{"gene":"COLQ","run_date":"2026-06-09T22:57:19","timeline":{"discoveries":[{"year":1998,"finding":"Human COLQ encodes the collagen-like tail subunit (ColQ) of asymmetric acetylcholinesterase (AChE). Truncation mutations proximal to the ColQ attachment domain for AChE prevent association of ColQ with AChE catalytic subunits (ACHET); mutations distal to the attachment domain generate a ~10.5S species lacking the C-terminal domain required for triple collagen helix formation, preventing insertion into the synaptic basal lamina.","method":"COS cell coexpression of COLQ mutants with wild-type ACHET, sedimentation analysis, mutation analysis in patients with endplate AChE deficiency","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — cell-based reconstitution with multiple mutants, functional readout (AChE complex assembly and basal lamina insertion), replicated across six patient mutations","pmids":["9689136"],"is_preprint":false},{"year":1998,"finding":"A missense mutation Y431S in the conserved C-terminal domain of COLQ causes congenital myasthenic syndrome type Ic (endplate AChE deficiency), mapped to chromosome 3p24.2; the C-terminal domain is required for attachment of collagen-tailed AChE to the neuromuscular junction basal lamina.","method":"Linkage analysis, Sanger sequencing, chromosomal mapping in a large consanguineous family","journal":"American journal of human genetics","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — human genetics with linkage and sequencing, no direct in vitro functional reconstitution of this specific mutation","pmids":["9758617"],"is_preprint":false},{"year":1999,"finding":"A splice-donor-site mutation at IVS16+3A→G in COLQ causes exon 16 skipping, demonstrated using a minigene in COS cells. Normal splicing requires concordance of nucleotides at positions +4 to +6 with U1 snRNA; restoring complementarity at +4 or +6 rescues normal splicing.","method":"Minigene splicing assay in COS cells, site-directed mutagenesis, analysis of U1 snRNA base-pairing","journal":"American journal of human genetics","confidence":"High","confidence_rationale":"Tier 1 / Strong — minigene reconstitution with mutagenesis rescue experiments directly establishing the splicing mechanism","pmids":["10441569"],"is_preprint":false},{"year":2003,"finding":"ColQ contains two distinct heparin-binding domains within its triple-helical collagen domain; each domain has different affinity for heparin determined not solely by basic residue number but also by local structural features of the triple helix, which can be influenced by distant regions within ColQ.","method":"Heparin affinity chromatography of ColQ mutants carrying mutations in each predicted heparin-binding domain","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — in vitro biochemical reconstitution with multiple defined mutants, direct measurement of heparin binding","pmids":["12684510"],"is_preprint":false},{"year":2004,"finding":"The COLQ gene contains two distinct promoters (pColQ-1 and pColQ-1a) driving differential expression of ColQ-1 and ColQ-1a transcripts in slow- and fast-twitch muscle fibers, respectively. Slow fiber-specific expression is regulated by a SURE element and an NFAT binding site in pColQ-1; fast fiber-specific expression is regulated by a FIRE element in pColQ-1a. Both promoters contain N-box elements responsible for synapse-specific expression.","method":"In vivo DNA transfection into soleus and tibialis muscles, promoter-reporter assays in cultured myotubes, mutation analysis of regulatory elements, calcineurin inhibition with cyclosporine A","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Strong — in vivo transfection, promoter mutagenesis, and pharmacological perturbation across multiple muscle types","pmids":["15102835"],"is_preprint":false},{"year":2005,"finding":"ColQ associates with the proline-rich attachment domain (PRAD) of ColQ via the tryptophan amphiphilic tetramerization (WAT) domain of AChE(T) subunits. The ColQ PRAD region contains two cysteines disulfide-linked to AChE(T) subunits forming a 'heavy' dimer, while the other two AChE subunits are disulfide-linked together as a 'light' dimer—a distinct arrangement from PRiMA-associated AChE tetramers.","method":"Block normal mode analysis of crystal structure-based atomic model of tetrameric [AChE(T)]4-ColQ complex","journal":"PLoS computational biology","confidence":"Medium","confidence_rationale":"Tier 1 / Weak — computational structural analysis based on published crystal structure, single study without experimental validation","pmids":["16299589"],"is_preprint":false},{"year":2007,"finding":"CGRP (calcitonin gene-related peptide) selectively induces expression of the ColQ-1a transcript (but not ColQ-1) via cAMP-CREB signaling. Two CRE sites in the pColQ-1a promoter are required; mutation of both CRE sites abolishes CGRP/cAMP responsiveness. CGRP receptor complex is predominantly expressed at neuromuscular junctions of fast muscle, explaining fast fiber-specific regulation.","method":"CGRP and Bt2-cAMP application to cultured myotubes, promoter-reporter assays, site-directed mutagenesis of CRE sites, adenylyl cyclase inhibitor, dominant-negative CREB overexpression","journal":"Journal of neurochemistry","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (pharmacology, dominant-negative, mutagenesis) in a single study","pmids":["17488278"],"is_preprint":false},{"year":2008,"finding":"ColQ associates differently with its two anchoring proteins: in complexes with ColQ PRAD, AChE(T) forms 'heavy' dimers (two subunits disulfide-linked to ColQ cysteines) and 'light' dimers; in complexes with PRiMA PRAD, light dimers predominate and heavy dimers are rare. The two cysteines upstream of the ColQ PRAD are responsible for this differential disulfide architecture.","method":"Transfection of COS cells with ColQ/PRiMA constructs and chimeras, non-reducing SDS-PAGE, comparison of mammalian brain complexes","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Strong — direct biochemical comparison with chimeric proteins, multiple constructs, orthogonal conditions","pmids":["18511416"],"is_preprint":false},{"year":2008,"finding":"Acetylcholine/nicotine stimulation of cultured myotubes induces ColQ-1 and ColQ-1a mRNA expression via CaMKII phosphorylation and downstream MEF2 activation. Overexpression of active CaMKII or MEF2 increases both ColQ transcripts; MEF2 potentiates CaMKII-induced ColQ expression.","method":"Acetylcholine/nicotine treatment of C2C12 myotubes, CaMKII phosphorylation assays, overexpression of active CaMKII mutant and MEF2","journal":"Molecular and cellular neurosciences","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — overexpression studies with multiple pathway components, single lab","pmids":["18718538"],"is_preprint":false},{"year":2010,"finding":"ColQ controls postsynaptic differentiation at the neuromuscular junction independent of its AChE-anchoring role: absence of ColQ leads to smaller, more densely-packed AChR clusters both in vitro and in vivo, decreased membrane-bound MuSK protein (despite increased MuSK mRNA), altered MuSK signaling pathway activation, perturbation of AChR clustering and β-AChR subunit phosphorylation, and modifications of AChR mRNA levels through ColQ-MuSK interaction.","method":"Comparison of wild-type and ColQ-deficient muscle cells in culture and at NMJ in vivo; immunofluorescence, biochemical analysis of MuSK and AChR clustering","journal":"The Journal of neuroscience : the official journal of the Society for Neuroscience","confidence":"High","confidence_rationale":"Tier 2 / Strong — in vitro and in vivo loss-of-function with multiple molecular readouts, consistent results across both systems","pmids":["20053883"],"is_preprint":false},{"year":2010,"finding":"In the absence of ColQ, AChE(R) and AChE(T) mRNAs are upregulated in muscle cells in vitro and in vivo, but AChE secretion into the medium is impaired. PRiMA mRNA is downregulated in the absence of ColQ. Overexpression of AChE but not ColQ alone drives AChE cluster formation.","method":"ColQ-deficient mouse and cell culture models, qPCR, AChE activity assays in conditioned medium","journal":"Chemico-biological interactions","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vitro and in vivo loss-of-function with multiple molecular readouts, single lab","pmids":["20153305"],"is_preprint":false},{"year":2013,"finding":"COOH-terminal mutations in ColQ do not affect assembly of ColQ with AChE or impair interaction with perlecan, but do impair interaction with MuSK and with basement membrane extract lacking detectable MuSK. This indicates the ColQ C-terminus interacts with additional basal lamina proteins beyond MuSK.","method":"Expression of mutant ColQ constructs, co-immunoprecipitation with perlecan and MuSK, basement membrane extract binding assays","journal":"Human genetics","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — co-immunoprecipitation and binding assays with multiple patient mutations, single lab","pmids":["24281389"],"is_preprint":false},{"year":2015,"finding":"An A-to-G mutation predicting p.E415G in COLQ exon 16 causes exclusive exon 16 skipping by disrupting binding of splicing-enhancing protein SRSF1 and de novo gaining binding of splicing-suppressing protein hnRNP H. SRSF1 and hnRNP H antagonistically regulate splicing by binding exclusively to the target site; the mutation also impairs binding of U1-70K to the downstream 5′ splice site.","method":"RNA affinity purification, mass spectrometry, siRNA knockdown of SRSF1 and hnRNP H, MS2-mediated artificial tethering, minigene splicing assays, early spliceosome complex isolation, RNA-seq","journal":"Scientific reports","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — multiple orthogonal methods including RNA affinity purification, MS, artificial tethering rescue, and spliceosome assembly assays","pmids":["26282582"],"is_preprint":false},{"year":2016,"finding":"ColQ deficiency leads to upregulation of all five nicotinic AChR subunit mRNAs, resulting in mixed mature and immature AChRs at the NMJ of adult ColQ-/- mice. ColQ also regulates ECM component expression (ECM mRNAs downregulated in vitro but compensated in vivo) and controls maturation of the postsynaptic domain through regulation of synaptic gene expression.","method":"Large-scale genetic screening and gene expression analysis of ColQ-deficient mice; NMJ and muscle phenotype analysis including AChR subunit expression profiling","journal":"FASEB journal : official publication of the Federation of American Societies for Experimental Biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo loss-of-function with comprehensive gene expression and morphological readouts, single lab","pmids":["26993635"],"is_preprint":false},{"year":2019,"finding":"Salbutamol (β-adrenergic agonist) treatment of ColQ-/- mice leads to gradual improvement in muscle strength and structural improvements at the postsynaptic NMJ including increased synaptic area, AChR area and density, and extent of postjunctional folds, without changes in muscle fiber size or type. This demonstrates that β-adrenergic signaling acts primarily at the postsynaptic membrane.","method":"In vivo drug treatment of ColQ-/- mice (7 weeks daily injection), grip strength testing, NMJ morphological analysis","journal":"Human molecular genetics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo treatment with functional and morphological readouts in a defined genetic model, single lab","pmids":["31220253"],"is_preprint":false},{"year":2023,"finding":"ColQ binds directly to LRP4 (not directly to MuSK), interacting indirectly with MuSK through LRP4. The LRP4 N-terminal region containing agrin-binding sites is also crucial for ColQ binding. ColQ and agrin compete for binding to LRP4. ColQ has two opposing effects on agrin-induced MuSK-LRP4 signaling: it constitutively reduces MuSK phosphorylation levels in agrin-stimulated myotubes but increases MuSK accumulation at the muscle cell surface.","method":"Co-immunoprecipitation, pull-down assays, plate-binding assays, surface plasmon resonance (SPR)","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — multiple orthogonal biochemical methods including SPR for direct binding, co-IP, and pull-down; functional signaling readouts","pmids":["37356721"],"is_preprint":false},{"year":2023,"finding":"A C-terminal splice site variant in COLQ (c.1281 C>T) alters the last 28 amino acids without impairing collagen triple helix formation, AChE association, or secretion of hetero-oligomers, but reduces interaction of ColQ with LRP4 by 44% and increases all AChR subunit mRNA levels in patient iPSC-derived muscle cells.","method":"COS cell and mouse muscle cell expression of COLQ variant, biochemical interaction assays with LRP4, iPSC-derived muscle cell analysis, AChR subunit mRNA quantification","journal":"International journal of molecular sciences","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vitro biochemical reconstitution with patient-derived iPSC model, single lab, multiple readouts","pmids":["38003406"],"is_preprint":false},{"year":2012,"finding":"ColQ interaction with MuSK is required for NMJ development and maintenance: ColQ controls aspects of postsynaptic differentiation such as AChR clustering through its interaction with MuSK, suggesting that defects in ColQ signaling (not only AChE deficiency) contribute to the pathophysiology of synaptic congenital myasthenic syndromes.","method":"Review/summary of cell culture and in vivo data from ColQ-deficient models analyzing MuSK interaction and postsynaptic differentiation","journal":"Chemico-biological interactions","confidence":"Low","confidence_rationale":"Tier 3 / Weak — review paper summarizing prior findings without new primary experiments","pmids":["23089045"],"is_preprint":false},{"year":2005,"finding":"ColQ PRAD-AChE interaction: the crystal structure of the WAT-PRAD complex was used to build a tetrameric [AChE(T)]4-ColQ atomic model. Normal mode analysis shows significant low-frequency motions among catalytic domains of the four AChE subunits while the [WAT]4PRAD holds the complex together, supporting a flexible tetramer model.","method":"Atomic model building from crystal structure coordinates, energy minimization, block normal mode analysis","journal":"PLoS computational biology","confidence":"Low","confidence_rationale":"Tier 4 / Weak — computational structural analysis only, no experimental validation in this paper","pmids":["16299589"],"is_preprint":false},{"year":2053,"finding":"COLQ protein localizes to the myenteric plexus in the colon, as demonstrated by immunohistochemistry of colon tissue from diverticulitis patients.","method":"Immunohistochemistry of human colon tissue","journal":"The Journal of surgical research","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single localization study, no functional consequence established","pmids":["34225052"],"is_preprint":false}],"current_model":"ColQ is a non-fibrillar collagen that forms the tail subunit of asymmetric acetylcholinesterase (AChE) at vertebrate neuromuscular junctions: its N-terminal proline-rich attachment domain (PRAD) assembles with WAT domains of AChE(T) tetramers via specific disulfide-linked heavy/light dimer architecture; its triple-helical collagen domain contains two heparin-binding sites for anchoring to heparan sulfate proteoglycans (including perlecan) in the synaptic basal lamina; and its C-terminal domain directly binds LRP4 (not MuSK directly), competing with agrin and modulating MuSK phosphorylation and surface accumulation, thereby controlling both AChE anchoring and postsynaptic differentiation including AChR clustering, AChR subunit maturation, and synaptic gene expression through LRP4-MuSK signaling."},"narrative":{"mechanistic_narrative":"COLQ encodes the non-fibrillar collagen-like tail subunit (ColQ) that organizes asymmetric acetylcholinesterase (AChE) and contributes to postsynaptic organization at the vertebrate neuromuscular junction [PMID:9689136, PMID:20053883]. Its N-terminal proline-rich attachment domain (PRAD) assembles with the WAT domains of AChE(T) tetramers, with two cysteines upstream of the PRAD imposing a characteristic 'heavy/light' disulfide-linked dimer architecture that distinguishes ColQ-anchored AChE from PRiMA-anchored AChE [PMID:18511416]; truncations proximal to this attachment domain abolish AChE association, while distal mutations prevent the C-terminal triple-helix formation needed for basal lamina insertion [PMID:9689136]. The triple-helical collagen domain carries two distinct heparin-binding sites for anchoring to heparan sulfate proteoglycans in the synaptic basal lamina [PMID:12684510], and the C-terminal domain binds directly to LRP4 (not MuSK directly), competing with agrin and thereby exerting opposing effects on agrin-induced signaling—reducing MuSK phosphorylation while increasing MuSK surface accumulation [PMID:37356721]. Through this LRP4-MuSK axis ColQ controls postsynaptic differentiation independent of its AChE-anchoring role, including AChR clustering, AChR subunit maturation, and synaptic gene expression [PMID:20053883, PMID:26993635]. COLQ is transcribed from two synapse-specific promoters that drive fiber-type-restricted ColQ-1 and ColQ-1a expression under control of NFAT, MEF2, and cAMP-CREB signaling [PMID:15102835, PMID:17488278, PMID:18718538]. Loss-of-function and splicing mutations in COLQ cause congenital myasthenic syndrome with endplate AChE deficiency [PMID:9758617, PMID:26282582].","teleology":[{"year":1998,"claim":"Established that COLQ encodes the collagen tail subunit of asymmetric AChE and defined which protein domains mediate AChE catalytic-subunit association versus basal lamina insertion, explaining how patient mutations cause endplate AChE deficiency.","evidence":"COS cell coexpression of COLQ mutants with ACHET, sedimentation analysis, and patient mutation analysis; linkage and sequencing in a consanguineous family","pmids":["9689136","9758617"],"confidence":"High","gaps":["The structural basis of the PRAD-AChE and C-terminal interactions was not resolved","The specific basal lamina partner bound by the C-terminus was not identified"]},{"year":1999,"claim":"Resolved a splicing mechanism by which a COLQ splice-donor mutation causes exon skipping, showing dependence on U1 snRNA complementarity.","evidence":"Minigene splicing assay in COS cells with mutagenesis rescue at +4/+6 positions","pmids":["10441569"],"confidence":"High","gaps":["Did not address trans-acting splicing factors at this site","Limited to one mutation"]},{"year":2003,"claim":"Defined the heparin-binding architecture of the ColQ collagen domain, showing two functionally distinct heparin-binding sites whose affinity depends on triple-helix conformation, explaining anchoring to synaptic proteoglycans.","evidence":"Heparin affinity chromatography of defined ColQ mutants","pmids":["12684510"],"confidence":"High","gaps":["The in vivo proteoglycan partner specificity was not directly established here","Did not quantify relative contributions of each site at the NMJ"]},{"year":2004,"claim":"Showed that COLQ is regulated by two distinct synapse-specific promoters driving fiber-type-specific transcripts via NFAT, SURE, FIRE, and N-box elements, explaining differential ColQ expression in slow versus fast muscle.","evidence":"In vivo muscle DNA transfection, promoter-reporter assays, regulatory element mutagenesis, calcineurin inhibition","pmids":["15102835"],"confidence":"High","gaps":["Upstream signals coupling nerve activity to each promoter were not fully defined","Did not establish functional consequences of fiber-type-specific isoforms"]},{"year":2005,"claim":"Provided a structural model of the AChE(T) tetramer-ColQ PRAD complex and the disulfide arrangement defining heavy/light dimers, distinguishing it from PRiMA-anchored AChE.","evidence":"Crystal-structure-based atomic model building and block normal mode analysis","pmids":["16299589"],"confidence":"Medium","gaps":["Computational model not experimentally validated in this study","Dynamics of the full collagen-tailed complex not addressed"]},{"year":2007,"claim":"Identified CGRP/cAMP-CREB signaling through two CRE sites as the selective inducer of the fast-fiber ColQ-1a transcript, linking neuropeptide signaling to fiber-type-specific COLQ expression.","evidence":"CGRP/Bt2-cAMP treatment of myotubes, CRE mutagenesis, adenylyl cyclase inhibition, dominant-negative CREB","pmids":["17488278"],"confidence":"High","gaps":["In vivo relevance of CGRP regulation at the NMJ not directly tested","Interaction with other activity-dependent pathways not resolved"]},{"year":2008,"claim":"Connected synaptic activity to COLQ expression by showing acetylcholine/nicotine induces both ColQ transcripts via CaMKII and MEF2, and refined the disulfide-architecture distinction between ColQ- and PRiMA-anchored AChE.","evidence":"Acetylcholine/nicotine treatment of C2C12 myotubes with active CaMKII/MEF2 overexpression; chimeric ColQ/PRiMA constructs with non-reducing SDS-PAGE","pmids":["18718538","18511416"],"confidence":"Medium","gaps":["Overexpression-based pathway evidence not validated by endogenous loss-of-function","Physiological signal integration in vivo not established"]},{"year":2010,"claim":"Revealed an AChE-independent role for ColQ in postsynaptic differentiation, showing that ColQ deficiency disrupts MuSK surface levels, AChR clustering, β-AChR phosphorylation, and AChE secretion.","evidence":"Loss-of-function comparison in cultured muscle cells and at the NMJ in vivo with immunofluorescence and biochemical readouts; qPCR and AChE activity assays","pmids":["20053883","20153305"],"confidence":"High","gaps":["Direct molecular link between ColQ and MuSK was not yet established","Mechanism coupling ColQ to AChR subunit transcription unclear"]},{"year":2013,"claim":"Separated the AChE-anchoring and signaling functions of the ColQ C-terminus, showing C-terminal mutations preserve AChE assembly and perlecan binding but impair MuSK and basement-membrane interactions.","evidence":"Mutant ColQ expression with co-immunoprecipitation against perlecan and MuSK and basement membrane extract binding","pmids":["24281389"],"confidence":"Medium","gaps":["The additional basal lamina partner inferred beyond MuSK was not identified","Single-lab co-IP without orthogonal binding quantification"]},{"year":2015,"claim":"Defined the molecular logic of a COLQ exon 16 splicing mutation as antagonistic SRSF1/hnRNP H binding and impaired U1-70K recruitment, explaining exon skipping in disease.","evidence":"RNA affinity purification, mass spectrometry, SRSF1/hnRNP H knockdown, MS2 tethering, minigene assays, spliceosome complex isolation, RNA-seq","pmids":["26282582"],"confidence":"High","gaps":["Did not address whether other COLQ exons share this regulatory logic","Therapeutic correction of splicing not tested"]},{"year":2016,"claim":"Demonstrated that ColQ controls postsynaptic maturation through synaptic gene expression, with ColQ deficiency upregulating all AChR subunit mRNAs and producing mixed mature/immature AChRs and altered ECM expression.","evidence":"Genetic screening and gene expression profiling of ColQ-deficient mice with NMJ morphological analysis","pmids":["26993635"],"confidence":"Medium","gaps":["Single-lab in vivo profiling","Direct signaling intermediaries to subunit transcription not pinpointed"]},{"year":2019,"claim":"Showed that β-adrenergic agonism rescues NMJ structure and muscle strength in ColQ-deficient mice, localizing the therapeutic effect to the postsynaptic membrane.","evidence":"In vivo salbutamol treatment of ColQ-/- mice with grip strength and NMJ morphometry","pmids":["31220253"],"confidence":"Medium","gaps":["Molecular target of β-adrenergic rescue at the NMJ not defined","Single-model, single-lab study"]},{"year":2023,"claim":"Established that ColQ binds LRP4 directly (not MuSK directly), competes with agrin, and exerts opposing effects on MuSK phosphorylation versus surface accumulation, providing the receptor-level mechanism for ColQ control of postsynaptic signaling.","evidence":"Co-immunoprecipitation, pull-down, plate-binding, and SPR; patient COLQ variant analysis in COS cells and iPSC-derived muscle cells","pmids":["37356721","38003406"],"confidence":"High","gaps":["Structural basis of the ColQ-LRP4 interface not resolved","How the two opposing effects are temporally integrated during synaptogenesis unclear"]},{"year":null,"claim":"The non-junctional functions of ColQ, the identity of additional basal lamina partners beyond LRP4/perlecan, and the structural mechanism by which ColQ tunes LRP4-MuSK signaling remain open.","evidence":"","pmids":[],"confidence":"Low","gaps":["No structure of the ColQ-LRP4 complex","Functional significance of reported myenteric plexus localization unestablished","Integration of competing agrin/ColQ inputs in vivo not resolved"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0005198","term_label":"structural molecule activity","supporting_discovery_ids":[0,5]},{"term_id":"GO:0008289","term_label":"lipid binding","supporting_discovery_ids":[3]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[9,15]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[15]}],"localization":[{"term_id":"GO:0031012","term_label":"extracellular matrix","supporting_discovery_ids":[0,3]},{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[9,15]}],"pathway":[{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[4,6,8]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[9,17]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[15]}],"complexes":["asymmetric acetylcholinesterase (collagen-tailed AChE)"],"partners":["ACHE","LRP4","PERLECAN/HSPG2","MUSK","SRSF1","HNRNPH"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q9Y215","full_name":"Acetylcholinesterase collagenic tail peptide","aliases":["AChE Q subunit","Acetylcholinesterase-associated collagen"],"length_aa":455,"mass_kda":47.8,"function":"Anchors the catalytic subunits of asymmetric AChE to the synaptic basal membrane, and is therefore involved in the down-regulation of colinergic synaptic transmission","subcellular_location":"Synapse","url":"https://www.uniprot.org/uniprotkb/Q9Y215/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/COLQ","classification":"Not Classified","n_dependent_lines":0,"n_total_lines":1208,"dependency_fraction":0.0},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/COLQ","total_profiled":1310},"omim":[{"mim_id":"603034","title":"MYASTHENIC SYNDROME, CONGENITAL, 5; CMS5","url":"https://www.omim.org/entry/603034"},{"mim_id":"603033","title":"COLLAGENIC TAIL OF ENDPLATE ACETYLCHOLINESTERASE; COLQ","url":"https://www.omim.org/entry/603033"},{"mim_id":"601462","title":"MYASTHENIC SYNDROME, CONGENITAL, 1A, SLOW-CHANNEL; CMS1A","url":"https://www.omim.org/entry/601462"},{"mim_id":"177400","title":"BUTYRYLCHOLINESTERASE; BCHE","url":"https://www.omim.org/entry/177400"},{"mim_id":"142461","title":"HEPARAN SULFATE PROTEOGLYCAN OF BASEMENT MEMBRANE; HSPG2","url":"https://www.omim.org/entry/142461"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Plasma membrane","reliability":"Approved"},{"location":"Cell Junctions","reliability":"Additional"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"choroid plexus","ntpm":14.2},{"tissue":"heart muscle","ntpm":16.8}],"url":"https://www.proteinatlas.org/search/COLQ"},"hgnc":{"alias_symbol":["EAD"],"prev_symbol":[]},"alphafold":{"accession":"Q9Y215","domains":[{"cath_id":"-","chopping":"320-358","consensus_level":"high","plddt":85.5731,"start":320,"end":358},{"cath_id":"-","chopping":"371-402","consensus_level":"medium","plddt":47.2025,"start":371,"end":402},{"cath_id":"-","chopping":"405-455","consensus_level":"medium","plddt":53.0212,"start":405,"end":455}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9Y215","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q9Y215-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q9Y215-F1-predicted_aligned_error_v6.png","plddt_mean":54.47},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=COLQ","jax_strain_url":"https://www.jax.org/strain/search?query=COLQ"},"sequence":{"accession":"Q9Y215","fasta_url":"https://rest.uniprot.org/uniprotkb/Q9Y215.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q9Y215/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9Y215"}},"corpus_meta":[{"pmid":"9689136","id":"PMC_9689136","title":"Human endplate acetylcholinesterase deficiency caused by mutations in the collagen-like tail subunit (ColQ) of the asymmetric enzyme.","date":"1998","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/9689136","citation_count":208,"is_preprint":false},{"pmid":"2164595","id":"PMC_2164595","title":"The Epstein-Barr virus (EBV) BMRF1 promoter for early antigen (EA-D) is regulated by the EBV transactivators, BRLF1 and BZLF1, in a cell-specific manner.","date":"1990","source":"Journal of virology","url":"https://pubmed.ncbi.nlm.nih.gov/2164595","citation_count":146,"is_preprint":false},{"pmid":"9758617","id":"PMC_9758617","title":"Mutation in the human acetylcholinesterase-associated collagen gene, COLQ, is responsible for congenital myasthenic syndrome with end-plate acetylcholinesterase deficiency (Type Ic).","date":"1998","source":"American journal of human 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encodes the collagen-like tail subunit (ColQ) of asymmetric acetylcholinesterase (AChE). Truncation mutations proximal to the ColQ attachment domain for AChE prevent association of ColQ with AChE catalytic subunits (ACHET); mutations distal to the attachment domain generate a ~10.5S species lacking the C-terminal domain required for triple collagen helix formation, preventing insertion into the synaptic basal lamina.\",\n      \"method\": \"COS cell coexpression of COLQ mutants with wild-type ACHET, sedimentation analysis, mutation analysis in patients with endplate AChE deficiency\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — cell-based reconstitution with multiple mutants, functional readout (AChE complex assembly and basal lamina insertion), replicated across six patient mutations\",\n      \"pmids\": [\"9689136\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1998,\n      \"finding\": \"A missense mutation Y431S in the conserved C-terminal domain of COLQ causes congenital myasthenic syndrome type Ic (endplate AChE deficiency), mapped to chromosome 3p24.2; the C-terminal domain is required for attachment of collagen-tailed AChE to the neuromuscular junction basal lamina.\",\n      \"method\": \"Linkage analysis, Sanger sequencing, chromosomal mapping in a large consanguineous family\",\n      \"journal\": \"American journal of human genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — human genetics with linkage and sequencing, no direct in vitro functional reconstitution of this specific mutation\",\n      \"pmids\": [\"9758617\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"A splice-donor-site mutation at IVS16+3A→G in COLQ causes exon 16 skipping, demonstrated using a minigene in COS cells. Normal splicing requires concordance of nucleotides at positions +4 to +6 with U1 snRNA; restoring complementarity at +4 or +6 rescues normal splicing.\",\n      \"method\": \"Minigene splicing assay in COS cells, site-directed mutagenesis, analysis of U1 snRNA base-pairing\",\n      \"journal\": \"American journal of human genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — minigene reconstitution with mutagenesis rescue experiments directly establishing the splicing mechanism\",\n      \"pmids\": [\"10441569\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"ColQ contains two distinct heparin-binding domains within its triple-helical collagen domain; each domain has different affinity for heparin determined not solely by basic residue number but also by local structural features of the triple helix, which can be influenced by distant regions within ColQ.\",\n      \"method\": \"Heparin affinity chromatography of ColQ mutants carrying mutations in each predicted heparin-binding domain\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — in vitro biochemical reconstitution with multiple defined mutants, direct measurement of heparin binding\",\n      \"pmids\": [\"12684510\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"The COLQ gene contains two distinct promoters (pColQ-1 and pColQ-1a) driving differential expression of ColQ-1 and ColQ-1a transcripts in slow- and fast-twitch muscle fibers, respectively. Slow fiber-specific expression is regulated by a SURE element and an NFAT binding site in pColQ-1; fast fiber-specific expression is regulated by a FIRE element in pColQ-1a. Both promoters contain N-box elements responsible for synapse-specific expression.\",\n      \"method\": \"In vivo DNA transfection into soleus and tibialis muscles, promoter-reporter assays in cultured myotubes, mutation analysis of regulatory elements, calcineurin inhibition with cyclosporine A\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — in vivo transfection, promoter mutagenesis, and pharmacological perturbation across multiple muscle types\",\n      \"pmids\": [\"15102835\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"ColQ associates with the proline-rich attachment domain (PRAD) of ColQ via the tryptophan amphiphilic tetramerization (WAT) domain of AChE(T) subunits. The ColQ PRAD region contains two cysteines disulfide-linked to AChE(T) subunits forming a 'heavy' dimer, while the other two AChE subunits are disulfide-linked together as a 'light' dimer—a distinct arrangement from PRiMA-associated AChE tetramers.\",\n      \"method\": \"Block normal mode analysis of crystal structure-based atomic model of tetrameric [AChE(T)]4-ColQ complex\",\n      \"journal\": \"PLoS computational biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Weak — computational structural analysis based on published crystal structure, single study without experimental validation\",\n      \"pmids\": [\"16299589\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"CGRP (calcitonin gene-related peptide) selectively induces expression of the ColQ-1a transcript (but not ColQ-1) via cAMP-CREB signaling. Two CRE sites in the pColQ-1a promoter are required; mutation of both CRE sites abolishes CGRP/cAMP responsiveness. CGRP receptor complex is predominantly expressed at neuromuscular junctions of fast muscle, explaining fast fiber-specific regulation.\",\n      \"method\": \"CGRP and Bt2-cAMP application to cultured myotubes, promoter-reporter assays, site-directed mutagenesis of CRE sites, adenylyl cyclase inhibitor, dominant-negative CREB overexpression\",\n      \"journal\": \"Journal of neurochemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (pharmacology, dominant-negative, mutagenesis) in a single study\",\n      \"pmids\": [\"17488278\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"ColQ associates differently with its two anchoring proteins: in complexes with ColQ PRAD, AChE(T) forms 'heavy' dimers (two subunits disulfide-linked to ColQ cysteines) and 'light' dimers; in complexes with PRiMA PRAD, light dimers predominate and heavy dimers are rare. The two cysteines upstream of the ColQ PRAD are responsible for this differential disulfide architecture.\",\n      \"method\": \"Transfection of COS cells with ColQ/PRiMA constructs and chimeras, non-reducing SDS-PAGE, comparison of mammalian brain complexes\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — direct biochemical comparison with chimeric proteins, multiple constructs, orthogonal conditions\",\n      \"pmids\": [\"18511416\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"Acetylcholine/nicotine stimulation of cultured myotubes induces ColQ-1 and ColQ-1a mRNA expression via CaMKII phosphorylation and downstream MEF2 activation. Overexpression of active CaMKII or MEF2 increases both ColQ transcripts; MEF2 potentiates CaMKII-induced ColQ expression.\",\n      \"method\": \"Acetylcholine/nicotine treatment of C2C12 myotubes, CaMKII phosphorylation assays, overexpression of active CaMKII mutant and MEF2\",\n      \"journal\": \"Molecular and cellular neurosciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — overexpression studies with multiple pathway components, single lab\",\n      \"pmids\": [\"18718538\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"ColQ controls postsynaptic differentiation at the neuromuscular junction independent of its AChE-anchoring role: absence of ColQ leads to smaller, more densely-packed AChR clusters both in vitro and in vivo, decreased membrane-bound MuSK protein (despite increased MuSK mRNA), altered MuSK signaling pathway activation, perturbation of AChR clustering and β-AChR subunit phosphorylation, and modifications of AChR mRNA levels through ColQ-MuSK interaction.\",\n      \"method\": \"Comparison of wild-type and ColQ-deficient muscle cells in culture and at NMJ in vivo; immunofluorescence, biochemical analysis of MuSK and AChR clustering\",\n      \"journal\": \"The Journal of neuroscience : the official journal of the Society for Neuroscience\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — in vitro and in vivo loss-of-function with multiple molecular readouts, consistent results across both systems\",\n      \"pmids\": [\"20053883\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"In the absence of ColQ, AChE(R) and AChE(T) mRNAs are upregulated in muscle cells in vitro and in vivo, but AChE secretion into the medium is impaired. PRiMA mRNA is downregulated in the absence of ColQ. Overexpression of AChE but not ColQ alone drives AChE cluster formation.\",\n      \"method\": \"ColQ-deficient mouse and cell culture models, qPCR, AChE activity assays in conditioned medium\",\n      \"journal\": \"Chemico-biological interactions\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vitro and in vivo loss-of-function with multiple molecular readouts, single lab\",\n      \"pmids\": [\"20153305\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"COOH-terminal mutations in ColQ do not affect assembly of ColQ with AChE or impair interaction with perlecan, but do impair interaction with MuSK and with basement membrane extract lacking detectable MuSK. This indicates the ColQ C-terminus interacts with additional basal lamina proteins beyond MuSK.\",\n      \"method\": \"Expression of mutant ColQ constructs, co-immunoprecipitation with perlecan and MuSK, basement membrane extract binding assays\",\n      \"journal\": \"Human genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — co-immunoprecipitation and binding assays with multiple patient mutations, single lab\",\n      \"pmids\": [\"24281389\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"An A-to-G mutation predicting p.E415G in COLQ exon 16 causes exclusive exon 16 skipping by disrupting binding of splicing-enhancing protein SRSF1 and de novo gaining binding of splicing-suppressing protein hnRNP H. SRSF1 and hnRNP H antagonistically regulate splicing by binding exclusively to the target site; the mutation also impairs binding of U1-70K to the downstream 5′ splice site.\",\n      \"method\": \"RNA affinity purification, mass spectrometry, siRNA knockdown of SRSF1 and hnRNP H, MS2-mediated artificial tethering, minigene splicing assays, early spliceosome complex isolation, RNA-seq\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — multiple orthogonal methods including RNA affinity purification, MS, artificial tethering rescue, and spliceosome assembly assays\",\n      \"pmids\": [\"26282582\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"ColQ deficiency leads to upregulation of all five nicotinic AChR subunit mRNAs, resulting in mixed mature and immature AChRs at the NMJ of adult ColQ-/- mice. ColQ also regulates ECM component expression (ECM mRNAs downregulated in vitro but compensated in vivo) and controls maturation of the postsynaptic domain through regulation of synaptic gene expression.\",\n      \"method\": \"Large-scale genetic screening and gene expression analysis of ColQ-deficient mice; NMJ and muscle phenotype analysis including AChR subunit expression profiling\",\n      \"journal\": \"FASEB journal : official publication of the Federation of American Societies for Experimental Biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo loss-of-function with comprehensive gene expression and morphological readouts, single lab\",\n      \"pmids\": [\"26993635\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Salbutamol (β-adrenergic agonist) treatment of ColQ-/- mice leads to gradual improvement in muscle strength and structural improvements at the postsynaptic NMJ including increased synaptic area, AChR area and density, and extent of postjunctional folds, without changes in muscle fiber size or type. This demonstrates that β-adrenergic signaling acts primarily at the postsynaptic membrane.\",\n      \"method\": \"In vivo drug treatment of ColQ-/- mice (7 weeks daily injection), grip strength testing, NMJ morphological analysis\",\n      \"journal\": \"Human molecular genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo treatment with functional and morphological readouts in a defined genetic model, single lab\",\n      \"pmids\": [\"31220253\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"ColQ binds directly to LRP4 (not directly to MuSK), interacting indirectly with MuSK through LRP4. The LRP4 N-terminal region containing agrin-binding sites is also crucial for ColQ binding. ColQ and agrin compete for binding to LRP4. ColQ has two opposing effects on agrin-induced MuSK-LRP4 signaling: it constitutively reduces MuSK phosphorylation levels in agrin-stimulated myotubes but increases MuSK accumulation at the muscle cell surface.\",\n      \"method\": \"Co-immunoprecipitation, pull-down assays, plate-binding assays, surface plasmon resonance (SPR)\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — multiple orthogonal biochemical methods including SPR for direct binding, co-IP, and pull-down; functional signaling readouts\",\n      \"pmids\": [\"37356721\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"A C-terminal splice site variant in COLQ (c.1281 C>T) alters the last 28 amino acids without impairing collagen triple helix formation, AChE association, or secretion of hetero-oligomers, but reduces interaction of ColQ with LRP4 by 44% and increases all AChR subunit mRNA levels in patient iPSC-derived muscle cells.\",\n      \"method\": \"COS cell and mouse muscle cell expression of COLQ variant, biochemical interaction assays with LRP4, iPSC-derived muscle cell analysis, AChR subunit mRNA quantification\",\n      \"journal\": \"International journal of molecular sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vitro biochemical reconstitution with patient-derived iPSC model, single lab, multiple readouts\",\n      \"pmids\": [\"38003406\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"ColQ interaction with MuSK is required for NMJ development and maintenance: ColQ controls aspects of postsynaptic differentiation such as AChR clustering through its interaction with MuSK, suggesting that defects in ColQ signaling (not only AChE deficiency) contribute to the pathophysiology of synaptic congenital myasthenic syndromes.\",\n      \"method\": \"Review/summary of cell culture and in vivo data from ColQ-deficient models analyzing MuSK interaction and postsynaptic differentiation\",\n      \"journal\": \"Chemico-biological interactions\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — review paper summarizing prior findings without new primary experiments\",\n      \"pmids\": [\"23089045\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"ColQ PRAD-AChE interaction: the crystal structure of the WAT-PRAD complex was used to build a tetrameric [AChE(T)]4-ColQ atomic model. Normal mode analysis shows significant low-frequency motions among catalytic domains of the four AChE subunits while the [WAT]4PRAD holds the complex together, supporting a flexible tetramer model.\",\n      \"method\": \"Atomic model building from crystal structure coordinates, energy minimization, block normal mode analysis\",\n      \"journal\": \"PLoS computational biology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 4 / Weak — computational structural analysis only, no experimental validation in this paper\",\n      \"pmids\": [\"16299589\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2053,\n      \"finding\": \"COLQ protein localizes to the myenteric plexus in the colon, as demonstrated by immunohistochemistry of colon tissue from diverticulitis patients.\",\n      \"method\": \"Immunohistochemistry of human colon tissue\",\n      \"journal\": \"The Journal of surgical research\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single localization study, no functional consequence established\",\n      \"pmids\": [\"34225052\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"ColQ is a non-fibrillar collagen that forms the tail subunit of asymmetric acetylcholinesterase (AChE) at vertebrate neuromuscular junctions: its N-terminal proline-rich attachment domain (PRAD) assembles with WAT domains of AChE(T) tetramers via specific disulfide-linked heavy/light dimer architecture; its triple-helical collagen domain contains two heparin-binding sites for anchoring to heparan sulfate proteoglycans (including perlecan) in the synaptic basal lamina; and its C-terminal domain directly binds LRP4 (not MuSK directly), competing with agrin and modulating MuSK phosphorylation and surface accumulation, thereby controlling both AChE anchoring and postsynaptic differentiation including AChR clustering, AChR subunit maturation, and synaptic gene expression through LRP4-MuSK signaling.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"COLQ encodes the non-fibrillar collagen-like tail subunit (ColQ) that organizes asymmetric acetylcholinesterase (AChE) and contributes to postsynaptic organization at the vertebrate neuromuscular junction [#0, #9]. Its N-terminal proline-rich attachment domain (PRAD) assembles with the WAT domains of AChE(T) tetramers, with two cysteines upstream of the PRAD imposing a characteristic 'heavy/light' disulfide-linked dimer architecture that distinguishes ColQ-anchored AChE from PRiMA-anchored AChE [#7]; truncations proximal to this attachment domain abolish AChE association, while distal mutations prevent the C-terminal triple-helix formation needed for basal lamina insertion [#0]. The triple-helical collagen domain carries two distinct heparin-binding sites for anchoring to heparan sulfate proteoglycans in the synaptic basal lamina [#3], and the C-terminal domain binds directly to LRP4 (not MuSK directly), competing with agrin and thereby exerting opposing effects on agrin-induced signaling—reducing MuSK phosphorylation while increasing MuSK surface accumulation [#15]. Through this LRP4-MuSK axis ColQ controls postsynaptic differentiation independent of its AChE-anchoring role, including AChR clustering, AChR subunit maturation, and synaptic gene expression [#9, #13]. COLQ is transcribed from two synapse-specific promoters that drive fiber-type-restricted ColQ-1 and ColQ-1a expression under control of NFAT, MEF2, and cAMP-CREB signaling [#4, #6, #8]. Loss-of-function and splicing mutations in COLQ cause congenital myasthenic syndrome with endplate AChE deficiency [#1, #12].\",\n  \"teleology\": [\n    {\n      \"year\": 1998,\n      \"claim\": \"Established that COLQ encodes the collagen tail subunit of asymmetric AChE and defined which protein domains mediate AChE catalytic-subunit association versus basal lamina insertion, explaining how patient mutations cause endplate AChE deficiency.\",\n      \"evidence\": \"COS cell coexpression of COLQ mutants with ACHET, sedimentation analysis, and patient mutation analysis; linkage and sequencing in a consanguineous family\",\n      \"pmids\": [\"9689136\", \"9758617\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"The structural basis of the PRAD-AChE and C-terminal interactions was not resolved\", \"The specific basal lamina partner bound by the C-terminus was not identified\"]\n    },\n    {\n      \"year\": 1999,\n      \"claim\": \"Resolved a splicing mechanism by which a COLQ splice-donor mutation causes exon skipping, showing dependence on U1 snRNA complementarity.\",\n      \"evidence\": \"Minigene splicing assay in COS cells with mutagenesis rescue at +4/+6 positions\",\n      \"pmids\": [\"10441569\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not address trans-acting splicing factors at this site\", \"Limited to one mutation\"]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"Defined the heparin-binding architecture of the ColQ collagen domain, showing two functionally distinct heparin-binding sites whose affinity depends on triple-helix conformation, explaining anchoring to synaptic proteoglycans.\",\n      \"evidence\": \"Heparin affinity chromatography of defined ColQ mutants\",\n      \"pmids\": [\"12684510\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"The in vivo proteoglycan partner specificity was not directly established here\", \"Did not quantify relative contributions of each site at the NMJ\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Showed that COLQ is regulated by two distinct synapse-specific promoters driving fiber-type-specific transcripts via NFAT, SURE, FIRE, and N-box elements, explaining differential ColQ expression in slow versus fast muscle.\",\n      \"evidence\": \"In vivo muscle DNA transfection, promoter-reporter assays, regulatory element mutagenesis, calcineurin inhibition\",\n      \"pmids\": [\"15102835\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Upstream signals coupling nerve activity to each promoter were not fully defined\", \"Did not establish functional consequences of fiber-type-specific isoforms\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Provided a structural model of the AChE(T) tetramer-ColQ PRAD complex and the disulfide arrangement defining heavy/light dimers, distinguishing it from PRiMA-anchored AChE.\",\n      \"evidence\": \"Crystal-structure-based atomic model building and block normal mode analysis\",\n      \"pmids\": [\"16299589\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Computational model not experimentally validated in this study\", \"Dynamics of the full collagen-tailed complex not addressed\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Identified CGRP/cAMP-CREB signaling through two CRE sites as the selective inducer of the fast-fiber ColQ-1a transcript, linking neuropeptide signaling to fiber-type-specific COLQ expression.\",\n      \"evidence\": \"CGRP/Bt2-cAMP treatment of myotubes, CRE mutagenesis, adenylyl cyclase inhibition, dominant-negative CREB\",\n      \"pmids\": [\"17488278\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"In vivo relevance of CGRP regulation at the NMJ not directly tested\", \"Interaction with other activity-dependent pathways not resolved\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Connected synaptic activity to COLQ expression by showing acetylcholine/nicotine induces both ColQ transcripts via CaMKII and MEF2, and refined the disulfide-architecture distinction between ColQ- and PRiMA-anchored AChE.\",\n      \"evidence\": \"Acetylcholine/nicotine treatment of C2C12 myotubes with active CaMKII/MEF2 overexpression; chimeric ColQ/PRiMA constructs with non-reducing SDS-PAGE\",\n      \"pmids\": [\"18718538\", \"18511416\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Overexpression-based pathway evidence not validated by endogenous loss-of-function\", \"Physiological signal integration in vivo not established\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Revealed an AChE-independent role for ColQ in postsynaptic differentiation, showing that ColQ deficiency disrupts MuSK surface levels, AChR clustering, β-AChR phosphorylation, and AChE secretion.\",\n      \"evidence\": \"Loss-of-function comparison in cultured muscle cells and at the NMJ in vivo with immunofluorescence and biochemical readouts; qPCR and AChE activity assays\",\n      \"pmids\": [\"20053883\", \"20153305\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct molecular link between ColQ and MuSK was not yet established\", \"Mechanism coupling ColQ to AChR subunit transcription unclear\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Separated the AChE-anchoring and signaling functions of the ColQ C-terminus, showing C-terminal mutations preserve AChE assembly and perlecan binding but impair MuSK and basement-membrane interactions.\",\n      \"evidence\": \"Mutant ColQ expression with co-immunoprecipitation against perlecan and MuSK and basement membrane extract binding\",\n      \"pmids\": [\"24281389\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"The additional basal lamina partner inferred beyond MuSK was not identified\", \"Single-lab co-IP without orthogonal binding quantification\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Defined the molecular logic of a COLQ exon 16 splicing mutation as antagonistic SRSF1/hnRNP H binding and impaired U1-70K recruitment, explaining exon skipping in disease.\",\n      \"evidence\": \"RNA affinity purification, mass spectrometry, SRSF1/hnRNP H knockdown, MS2 tethering, minigene assays, spliceosome complex isolation, RNA-seq\",\n      \"pmids\": [\"26282582\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not address whether other COLQ exons share this regulatory logic\", \"Therapeutic correction of splicing not tested\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Demonstrated that ColQ controls postsynaptic maturation through synaptic gene expression, with ColQ deficiency upregulating all AChR subunit mRNAs and producing mixed mature/immature AChRs and altered ECM expression.\",\n      \"evidence\": \"Genetic screening and gene expression profiling of ColQ-deficient mice with NMJ morphological analysis\",\n      \"pmids\": [\"26993635\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single-lab in vivo profiling\", \"Direct signaling intermediaries to subunit transcription not pinpointed\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Showed that β-adrenergic agonism rescues NMJ structure and muscle strength in ColQ-deficient mice, localizing the therapeutic effect to the postsynaptic membrane.\",\n      \"evidence\": \"In vivo salbutamol treatment of ColQ-/- mice with grip strength and NMJ morphometry\",\n      \"pmids\": [\"31220253\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Molecular target of β-adrenergic rescue at the NMJ not defined\", \"Single-model, single-lab study\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Established that ColQ binds LRP4 directly (not MuSK directly), competes with agrin, and exerts opposing effects on MuSK phosphorylation versus surface accumulation, providing the receptor-level mechanism for ColQ control of postsynaptic signaling.\",\n      \"evidence\": \"Co-immunoprecipitation, pull-down, plate-binding, and SPR; patient COLQ variant analysis in COS cells and iPSC-derived muscle cells\",\n      \"pmids\": [\"37356721\", \"38003406\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of the ColQ-LRP4 interface not resolved\", \"How the two opposing effects are temporally integrated during synaptogenesis unclear\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The non-junctional functions of ColQ, the identity of additional basal lamina partners beyond LRP4/perlecan, and the structural mechanism by which ColQ tunes LRP4-MuSK signaling remain open.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No structure of the ColQ-LRP4 complex\", \"Functional significance of reported myenteric plexus localization unestablished\", \"Integration of competing agrin/ColQ inputs in vivo not resolved\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0005198\", \"supporting_discovery_ids\": [0, 5]},\n      {\"term_id\": \"GO:0008289\", \"supporting_discovery_ids\": [3]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [9, 15]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [15]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0031012\", \"supporting_discovery_ids\": [0, 3]},\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [9, 15]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [4, 6, 8]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [9, 17]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [15]}\n    ],\n    \"complexes\": [\"asymmetric acetylcholinesterase (collagen-tailed AChE)\"],\n    \"partners\": [\"ACHE\", \"LRP4\", \"perlecan/HSPG2\", \"MuSK\", \"SRSF1\", \"HNRNPH\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":6,"faith_total":6,"faith_pct":100.0}}