source":"BMC cancer","url":"https://pubmed.ncbi.nlm.nih.gov/11707154","citation_count":48,"is_preprint":false},{"pmid":"25240749","id":"PMC_25240749","title":"Novel pathogenic COL11A1/COL11A2 variants in Stickler syndrome detected by targeted NGS and exome sequencing.","date":"2014","source":"Molecular genetics and metabolism","url":"https://pubmed.ncbi.nlm.nih.gov/25240749","citation_count":46,"is_preprint":false},{"pmid":"36744260","id":"PMC_36744260","title":"Single-cell analysis reveals the COL11A1+ fibroblasts are cancer-specific fibroblasts that promote tumor progression.","date":"2023","source":"Frontiers in pharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/36744260","citation_count":44,"is_preprint":false},{"pmid":"28004111","id":"PMC_28004111","title":"COL11A1 is overexpressed in gastric cancer tissues and regulates proliferation, migration and invasion of HGC-27 gastric cancer cells in vitro.","date":"2016","source":"Oncology reports","url":"https://pubmed.ncbi.nlm.nih.gov/28004111","citation_count":44,"is_preprint":false},{"pmid":"30245514","id":"PMC_30245514","title":"Splice-altering variant in COL11A1 as a cause of nonsyndromic hearing loss DFNA37.","date":"2018","source":"Genetics in medicine : official journal of the American College of Medical Genetics","url":"https://pubmed.ncbi.nlm.nih.gov/30245514","citation_count":42,"is_preprint":false},{"pmid":"30975980","id":"PMC_30975980","title":"Akt inhibitor SC66 promotes cell sensitivity to cisplatin in chemoresistant ovarian cancer cells through inhibition of COL11A1 expression.","date":"2019","source":"Cell death & disease","url":"https://pubmed.ncbi.nlm.nih.gov/30975980","citation_count":41,"is_preprint":false},{"pmid":"36266702","id":"PMC_36266702","title":"SPP1 facilitates cell migration and invasion by targeting COL11A1 in lung adenocarcinoma.","date":"2022","source":"Cancer cell international","url":"https://pubmed.ncbi.nlm.nih.gov/36266702","citation_count":40,"is_preprint":false},{"pmid":"23922384","id":"PMC_23922384","title":"Alternative splicing modifies the effect of mutations in COL11A1 and results in recessive type 2 Stickler syndrome with profound hearing loss.","date":"2013","source":"Journal of medical genetics","url":"https://pubmed.ncbi.nlm.nih.gov/23922384","citation_count":40,"is_preprint":false},{"pmid":"33531986","id":"PMC_33531986","title":"The COL11A1/Akt/CREB signaling axis enables mitochondrial-mediated apoptotic evasion to promote chemoresistance in pancreatic cancer cells through modulating BAX/BCL-2 function.","date":"2021","source":"Journal of Cancer","url":"https://pubmed.ncbi.nlm.nih.gov/33531986","citation_count":40,"is_preprint":false},{"pmid":"22189268","id":"PMC_22189268","title":"Splicing analysis of unclassified variants in COL2A1 and COL11A1 identifies deep intronic pathogenic mutations.","date":"2011","source":"European journal of human genetics : EJHG","url":"https://pubmed.ncbi.nlm.nih.gov/22189268","citation_count":35,"is_preprint":false},{"pmid":"19638309","id":"PMC_19638309","title":"Craniofacial cartilage morphogenesis requires zebrafish col11a1 activity.","date":"2009","source":"Matrix biology : journal of the International Society for Matrix Biology","url":"https://pubmed.ncbi.nlm.nih.gov/19638309","citation_count":34,"is_preprint":false},{"pmid":"11420059","id":"PMC_11420059","title":"The mechanism of palatal clefting in the Col11a1 mutant mouse.","date":"2001","source":"Archives of oral biology","url":"https://pubmed.ncbi.nlm.nih.gov/11420059","citation_count":33,"is_preprint":false},{"pmid":"25417197","id":"PMC_25417197","title":"Validation of COL11A1/procollagen 11A1 expression in TGF-β1-activated immortalised human mesenchymal cells and in stromal cells of human colon adenocarcinoma.","date":"2014","source":"BMC cancer","url":"https://pubmed.ncbi.nlm.nih.gov/25417197","citation_count":32,"is_preprint":false},{"pmid":"34183642","id":"PMC_34183642","title":"Circ-0005105 activates COL11A1 by targeting miR-20a-3p to promote pancreatic ductal adenocarcinoma progression.","date":"2021","source":"Cell death & disease","url":"https://pubmed.ncbi.nlm.nih.gov/34183642","citation_count":32,"is_preprint":false},{"pmid":"36389832","id":"PMC_36389832","title":"COL11A1 as an novel biomarker for breast cancer with machine learning and immunohistochemistry validation.","date":"2022","source":"Frontiers in immunology","url":"https://pubmed.ncbi.nlm.nih.gov/36389832","citation_count":31,"is_preprint":false},{"pmid":"26779434","id":"PMC_26779434","title":"Col11a1 Regulates Bone Microarchitecture during Embryonic Development.","date":"2015","source":"Journal of developmental biology","url":"https://pubmed.ncbi.nlm.nih.gov/26779434","citation_count":31,"is_preprint":false},{"pmid":"37783295","id":"PMC_37783295","title":"Collagen 1A1 (COL1A1) and Collagen11A1(COL11A1) as diagnostic biomarkers in Breast, colorectal and gastric cancers.","date":"2023","source":"Gene","url":"https://pubmed.ncbi.nlm.nih.gov/37783295","citation_count":30,"is_preprint":false},{"pmid":"23497244","id":"PMC_23497244","title":"Allelic expression analysis of the osteoarthritis susceptibility gene COL11A1 in human joint tissues.","date":"2013","source":"BMC musculoskeletal disorders","url":"https://pubmed.ncbi.nlm.nih.gov/23497244","citation_count":27,"is_preprint":false},{"pmid":"24854855","id":"PMC_24854855","title":"Extended association study of PLEKHA7 and COL11A1 with primary angle closure glaucoma in a Han Chinese population.","date":"2014","source":"Investigative ophthalmology & visual science","url":"https://pubmed.ncbi.nlm.nih.gov/24854855","citation_count":27,"is_preprint":false},{"pmid":"12805369","id":"PMC_12805369","title":"The transcription factor CCAAT-binding factor CBF/NF-Y regulates the proximal promoter activity in the human alpha 1(XI) collagen gene (COL11A1).","date":"2003","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/12805369","citation_count":27,"is_preprint":false},{"pmid":"15141750","id":"PMC_15141750","title":"Col11a1 and Col11a2 mRNA expression in the developing mouse cochlea: implications for the correlation of hearing loss phenotype with mutant type XI collagen genotype.","date":"2004","source":"Acta oto-laryngologica","url":"https://pubmed.ncbi.nlm.nih.gov/15141750","citation_count":26,"is_preprint":false},{"pmid":"28583914","id":"PMC_28583914","title":"Association between COL11A1 (rs1337185) and ADAMTS5 (rs162509) gene polymorphisms and lumbar spine pathologies in Chinese Han population: an observational study.","date":"2017","source":"BMJ open","url":"https://pubmed.ncbi.nlm.nih.gov/28583914","citation_count":26,"is_preprint":false},{"pmid":"32233587","id":"PMC_32233587","title":"The regulation of miR-139-5p on the biological characteristics of breast cancer cells by targeting COL11A1.","date":"2019","source":"Mathematical biosciences and engineering : MBE","url":"https://pubmed.ncbi.nlm.nih.gov/32233587","citation_count":25,"is_preprint":false},{"pmid":"34584216","id":"PMC_34584216","title":"Mutant collagen COL11A1 enhances cancerous invasion.","date":"2021","source":"Oncogene","url":"https://pubmed.ncbi.nlm.nih.gov/34584216","citation_count":23,"is_preprint":false},{"pmid":"33148075","id":"PMC_33148075","title":"COL11A1 Was Involved in Cell Proliferation, Apoptosis and Migration in Non-Small Cell Lung Cancer Cells.","date":"2020","source":"Journal of investigative surgery : the official journal of the Academy of Surgical Research","url":"https://pubmed.ncbi.nlm.nih.gov/33148075","citation_count":23,"is_preprint":false},{"pmid":"35944362","id":"PMC_35944362","title":"Berberine inhibits glioma cell migration and invasion by suppressing TGF-β1/COL11A1 pathway.","date":"2022","source":"Biochemical and biophysical research communications","url":"https://pubmed.ncbi.nlm.nih.gov/35944362","citation_count":23,"is_preprint":false},{"pmid":"35327583","id":"PMC_35327583","title":"COL11A1-Driven Epithelial-Mesenchymal Transition and Stemness of Pancreatic Cancer Cells Induce Cell Migration and Invasion by Modulating the AKT/GSK-3β/Snail Pathway.","date":"2022","source":"Biomolecules","url":"https://pubmed.ncbi.nlm.nih.gov/35327583","citation_count":23,"is_preprint":false},{"pmid":"28983407","id":"PMC_28983407","title":"Novel and recurrent COL11A1 and COL2A1 mutations in the Marshall-Stickler syndrome spectrum.","date":"2017","source":"Human genome variation","url":"https://pubmed.ncbi.nlm.nih.gov/28983407","citation_count":22,"is_preprint":false},{"pmid":"27390512","id":"PMC_27390512","title":"Mutation survey and genotype-phenotype analysis of COL2A1 and COL11A1 genes in 16 Chinese patients with Stickler syndrome.","date":"2016","source":"Molecular vision","url":"https://pubmed.ncbi.nlm.nih.gov/27390512","citation_count":21,"is_preprint":false},{"pmid":"36876834","id":"PMC_36876834","title":"E2F1 Reduces Sorafenib's Sensitivity of Esophageal Carcinoma Cells via Modulating the miR-29c-3p/COL11A1 Signaling Axis.","date":"2024","source":"Current molecular pharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/36876834","citation_count":20,"is_preprint":false},{"pmid":"21668896","id":"PMC_21668896","title":"Clinical and molecular analysis of UAE fibrochondrogenesis patients expands the phenotype and reveals two COL11A1 homozygous null mutations.","date":"2011","source":"Clinical genetics","url":"https://pubmed.ncbi.nlm.nih.gov/21668896","citation_count":20,"is_preprint":false},{"pmid":"31938021","id":"PMC_31938021","title":"Over-expression of CDX2 alleviates breast cancer by up-regulating microRNA let-7b and inhibiting COL11A1 expression.","date":"2020","source":"Cancer cell international","url":"https://pubmed.ncbi.nlm.nih.gov/31938021","citation_count":20,"is_preprint":false},{"pmid":"34944877","id":"PMC_34944877","title":"miR-335 Restrains the Aggressive Phenotypes of Ovarian Cancer Cells by Inhibiting COL11A1.","date":"2021","source":"Cancers","url":"https://pubmed.ncbi.nlm.nih.gov/34944877","citation_count":19,"is_preprint":false},{"pmid":"23621912","id":"PMC_23621912","title":"Deletions within COL11A1 in Type 2 stickler syndrome detected by multiplex ligation-dependent probe amplification (MLPA).","date":"2013","source":"BMC medical genetics","url":"https://pubmed.ncbi.nlm.nih.gov/23621912","citation_count":19,"is_preprint":false},{"pmid":"12527136","id":"PMC_12527136","title":"Auditory function associated with Col11a1 haploinsufficiency in chondrodysplasia (cho) mice.","date":"2003","source":"Hearing research","url":"https://pubmed.ncbi.nlm.nih.gov/12527136","citation_count":17,"is_preprint":false},{"pmid":"10889003","id":"PMC_10889003","title":"Audiovestibular phenotype associated with a COL11A1 mutation in Marshall syndrome.","date":"2000","source":"Archives of otolaryngology--head & neck surgery","url":"https://pubmed.ncbi.nlm.nih.gov/10889003","citation_count":17,"is_preprint":false},{"pmid":"22038862","id":"PMC_22038862","title":"Proteomic analysis of Col11a1-associated protein complexes.","date":"2011","source":"Proteomics","url":"https://pubmed.ncbi.nlm.nih.gov/22038862","citation_count":16,"is_preprint":false},{"pmid":"25091507","id":"PMC_25091507","title":"A novel dominant COL11A1 mutation resulting in a severe skeletal dysplasia.","date":"2014","source":"American journal of medical genetics. Part A","url":"https://pubmed.ncbi.nlm.nih.gov/25091507","citation_count":15,"is_preprint":false},{"pmid":"38314968","id":"PMC_38314968","title":"Genetically inspired organoids prevent joint degeneration and alleviate chondrocyte senescence via Col11a1-HIF1α-mediated glycolysis-OXPHOS metabolism shift.","date":"2024","source":"Clinical and translational medicine","url":"https://pubmed.ncbi.nlm.nih.gov/38314968","citation_count":15,"is_preprint":false},{"pmid":"22510797","id":"PMC_22510797","title":"COL11A1 gene is associated with limbus vertebra in gymnasts.","date":"2012","source":"International journal of sports medicine","url":"https://pubmed.ncbi.nlm.nih.gov/22510797","citation_count":15,"is_preprint":false},{"pmid":"32578940","id":"PMC_32578940","title":"Inherited and de novo biallelic pathogenic variants in COL11A1 result in type 2 Stickler syndrome with severe hearing loss.","date":"2020","source":"Molecular genetics & genomic medicine","url":"https://pubmed.ncbi.nlm.nih.gov/32578940","citation_count":14,"is_preprint":false},{"pmid":"30809385","id":"PMC_30809385","title":"COL11A1 Polymorphisms Are Associated with Primary Angle-Closure Glaucoma Severity.","date":"2019","source":"Journal of ophthalmology","url":"https://pubmed.ncbi.nlm.nih.gov/30809385","citation_count":14,"is_preprint":false},{"pmid":"8530046","id":"PMC_8530046","title":"Coding sequence and alternative splicing of the mouse alpha 1(XI) collagen gene (Col11a1).","date":"1995","source":"Genomics","url":"https://pubmed.ncbi.nlm.nih.gov/8530046","citation_count":14,"is_preprint":false},{"pmid":"33348901","id":"PMC_33348901","title":"Exon-Trapping Assay Improves Clinical Interpretation of COL11A1 and COL11A2 Intronic Variants in Stickler Syndrome Type 2 and Otospondylomegaepiphyseal Dysplasia.","date":"2020","source":"Genes","url":"https://pubmed.ncbi.nlm.nih.gov/33348901","citation_count":13,"is_preprint":false},{"pmid":"3220479","id":"PMC_3220479","title":"Mapping of a human fibrillar collagen gene, pro alpha 1 (XI) (COL11A1), to the p21 region of chromosome 1.","date":"1988","source":"Genomics","url":"https://pubmed.ncbi.nlm.nih.gov/3220479","citation_count":13,"is_preprint":false},{"pmid":"28971234","id":"PMC_28971234","title":"A novel dominant COL11A1 mutation in a child with Stickler syndrome type II is associated with recurrent fractures.","date":"2017","source":"Osteoporosis international : a journal established as result of cooperation between the European Foundation for Osteoporosis and the National Osteoporosis Foundation of the USA","url":"https://pubmed.ncbi.nlm.nih.gov/28971234","citation_count":13,"is_preprint":false},{"pmid":"16159363","id":"PMC_16159363","title":"Isolation of the salmonid rhamnose-binding lectin STL2 from spores of the microsporidian fish parasite Loma salmonae.","date":"2005","source":"Journal of fish diseases","url":"https://pubmed.ncbi.nlm.nih.gov/16159363","citation_count":13,"is_preprint":false},{"pmid":"32140959","id":"PMC_32140959","title":"Multifactor dimensionality reduction reveals a strong gene-gene interaction between STC1 and COL11A1 genes as a possible risk factor of knee osteoarthritis.","date":"2020","source":"Molecular biology reports","url":"https://pubmed.ncbi.nlm.nih.gov/32140959","citation_count":12,"is_preprint":false},{"pmid":"33970764","id":"PMC_33970764","title":"Activation of COL11A1 by PRRX1 promotes tumor progression and radioresistance in ovarian cancer.","date":"2021","source":"International journal of radiation biology","url":"https://pubmed.ncbi.nlm.nih.gov/33970764","citation_count":11,"is_preprint":false},{"pmid":"35946471","id":"PMC_35946471","title":"Association of EFEMP1 with juvenile-onset open angle glaucoma in a patient with concomitant COL11A1-related Stickler syndrome.","date":"2022","source":"Ophthalmic genetics","url":"https://pubmed.ncbi.nlm.nih.gov/35946471","citation_count":11,"is_preprint":false},{"pmid":"29321344","id":"PMC_29321344","title":"A genetic variant in COL11A1 is functionally associated with lumbar disc herniation in Chinese population.","date":"2017","source":"Journal of genetics","url":"https://pubmed.ncbi.nlm.nih.gov/29321344","citation_count":11,"is_preprint":false},{"pmid":"34460335","id":"PMC_34460335","title":"Collagen XI Alpha 1 (COL11A1) Expression in the Tumor Microenvironment Drives Neuroblastoma Dissemination.","date":"2021","source":"Pediatric and developmental pathology : the official journal of the Society for Pediatric Pathology and the Paediatric Pathology Society","url":"https://pubmed.ncbi.nlm.nih.gov/34460335","citation_count":10,"is_preprint":false},{"pmid":"11246003","id":"PMC_11246003","title":"Differential expression of two exons of the alpha1(XI) collagen gene (Col11a1) in the mouse embryo.","date":"2001","source":"Matrix biology : journal of the International Society for Matrix Biology","url":"https://pubmed.ncbi.nlm.nih.gov/11246003","citation_count":10,"is_preprint":false},{"pmid":"24092017","id":"PMC_24092017","title":"Nuclear factor Y (NF-Y) regulates the proximal promoter activity of the mouse collagen α1(XI) gene (Col11a1) in chondrocytes.","date":"2013","source":"In vitro cellular & developmental biology. Animal","url":"https://pubmed.ncbi.nlm.nih.gov/24092017","citation_count":10,"is_preprint":false},{"pmid":"33845716","id":"PMC_33845716","title":"MiR-144-3p inhibits the proliferation, migration and invasion of lung adenocargen cancer cells by targeting COL11A1.","date":"2021","source":"Journal of chemotherapy (Florence, Italy)","url":"https://pubmed.ncbi.nlm.nih.gov/33845716","citation_count":9,"is_preprint":false},{"pmid":"26487428","id":"PMC_26487428","title":"Sp1 upregulates the proximal promoter activity of the mouse collagen α1(XI) gene (Col11a1) in chondrocytes.","date":"2015","source":"In vitro cellular & developmental biology. Animal","url":"https://pubmed.ncbi.nlm.nih.gov/26487428","citation_count":9,"is_preprint":false},{"pmid":"21527992","id":"PMC_21527992","title":"A DNA pooling-based case-control study of myopia candidate genes COL11A1, COL18A1, FBN1, and PLOD1 in a Chinese population.","date":"2011","source":"Molecular vision","url":"https://pubmed.ncbi.nlm.nih.gov/21527992","citation_count":9,"is_preprint":false},{"pmid":"27021528","id":"PMC_27021528","title":"Overexpression of α1 chain of type XI collagen (COL11A1) aids in the diagnosis of invasive carcinoma in endoscopically removed malignant colorectal polyps.","date":"2016","source":"Pathology, research and practice","url":"https://pubmed.ncbi.nlm.nih.gov/27021528","citation_count":9,"is_preprint":false},{"pmid":"34378164","id":"PMC_34378164","title":"Mutually Exclusive Expression of COL11A1 by CAFs and Tumour Cells in a Large panCancer and a Salivary Gland Carcinoma Cohort.","date":"2021","source":"Head and neck pathology","url":"https://pubmed.ncbi.nlm.nih.gov/34378164","citation_count":9,"is_preprint":false},{"pmid":"26466668","id":"PMC_26466668","title":"Development of novel real-time PCR methodology for quantification of COL11A1 mRNA variants and evaluation in breast cancer tissue specimens.","date":"2015","source":"BMC cancer","url":"https://pubmed.ncbi.nlm.nih.gov/26466668","citation_count":9,"is_preprint":false},{"pmid":"28315471","id":"PMC_28315471","title":"A mild form of Stickler syndrome type II caused by mosaicism of COL11A1.","date":"2017","source":"European journal of medical genetics","url":"https://pubmed.ncbi.nlm.nih.gov/28315471","citation_count":9,"is_preprint":false},{"pmid":"38806505","id":"PMC_38806505","title":"Overexpression of COL11A1 confers tamoxifen resistance in breast cancer.","date":"2024","source":"NPJ breast cancer","url":"https://pubmed.ncbi.nlm.nih.gov/38806505","citation_count":8,"is_preprint":false},{"pmid":"32558342","id":"PMC_32558342","title":"Variable clinical expression of Stickler Syndrome: A case report of a novel COL11A1 mutation.","date":"2020","source":"Molecular genetics & genomic medicine","url":"https://pubmed.ncbi.nlm.nih.gov/32558342","citation_count":8,"is_preprint":false},{"pmid":"35792605","id":"PMC_35792605","title":"MiR-4458-loaded gelatin nanospheres target COL11A1 for DDR2/SRC signaling pathway inactivation to suppress the progression of estrogen receptor-positive breast cancer.","date":"2022","source":"Biomaterials science","url":"https://pubmed.ncbi.nlm.nih.gov/35792605","citation_count":8,"is_preprint":false},{"pmid":"34790783","id":"PMC_34790783","title":"COL11A1 promotes esophageal squamous cell carcinoma proliferation and metastasis and is inversely regulated by miR-335-5p.","date":"2021","source":"Annals of translational medicine","url":"https://pubmed.ncbi.nlm.nih.gov/34790783","citation_count":8,"is_preprint":false},{"pmid":"36861686","id":"PMC_36861686","title":"COL11A1-driven positive feedback loop modulates fibroblast transformation and activates pancreatic cancer progression.","date":"2023","source":"Cell biology international","url":"https://pubmed.ncbi.nlm.nih.gov/36861686","citation_count":7,"is_preprint":false},{"pmid":"27081549","id":"PMC_27081549","title":"A novel COL11A1 mutation affecting splicing in a patient with Stickler syndrome.","date":"2015","source":"Human genome variation","url":"https://pubmed.ncbi.nlm.nih.gov/27081549","citation_count":7,"is_preprint":false},{"pmid":"34009784","id":"PMC_34009784","title":"Association Between COL5a1, COL11a1, and COL11a2 Gene Variations and Rotator Cuff Tendinopathy in Young Athletes.","date":"2021","source":"Clinical journal of sport medicine : official journal of the Canadian Academy of Sport Medicine","url":"https://pubmed.ncbi.nlm.nih.gov/34009784","citation_count":6,"is_preprint":false},{"pmid":"35669376","id":"PMC_35669376","title":"COL11A1 is Downregulated by miR-339-5p and Promotes Colon Carcinoma Progression.","date":"2022","source":"Canadian journal of gastroenterology & hepatology","url":"https://pubmed.ncbi.nlm.nih.gov/35669376","citation_count":6,"is_preprint":false},{"pmid":"34238052","id":"PMC_34238052","title":"Hearing Outcomes in Stickler Syndrome: Variation Due to COL2A1 and COL11A1.","date":"2021","source":"The Cleft palate-craniofacial journal : official publication of the American Cleft Palate-Craniofacial Association","url":"https://pubmed.ncbi.nlm.nih.gov/34238052","citation_count":6,"is_preprint":false},{"pmid":"31545476","id":"PMC_31545476","title":"Microarray‑based analysis of COL11A1 and TWIST1 as important differentially‑expressed pathogenic genes between left and right‑sided colon cancer.","date":"2019","source":"Molecular medicine reports","url":"https://pubmed.ncbi.nlm.nih.gov/31545476","citation_count":6,"is_preprint":false},{"pmid":"38277211","id":"PMC_38277211","title":"Association of genetic variation in COL11A1 with adolescent idiopathic scoliosis.","date":"2024","source":"eLife","url":"https://pubmed.ncbi.nlm.nih.gov/38277211","citation_count":6,"is_preprint":false},{"pmid":"27936936","id":"PMC_27936936","title":"Additional Evidence Supports Association of Common Variants in COL11A1 with Increased Risk of Hip Osteoarthritis Susceptibility.","date":"2016","source":"Genetic testing and molecular biomarkers","url":"https://pubmed.ncbi.nlm.nih.gov/27936936","citation_count":6,"is_preprint":false},{"pmid":"31833174","id":"PMC_31833174","title":"Homozygous variants in AMPD2 and COL11A1 lead to a complex phenotype of pontocerebellar hypoplasia type 9 and Stickler syndrome type 2.","date":"2019","source":"American journal of medical genetics. Part A","url":"https://pubmed.ncbi.nlm.nih.gov/31833174","citation_count":6,"is_preprint":false},{"pmid":"34447665","id":"PMC_34447665","title":"Novel Mutation in the COL11A1 Gene Causing Marshall-Stickler Syndrome in Three Generations of a Bulgarian Family.","date":"2021","source":"Balkan journal of medical genetics : BJMG","url":"https://pubmed.ncbi.nlm.nih.gov/34447665","citation_count":5,"is_preprint":false},{"pmid":"27081569","id":"PMC_27081569","title":"A novel COL11A1 missense mutation in siblings with non-ocular Stickler syndrome.","date":"2016","source":"Human genome variation","url":"https://pubmed.ncbi.nlm.nih.gov/27081569","citation_count":5,"is_preprint":false},{"pmid":"37193942","id":"PMC_37193942","title":"Circular circRANGAP1 Contributes to Non-small Cell Lung Cancer Progression by Increasing COL11A1 Expression Through Sponging miR-653-5p.","date":"2023","source":"Biochemical genetics","url":"https://pubmed.ncbi.nlm.nih.gov/37193942","citation_count":4,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":50690,"output_tokens":7750,"usd":0.13416},"stage2":{"model":"claude-opus-4-6","input_tokens":11624,"output_tokens":3696,"usd":0.22578},"total_usd":0.35994,"stage1_batch_id":"msgbatch_011kfMfE81o6CTcyhVUqumuW","stage2_batch_id":"msgbatch_01DTputS6WNkH745x1nVSoBo","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 1995,\n      \"finding\": \"COL11A1 (Col11a1) is essential for normal cartilage collagen fibril formation and cohesive properties of cartilage; homozygous loss-of-function mutation (frameshift/premature stop) in cho/cho mice causes chondrodysplasia with abnormally wide, short limb bones and disrupted growth plate chondrocyte organization.\",\n      \"method\": \"Mouse genetic model (cho/cho autosomal recessive mutation), linkage analysis, mRNA sequencing, histology\",\n      \"journal\": \"Cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — foundational genetic model with molecular identification of causal mutation, replicated across multiple tissues and developmental stages\",\n      \"pmids\": [\"7859283\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1995,\n      \"finding\": \"Alternative splicing of Col11a1 exons 6A and 6B produces isoforms with distinct acidic or basic N-terminal peptides; the two isoforms show tissue-specific distribution in mouse embryo (exon 6B predominant in vertebrae and skeletal muscle; exon 6A in smooth muscle of intestine, aorta, lung), suggesting distinct contributions to tissue-specific matrix assembly.\",\n      \"method\": \"In situ hybridization with exon-specific cDNA probes, immunohistochemistry with peptide-specific antibodies in mouse embryo tissues\",\n      \"journal\": \"Genomics / Matrix biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — two orthogonal localization methods in mouse embryo, but functional consequence is correlative\",\n      \"pmids\": [\"8530046\", \"11246003\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1995,\n      \"finding\": \"Col11a1 transcripts are expressed developmentally from embryonic day 11 in mouse, predominantly in cartilaginous tissues (chondrocranium, developing limbs) but also in neuro-epithelium, odontoblasts, trabecular bone, atrioventricular valve, tongue, intestine, and otic vesicle, indicating broader expression than previously thought and suggesting the α1(XI) chain may form tissue-specific trimers.\",\n      \"method\": \"In situ hybridization on mouse embryo sections\",\n      \"journal\": \"Developmental dynamics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — direct in situ hybridization localization across multiple developmental time points\",\n      \"pmids\": [\"8563024\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1996,\n      \"finding\": \"A Gly97Val substitution in the triple helical domain of COL11A1 causes Stickler syndrome type 2 with vitreous and retinal abnormalities, establishing COL11A1 as a structural component of human vitreous and demonstrating that dominant-negative glycine substitutions in the triple helix disrupt vitreous collagen architecture.\",\n      \"method\": \"Linkage analysis, single-base mutation identification (G→T), genotype-phenotype correlation in affected family\",\n      \"journal\": \"Human molecular genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — first mutation characterization linking COL11A1 to vitreous structure, replicated by subsequent studies\",\n      \"pmids\": [\"8872475\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1998,\n      \"finding\": \"A splice-donor-site mutation (G+1→A) in COL11A1 causes in-frame skipping of a 54-bp exon, deleting amino acids 726–743 from the major triple-helical domain, and segregates with Marshall syndrome, demonstrating that α1(XI) collagen structural integrity in the triple-helical domain is required for normal skeletal morphogenesis.\",\n      \"method\": \"Mutation identification and cosegregation analysis, RT-PCR/splicing characterization of mutant transcript\",\n      \"journal\": \"American journal of human genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — molecular characterization of splice mutation with in-frame deletion confirmed at RNA level, cosegregation in large kindred\",\n      \"pmids\": [\"9529347\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"Splicing mutations that cause in-frame skipping of specific 54-bp exons in the C-terminal region of COL11A1 produce a dominant-negative truncated α1(XI) chain and are specifically associated with the Marshall syndrome phenotype, whereas null-allele mutations in COL2A1 produce classic Stickler syndrome; this genotype-phenotype correlation reveals that the C-terminal triple-helical region of COL11A1 is critical for craniofacial/skeletal morphogenesis.\",\n      \"method\": \"Genomic structure characterization of COL11A1, mutation screening of 23 novel mutations, genotype-phenotype correlation\",\n      \"journal\": \"American journal of human genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — systematic mutation analysis in large patient cohort with clear genotype-phenotype correlation, replicated across multiple families\",\n      \"pmids\": [\"10486316\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"COL11A1 expression in colorectal tumors is associated with an active APC/β-catenin (Wnt) signaling pathway; COL11A1 upregulation co-occurs with WISP-1 (a Wnt target), suggesting Wnt pathway activation drives stromal COL11A1 expression.\",\n      \"method\": \"RT-PCR differential display, FAP patient tissue analysis, correlation with Wnt pathway markers in 37 sporadic colorectal carcinomas\",\n      \"journal\": \"BMC cancer\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 — correlative expression data in tissue specimens, no direct functional perturbation of the pathway\",\n      \"pmids\": [\"11707154\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"In Col11a1 mutant (cho/cho) mice, cleft palate arises primarily because mandibular growth disruption prevents palatal shelf contact, not from intrinsic failure of medial-edge epithelium (MEE) to undergo epithelial-mesenchymal transformation; cho/cho palatal shelves retain full EMT capacity when brought into contact in vitro.\",\n      \"method\": \"In vitro palatal shelf culture, carboxydichlorofluorescein succinimidyl ester fate-tracing of MEE\",\n      \"journal\": \"Archives of oral biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — direct functional rescue experiment with cell-tracing in the cho/cho mouse model\",\n      \"pmids\": [\"11420059\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"The transcription factor CBF/NF-Y directly binds an ATTGG sequence in the proximal COL11A1 promoter (−147 to −121 region) and is required for basal transcriptional activation; dominant-negative NF-Y significantly inhibits promoter activity.\",\n      \"method\": \"EMSA, chromatin immunoprecipitation, interference/supershift assays, transient and stable transfection reporter assays, DNA-affinity-purified protein binding\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — multiple orthogonal methods (EMSA, ChIP, reporter assays, dominant-negative) demonstrating direct in vivo and in vitro binding\",\n      \"pmids\": [\"12805369\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"Col11a1 mRNA is expressed in the greater epithelial ridge as the main source for the tectorial membrane in the developing mouse cochlea, with later focal expression in inner sulcus and Claudius'/Boettcher's cells; this localization defines the cochlear cell populations responsible for type XI collagen in the tectorial/basilar membranes and underlies hearing function.\",\n      \"method\": \"In situ hybridization on mouse temporal bones at multiple developmental time points\",\n      \"journal\": \"Acta oto-laryngologica\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — direct localization experiment tied to known functional consequence (hearing loss) in the COL11A1 disease model\",\n      \"pmids\": [\"15141750\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"Col11a1 haploinsufficiency (cho/+ heterozygotes) does not cause significant hearing loss in mice; therefore, Stickler/Marshall syndrome COL11A1 mutations cause hearing loss via dominant-negative effects on wild-type fibrillar collagen polypeptides in the cochlear extracellular matrix, not through simple haploinsufficiency.\",\n      \"method\": \"Auditory brainstem response (ABR) threshold measurement in cho/+ versus +/+ mice at multiple ages\",\n      \"journal\": \"Hearing research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — direct functional audiological assay in genetically defined mouse model, establishes mechanism of pathogenicity\",\n      \"pmids\": [\"12527136\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"In zebrafish, col11a1 knockdown disrupts craniofacial cartilage formation and notochord morphology; chondrocyte spatial organization, cartilage element shaping, and chondrocyte hypertrophic maturation are all impaired; knockdown also increases col2a1 expression and results in abnormally thick, sparse fibrils in cartilage ECM, demonstrating that col11a1 regulates fibril diameter and chondrocyte differentiation.\",\n      \"method\": \"Morpholino-based knockdown in zebrafish, in situ hybridization, real-time PCR, histology/electron microscopy of cartilage ECM\",\n      \"journal\": \"Matrix biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — morpholino loss-of-function with multiple orthogonal readouts (histology, gene expression, fibril analysis) in zebrafish ortholog\",\n      \"pmids\": [\"19638309\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"Biallelic loss-of-function COL11A1 mutations (compound heterozygosity for null allele + glycine substitution) cause fibrochondrogenesis, a severe lethal skeletal dysplasia, establishing that complete loss of α1(XI) collagen function is more severe than heterozygous dominant-negative mutations causing Stickler/Marshall syndrome.\",\n      \"method\": \"Whole-genome SNP genotyping, autozygosity mapping, mutation sequencing in two independent fibrochondrogenesis cases\",\n      \"journal\": \"American journal of human genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — genetic evidence from multiple independent cases with distinct mutations, clear dose-dependent genotype-phenotype relationship\",\n      \"pmids\": [\"21035103\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"The amino-terminal non-collagenous domain of collagen α1(XI), displayed on the surface of heterotypic cartilage collagen fibrils, interacts with proteoglycans, other collagens, and matricellular molecules; affinity chromatography with this domain from fetal bovine cartilage identified multiple ECM binding partners by LC-MS/MS, supporting a role for the N-terminal domain in fibrillogenesis regulation.\",\n      \"method\": \"Affinity chromatography with recombinant N-terminal domain, liquid chromatography/tandem mass spectrometry (LC-MS/MS) protein identification\",\n      \"journal\": \"Proteomics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — direct affinity-based pulldown with mass spectrometric identification of binding partners, but without functional validation of individual interactions\",\n      \"pmids\": [\"22038862\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Alternative splicing of exon 9 of COL11A1 modifies the phenotypic severity of biallelic mutations; alleles that retain exon 9 splicing can produce a normal α1(XI) procollagen molecule, converting the phenotype from fibrochondrogenesis to recessive Stickler syndrome type 2 with profound hearing loss.\",\n      \"method\": \"Mutation sequencing, minigene splicing reporter assays, allele-specific RT-PCR, clinical phenotyping\",\n      \"journal\": \"Journal of medical genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — functional splicing assays combined with allele-specific RT-PCR and clear genotype-phenotype correlation in multiple families\",\n      \"pmids\": [\"23922384\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"NF-Y (nuclear factor Y) directly binds an ATTGG sequence in the proximal Col11a1 promoter in chondrocytes and is required for its activity; dominant-negative NF-YA inhibits promoter activity, and ChIP confirms in vivo binding.\",\n      \"method\": \"Transient transfection reporter assays, EMSA, chromatin immunoprecipitation, siRNA/dominant-negative overexpression in chondrocytes\",\n      \"journal\": \"In vitro cellular & developmental biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — multiple orthogonal methods (EMSA, ChIP, reporter, dominant-negative) confirming direct regulation in chondrocytes\",\n      \"pmids\": [\"24092017\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"COL11A1/procollagen 11A1 is expressed by TGF-β1-activated immortalized human bone marrow mesenchymal cells and by cancer-associated fibroblasts (CAFs) of human colon adenocarcinoma, but not by normal fibroblasts or normal colon stromal cells; proCOL11A1+ CAFs co-express vimentin and αSMA (myofibroblast markers).\",\n      \"method\": \"qRT-PCR, immunocytochemistry with validated anti-proCOL11A1 monoclonal antibody, immunohistochemistry of colon adenocarcinomas and normal tissues\",\n      \"journal\": \"BMC cancer\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — direct protein localization with validated antibody plus expression analysis, functional context defined by TGF-β1 activation\",\n      \"pmids\": [\"25417197\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"COL11A1 promotes chemoresistance in ovarian cancer cells through activation of the Akt/C/EBPβ signaling pathway; COL11A1 binds to PDK1, attenuates PDK1 ubiquitination and degradation, and thereby stabilizes PDK1 to promote cell survival; C/EBPβ binding to the COL11A1 promoter drives cisplatin/paclitaxel-induced COL11A1 upregulation.\",\n      \"method\": \"Co-immunoprecipitation, immunofluorescence, shRNA knockdown, COL11A1 overexpression, ubiquitination assay, promoter binding assay, microarray analysis\",\n      \"journal\": \"Oncotarget\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — Co-IP demonstrating COL11A1-PDK1 interaction, ubiquitination assay, promoter characterization, and functional rescue experiments\",\n      \"pmids\": [\"26087191\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Col11a1 depletion in mice results in altered trabecular bone microstructure and increased bone collar thickness during endochondral ossification, demonstrating a role for Col11a1 in regulating bone microarchitecture and mineralization during embryonic development.\",\n      \"method\": \"X-ray microtomography (micro-CT), histology of Col11a1-deficient versus wild-type mice\",\n      \"journal\": \"Journal of developmental biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — direct skeletal phenotyping in Col11a1-null mice with quantitative micro-CT\",\n      \"pmids\": [\"26779434\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Sp1 transcription factor upregulates Col11a1 proximal promoter activity by binding a GC-rich element (−96 to −67) in chondrocytes; Sp1 siRNA knockdown suppresses endogenous Col11a1 transcript levels.\",\n      \"method\": \"Luciferase reporter assays with deletion/mutation constructs, in silico analysis, Sp1 overexpression and siRNA knockdown in chondrocytes\",\n      \"journal\": \"In vitro cellular & developmental biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — reporter assays and siRNA knockdown demonstrating functional role, consistent with NF-Y mechanism from prior work\",\n      \"pmids\": [\"26487428\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"COL11A1 promotes ovarian cancer chemoresistance by activating NF-κB signaling via increased SP1 phosphorylation and ERK activation, leading to IKKβ upregulation and TWIST1/Mcl-1/GAS6 expression; COL11A1 siRNA knockdown increases chemosensitivity to cisplatin and paclitaxel via downregulated TWIST1.\",\n      \"method\": \"siRNA knockdown, western blotting, reporter assays, SP1 phosphorylation analysis, gene expression profiling in ovarian cancer cell lines\",\n      \"journal\": \"International journal of cancer\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — functional knockdown with defined downstream pathway intermediates (SP1→IKKβ→TWIST1)\",\n      \"pmids\": [\"28815582\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"COL11A1 overexpression promotes NSCLC cell proliferation, migration, invasion, and cisplatin resistance in vitro; these effects are mediated through Smad signaling; COL11A1 suppression by shRNA causes G1-phase cell cycle arrest and reduced cyclin D1, and elevated p21/cleaved caspase-3.\",\n      \"method\": \"shRNA knockdown, cell proliferation/migration/invasion assays, western blotting, cDNA microarray analysis with RT-PCR validation\",\n      \"journal\": \"Oncology reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — functional KD/OE experiments with molecular pathway characterization in NSCLC cell lines\",\n      \"pmids\": [\"27373316\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"A canonical acceptor splice-site variant (c.652-2A>C) in COL11A1 confirmed in vitro to alter RNA splicing causes autosomal dominant nonsyndromic hearing loss (DFNA37), expanding the COL11A1 phenotypic spectrum beyond syndromic collagenopathies.\",\n      \"method\": \"Genome-wide linkage analysis (LOD 8.29), exome sequencing, in vitro splicing assay, genotyping of 48 family members\",\n      \"journal\": \"Genetics in medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — functional in vitro splicing assay confirming pathogenicity, strong LOD score, segregation in large family\",\n      \"pmids\": [\"30245514\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"COL11A1 activates cancer-associated fibroblasts by triggering ERK-mediated SP1 phosphorylation, which promotes p65 nuclear translocation and NF-κB-driven IGFBP2 expression, ultimately activating TGF-β3; this CAF-cancer cell crosstalk induces IL-6 secretion promoting EOC cell proliferation and invasiveness; in vivo, COL11A1 overexpression promotes tumor formation and CAF activation reversible by anti-TGF-β3 antibody.\",\n      \"method\": \"Co-culture experiments, conditioned medium assays, shRNA/overexpression in human ovarian fibroblasts, western blotting, ChIP for p65 binding to IGFBP2 promoter, mouse xenograft model, TGF-β3 antibody rescue\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — multiple orthogonal in vitro and in vivo methods including ChIP, conditioned medium, in vivo rescue with antibody\",\n      \"pmids\": [\"34117361\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"COL11A1 activates the Akt/CREB pathway in pancreatic cancer cells, phosphorylating AktSer473 and shifting the BCL-2/BAX balance toward anti-apoptosis; COL11A1/Akt disrupts mitochondrial transmembrane potential, inhibits cytochrome c release and Apaf-1/procaspase-9/Cyt-C complex formation, suppressing the intrinsic apoptosis program and promoting gemcitabine resistance.\",\n      \"method\": \"COL11A1 overexpression/siRNA knockdown in PDAC cell lines, western blotting for Akt/CREB/BCL-2/BAX/caspase-9/cytochrome c, mitochondrial translocation assays\",\n      \"journal\": \"Journal of Cancer\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — functional OE/KD experiments with mechanistic pathway analysis at protein level in cancer cells\",\n      \"pmids\": [\"33531986\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Mutant COL11A1 (identified in 66/100 cutaneous SCCs, concentrated in the triple-helical domain) promotes tumorigenesis and accelerates neoplastic invasion by inducing β1 integrin targets; knockout of mutant COL11A1 impairs cSCC tumorigenesis in vivo; mosaic mutant COL11A1 cells also enhance invasion by neighboring wild-type cells in trans.\",\n      \"method\": \"Tumor sequencing, gene editing (CRISPR-generated mutant COL11A1 knockin), in vivo xenograft tumorigenesis, gene expression analysis (β1 integrin pathway), mosaic tissue invasion assays\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — gene-edited isogenic models with in vivo rescue and trans-cell non-cell-autonomous effect demonstrated\",\n      \"pmids\": [\"34584216\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"COL11A1 promotes epithelial-mesenchymal transition (EMT) and stemness in pancreatic cancer cells by activating the AKT/GSK-3β/Snail signaling axis, increasing p-AKTSer473, p-GSK-3βSer9, and Snail, thereby facilitating invasion and migration.\",\n      \"method\": \"siRNA/plasmid overexpression, Transwell invasion/migration assays, western blotting, flow cytometry, clone formation\",\n      \"journal\": \"Biomolecules\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — functional KD/OE with defined signaling intermediates, but single-lab study\",\n      \"pmids\": [\"35327583\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"miR-335 directly inhibits COL11A1 transcription in ovarian cancer cells; miR-335-mediated COL11A1 suppression reduces invasiveness via the Ets-1/MMP3 axis and reduces chemoresistance via the Akt/C/EBPβ/PDK1 axis, including increased PDK1 ubiquitination and degradation.\",\n      \"method\": \"miRNA mimic/inhibitor transfection, reporter assays, Akt/PDK1/ubiquitination western blots, in vivo miR-335 expression in EOC samples\",\n      \"journal\": \"Cancers\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — functional miRNA perturbation with two defined downstream pathways identified\",\n      \"pmids\": [\"34944877\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Wild-type COL11A1 expression in costal chondrocytes suppresses PAX1 and MMP3 expression; the AIS-associated COL11A1P1335L mutant abrogates suppression of MMP3, implicating a PAX1-COL11A1-MMP3 signaling axis in spinal chondrocytes; estrogen receptor (ESR2) knockdown or tamoxifen treatment also alters Col11a1 and Mmp3 expression in chondrocytes.\",\n      \"method\": \"GWAS and exome sequencing (genetic mapping), CRISPR Pax1-knockout mice, scRNA-seq, protein co-localization in spinal tissue, genetic targeting (Col11a1 overexpression in chondrocytes), ESR2 siRNA knockdown, tamoxifen treatment\",\n      \"journal\": \"eLife\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — CRISPR genetic model combined with multiple orthogonal molecular methods establishing a defined PAX1-COL11A1-MMP3 axis\",\n      \"pmids\": [\"38277211\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Col11a1-KO mice show aggravated joint degeneration and OA phenotype with disrupted chondrocyte homeostasis; scRNA-seq reveals that COL11A1 loss causes a shift from glycolysis to OXPHOS metabolism mediated by HIF1α, leading to chondrocyte cellular senescence; Col11a1-overexpressing SMSC organoids ameliorate cartilage degeneration in DDH mice by restoring HIF1α-mediated glycolysis.\",\n      \"method\": \"Col11a1-KO mice, scRNA-seq of DDH and KO cartilage, Col11a1 overexpression in SMSC organoids, intra-articular injection, histology\",\n      \"journal\": \"Clinical and translational medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — KO mouse plus scRNA-seq and organoid rescue define a metabolic mechanism, but novel pathway requires replication\",\n      \"pmids\": [\"38314968\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"COL11A1 overexpression confers tamoxifen resistance in breast cancer cells by elevating estrogen receptor α (ERα) expression and its downstream target genes; COL11A1 knockdown decreases ERα and sensitizes tamoxifen-resistant cells to 4-OHT in vitro and in vivo.\",\n      \"method\": \"Stable COL11A1 overexpression in MCF-7/T47D, tamoxifen-resistant cell line generation, siRNA knockdown, xenograft model, western blotting for ERα pathway\",\n      \"journal\": \"NPJ breast cancer\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — OE/KD with in vivo xenograft confirmation and ERα pathway mechanistic link\",\n      \"pmids\": [\"38806505\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"PDAC-derived COL11A1 promotes conversion of normal fibroblasts to CAF-like cells via NF-κB pathway activation; CAFs then secrete IL-6, which promotes PDAC cell invasion and EMT, and IL-6 activates the MAPK/ERK pathway to increase ATF4, which directly transcribes COL11A1, forming a positive feedback loop between PDAC cells and CAFs.\",\n      \"method\": \"Co-culture experiments, siRNA knockdown, western blotting for NF-κB/ERK/ATF4/COL11A1, PDAC-CAF interaction assays\",\n      \"journal\": \"Cell biology international\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — co-culture system with mechanistic intermediates defined, positive feedback loop supported by multiple assays\",\n      \"pmids\": [\"36861686\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"COL11A1 encodes the α1 chain of type XI collagen, a minor fibrillar collagen essential for heterotypic collagen fibril nucleation and diameter regulation in cartilage ECM; its N-terminal domain is surface-exposed on fibrils and mediates interactions with proteoglycans and other ECM molecules, its transcription is driven by NF-Y and Sp1 in chondrocytes, and in cancer contexts it acts as a secreted extracellular ligand that activates pro-survival signaling (Akt/PDK1 stabilization, NF-κB/IGFBP2/TGF-β3, AKT/GSK-3β/Snail, ERα upregulation) to promote chemoresistance, EMT, CAF activation, and invasion, with mutant COL11A1 additionally inducing β1-integrin-driven neoplastic invasion.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"COL11A1 encodes the α1 chain of type XI collagen, a minor fibrillar collagen that nucleates heterotypic collagen fibrils and regulates their diameter in cartilage and other connective tissues; it is essential for skeletal morphogenesis, craniofacial development, and auditory function. Loss-of-function in mice causes chondrodysplasia with disordered growth plate architecture and abnormally thick collagen fibrils, while in humans, heterozygous dominant-negative mutations cause Stickler syndrome type 2 and Marshall syndrome, biallelic null mutations cause lethal fibrochondrogenesis, and splice-site mutations cause nonsyndromic hearing loss (DFNA37) [PMID:7859283, PMID:8872475, PMID:9529347, PMID:21035103, PMID:30245514]. The N-terminal non-collagenous domain is surface-exposed on fibrils and interacts with proteoglycans and matricellular proteins to regulate fibrillogenesis, while basal transcription in chondrocytes requires NF-Y binding to the proximal promoter and Sp1 binding to a GC-rich element [PMID:22038862, PMID:12805369, PMID:26487428]. In cancer, COL11A1 is expressed by cancer-associated fibroblasts and tumor cells, where it stabilizes PDK1 to activate Akt signaling, drives NF-κB-dependent transcription of pro-survival genes, promotes epithelial-mesenchymal transition via AKT/GSK-3β/Snail, and establishes a positive-feedback loop with IL-6/ATF4 to sustain chemoresistance and stromal activation [PMID:26087191, PMID:34117361, PMID:35327583, PMID:36861686].\",\n  \"teleology\": [\n    {\n      \"year\": 1995,\n      \"claim\": \"Establishing that COL11A1 is essential for cartilage fibril organization and skeletal morphogenesis resolved the question of whether type XI collagen is structurally required or merely accessory in cartilage ECM.\",\n      \"evidence\": \"Molecular identification of the cho/cho frameshift mutation in Col11a1 in mice with chondrodysplasia, wide limb bones, and disrupted growth plates\",\n      \"pmids\": [\"7859283\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism by which α1(XI) controls fibril diameter not defined at the molecular level\", \"Role in non-cartilaginous tissues expressing Col11a1 not tested\"]\n    },\n    {\n      \"year\": 1995,\n      \"claim\": \"Demonstrating tissue-specific alternative splicing of the N-terminal variable region (exons 6A/6B) and broad embryonic expression beyond cartilage indicated that COL11A1 contributes to ECM organization in multiple organ systems.\",\n      \"evidence\": \"Exon-specific in situ hybridization and immunohistochemistry in mouse embryos showing differential exon 6A/6B distribution across skeletal, smooth muscle, and neural tissues\",\n      \"pmids\": [\"8530046\", \"8563024\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Functional consequence of each splice isoform not directly tested\", \"Whether different trimeric partners form in non-cartilage tissues is unknown\"]\n    },\n    {\n      \"year\": 1996,\n      \"claim\": \"Identifying a glycine substitution in COL11A1 as the cause of Stickler syndrome type 2 established this gene as a human disease gene and showed that the triple-helical domain is critical for vitreous collagen integrity.\",\n      \"evidence\": \"Linkage analysis and mutation identification (Gly97Val) cosegregating with vitreous/retinal disease in a family\",\n      \"pmids\": [\"8872475\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis for dominant-negative disruption not resolved\", \"Whether all glycine substitutions are equally pathogenic is unclear\"]\n    },\n    {\n      \"year\": 1999,\n      \"claim\": \"Systematic genotype-phenotype analysis distinguished Marshall syndrome (in-frame exon-skipping mutations in the C-terminal triple helix) from Stickler syndrome, revealing regional functional domains within the COL11A1 triple helix.\",\n      \"evidence\": \"Screening 23 novel mutations across COL11A1 in Marshall and Stickler families with splice-site characterization by RT-PCR\",\n      \"pmids\": [\"9529347\", \"10486316\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis for region-specific phenotypic differences not determined\", \"Whether interallelic complementation modulates severity is unknown\"]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"Identifying NF-Y as a direct transcriptional activator of the COL11A1 proximal promoter provided the first defined mechanism for basal COL11A1 transcription in chondrocytes.\",\n      \"evidence\": \"ChIP, EMSA, reporter assays, and dominant-negative NF-YA experiments in chondrocyte cell lines\",\n      \"pmids\": [\"12805369\", \"24092017\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Chondrocyte-specific cofactors beyond NF-Y and Sp1 not identified\", \"Chromatin-level regulation (enhancers, epigenetic marks) largely unexplored\"]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"Showing that Col11a1 haploinsufficiency does not cause hearing loss while dominant-negative mutations do established that Stickler/Marshall hearing phenotypes result from poisoning of wild-type collagen fibrils, not simple dosage reduction.\",\n      \"evidence\": \"ABR threshold measurement in cho/+ versus wild-type mice across multiple ages\",\n      \"pmids\": [\"12527136\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Molecular mechanism of dominant-negative interference in the cochlear tectorial membrane not defined\", \"Whether cochlear fibril diameter changes parallel the cartilage phenotype is untested\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Zebrafish col11a1 knockdown confirmed an evolutionarily conserved role in fibril diameter regulation and additionally revealed a requirement for chondrocyte hypertrophic maturation, linking ECM composition to chondrocyte differentiation.\",\n      \"evidence\": \"Morpholino knockdown in zebrafish with electron microscopy of fibrils, in situ hybridization, and histological analysis\",\n      \"pmids\": [\"19638309\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether the chondrocyte maturation defect is cell-autonomous or secondary to matrix disorganization is unclear\", \"Signaling pathway connecting fibril defects to differentiation not identified\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Identification of biallelic null COL11A1 mutations causing lethal fibrochondrogenesis — and later, demonstration that alternative splicing of exon 9 modulates severity — established a dose-dependent allelic series from null (lethal) through dominant-negative (Stickler/Marshall) phenotypes.\",\n      \"evidence\": \"SNP genotyping and autozygosity mapping in fibrochondrogenesis cases; minigene splicing assays and allele-specific RT-PCR for exon 9 effects\",\n      \"pmids\": [\"21035103\", \"23922384\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Residual function of partially spliced alleles not quantified at the protein level\", \"Whether modifier genes influence phenotypic severity is unknown\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Affinity chromatography with the N-terminal non-collagenous domain identified proteoglycans and matricellular proteins as direct binding partners, establishing this domain as a molecular hub on the fibril surface for ECM interactions.\",\n      \"evidence\": \"Recombinant N-terminal domain affinity pulldown from fetal bovine cartilage with LC-MS/MS identification\",\n      \"pmids\": [\"22038862\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Individual interactions not validated by reciprocal binding or functional assays\", \"Binding affinities and stoichiometries not determined\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Discovery that COL11A1 binds PDK1 and attenuates its ubiquitination, stabilizing Akt signaling to promote chemoresistance, revealed a non-structural oncogenic function for COL11A1 as a signaling ligand in cancer.\",\n      \"evidence\": \"Co-IP of COL11A1-PDK1, ubiquitination assays, shRNA knockdown, and overexpression in ovarian cancer cells with cisplatin/paclitaxel resistance readouts\",\n      \"pmids\": [\"26087191\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Receptor mediating COL11A1-PDK1 interaction not identified\", \"Whether PDK1 stabilization is direct or through an intermediate adaptor is unclear\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Elucidation of COL11A1-driven NF-κB activation via SP1 phosphorylation and IKKβ upregulation, leading to TWIST1/Mcl-1 transcription, expanded the downstream signaling repertoire linking COL11A1 to survival and invasion programs.\",\n      \"evidence\": \"siRNA knockdown in ovarian cancer cells with western blotting for phospho-SP1, IKKβ, TWIST1, and chemosensitivity assays\",\n      \"pmids\": [\"28815582\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"How COL11A1 activates ERK/SP1 phosphorylation at the receptor level is undefined\", \"Relative contribution of NF-κB versus Akt pathways to chemoresistance not dissected\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Demonstration that COL11A1 activates CAFs through NF-κB/IGFBP2/TGF-β3 and establishes a positive-feedback IL-6/ATF4 loop with tumor cells unified the paracrine and autocrine circuits by which COL11A1 remodels the tumor microenvironment.\",\n      \"evidence\": \"Co-culture, ChIP for p65 on IGFBP2 promoter, xenograft rescue with anti-TGF-β3 antibody; parallel study showing IL-6/MAPK/ATF4 feedback driving COL11A1 transcription in PDAC-CAF co-cultures\",\n      \"pmids\": [\"34117361\", \"36861686\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Cell-surface receptor on CAFs that senses COL11A1 is not identified\", \"Whether the feedback loop operates in non-ovarian/non-pancreatic cancers is untested\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Finding that somatic COL11A1 mutations in cutaneous SCC induce β1-integrin-dependent invasion — and non-cell-autonomously promote neighboring wild-type cell invasion — revealed a gain-of-function oncogenic mechanism distinct from the secreted wild-type protein's role.\",\n      \"evidence\": \"CRISPR knockin of mutant COL11A1 in keratinocytes, xenograft tumorigenesis, mosaic tissue invasion assays\",\n      \"pmids\": [\"34584216\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Which specific mutations are gain-of-function versus loss-of-function is not systematically classified\", \"Structural basis for mutant COL11A1 activating β1 integrin is unknown\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Identification of a PAX1-COL11A1-MMP3 axis in spinal chondrocytes and the demonstration that COL11A1 loss shifts chondrocyte metabolism from glycolysis to OXPHOS via HIF1α, driving cellular senescence, expanded COL11A1's role to a metabolic regulator of chondrocyte homeostasis.\",\n      \"evidence\": \"CRISPR Pax1-KO mice, Col11a1-KO mice, scRNA-seq, Col11a1-overexpressing SMSC organoid rescue in DDH model\",\n      \"pmids\": [\"38277211\", \"38314968\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct molecular link between COL11A1 and HIF1α stabilization is undefined\", \"Whether the metabolic shift is a direct intracellular effect or secondary to ECM changes is unclear\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The cell-surface receptor(s) through which extracellular COL11A1 activates Akt, NF-κB, and integrin signaling in cancer cells and fibroblasts remain unidentified, leaving the proximal step of its oncogenic signaling undefined.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No receptor identification study performed\", \"Whether COL11A1 signals as intact trimer, processed fragment, or monomeric chain is unknown\", \"Structural basis for COL11A1-PDK1 interaction not resolved\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0005198\", \"supporting_discovery_ids\": [0, 3, 11, 13]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [17, 23, 24, 26]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0031012\", \"supporting_discovery_ids\": [0, 11, 13]},\n      {\"term_id\": \"GO:0005576\", \"supporting_discovery_ids\": [13, 16, 17]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1474244\", \"supporting_discovery_ids\": [0, 11, 13]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [17, 20, 23, 24, 26]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [0, 7, 11, 18]}\n    ],\n    \"complexes\": [\n      \"Type XI collagen heterotrimer (α1(XI)/α2(XI)/α1(II))\"\n    ],\n    \"partners\": [\n      \"PDK1\",\n      \"NF-Y\",\n      \"SP1\",\n      \"COL2A1\",\n      \"ATF4\",\n      \"IGFBP2\",\n      \"PAX1\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}