{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,23]],"date-time":"2026-08-23T15:59:36Z","timestamp":1787500776959,"version":"build-2736575974"},"reference-count":30,"publisher":"MDPI AG","issue":"22","license":[{"start":{"date-parts":[[2023,11,11]],"date-time":"2023-11-11T00:00:00Z","timestamp":1699660800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"ANR","award":["ANR Humanism 15-CE14-0022"],"award-info":[{"award-number":["ANR Humanism 15-CE14-0022"]}]},{"name":"ANR","award":["AFM-T\u00e9l\u00e9thon"],"award-info":[{"award-number":["AFM-T\u00e9l\u00e9thon"]}]},{"name":"ANR. I-Stem (CM) is part of the Biotherapies Institute for Rare Diseases (BIRD)","award":["ANR Humanism 15-CE14-0022"],"award-info":[{"award-number":["ANR Humanism 15-CE14-0022"]}]},{"name":"ANR. I-Stem (CM) is part of the Biotherapies Institute for Rare Diseases (BIRD)","award":["AFM-T\u00e9l\u00e9thon"],"award-info":[{"award-number":["AFM-T\u00e9l\u00e9thon"]}]},{"name":"Association Fran\u00e7aise contre les Myopathies","award":["ANR Humanism 15-CE14-0022"],"award-info":[{"award-number":["ANR Humanism 15-CE14-0022"]}]},{"name":"Association Fran\u00e7aise contre les Myopathies","award":["AFM-T\u00e9l\u00e9thon"],"award-info":[{"award-number":["AFM-T\u00e9l\u00e9thon"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Congenital Myasthenic Syndromes (CMSs) are rare inherited diseases of the neuromuscular junction characterized by muscle weakness. CMSs with acetylcholinesterase deficiency are due to pathogenic variants in COLQ, a collagen that anchors the enzyme at the synapse. The two COLQ N-terminal domains have been characterized as being biochemical and functional. They are responsible for the structure of the protein in the triple helix and the association of COLQ with acetylcholinesterase. To deepen the analysis of the distal C-terminal peptide properties and understand the CMSs associated to pathogenic variants in this domain, we have analyzed the case of a 32 year old male patient bearing a homozygote splice site variant c.1281 C &gt; T that changes the sequence of the last 28 aa in COLQ. Using COS cell and mouse muscle cell expression, we show that the COLQ variant does not impair the formation of the collagen triple helix in these cells, nor its association with acetylcholinesterase, and that the hetero-oligomers are secreted. However, the interaction of COLQ variant with LRP4, a signaling hub at the neuromuscular junction, is decreased by 44% as demonstrated by in vitro biochemical methods. In addition, an increase in all acetylcholine receptor subunit mRNA levels is observed in muscle cells derived from the patient iPSC. All these approaches point to pathophysiological mechanisms essentially characterized by a decrease in signaling and the presence of immature acetylcholine receptors.<\/jats:p>","DOI":"10.3390\/ijms242216217","type":"journal-article","created":{"date-parts":[[2023,11,13]],"date-time":"2023-11-13T02:10:43Z","timestamp":1699841443000},"page":"16217","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Molecular Analysis of a Congenital Myasthenic Syndrome Due to a Pathogenic Variant Affecting the C-Terminus of ColQ"],"prefix":"10.3390","volume":"24","author":[{"given":"Susie","family":"Barbeau","sequence":"first","affiliation":[{"name":"CNRS, Saint P\u00e8res Paris Institute for the Neurosciences (SPPIN), Universit\u00e9 Paris Cit\u00e9, 75270 Paris, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fannie","family":"Semprez","sequence":"additional","affiliation":[{"name":"CNRS, Saint P\u00e8res Paris Institute for the Neurosciences (SPPIN), Universit\u00e9 Paris Cit\u00e9, 75270 Paris, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alexandre","family":"Dobbertin","sequence":"additional","affiliation":[{"name":"CNRS, Saint P\u00e8res Paris Institute for the Neurosciences (SPPIN), Universit\u00e9 Paris Cit\u00e9, 75270 Paris, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Laurine","family":"Merriadec","sequence":"additional","affiliation":[{"name":"INSERM\/UEPS UMR 861, Universit\u00e9 Paris Saclay, I-STEM, 91100 Corbeil-Essonnes, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Florine","family":"Roussange","sequence":"additional","affiliation":[{"name":"INSERM\/UEPS UMR 861, Universit\u00e9 Paris Saclay, I-STEM, 91100 Corbeil-Essonnes, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bruno","family":"Eymard","sequence":"additional","affiliation":[{"name":"Inserm U 1127, CNRS UMR 7225, Sorbonne Universite\u0301 Paris 06 UMR S 1127, Institut du Cerveau et de la Moelle E\u0301pinie\u0300re, ICM, Sorbonne Universite\u0301, 75013 Paris, France"},{"name":"AP-HP, H\u00f4pital Pitie\u0301-Salp\u00eatrie\u0300re, 75013 Paris, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Damien","family":"Sternberg","sequence":"additional","affiliation":[{"name":"Inserm U 1127, CNRS UMR 7225, Sorbonne Universite\u0301 Paris 06 UMR S 1127, Institut du Cerveau et de la Moelle E\u0301pinie\u0300re, ICM, Sorbonne Universite\u0301, 75013 Paris, France"},{"name":"AP-HP, H\u00f4pital Pitie\u0301-Salp\u00eatrie\u0300re, 75013 Paris, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Emmanuel","family":"Fournier","sequence":"additional","affiliation":[{"name":"Department of Physiology, Facult\u00e9 de M\u00e9decine Piti\u00e9-Salp\u00eatri\u00e8re, Sorbonne Universit\u00e9, 75006 Paris, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hanice","family":"Karasoy","sequence":"additional","affiliation":[{"name":"Department of Neurology, Faculty of Medicine, Ege University, Izmir 35100, Turkey"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5234-1064","authenticated-orcid":false,"given":"C\u00e9cile","family":"Martinat","sequence":"additional","affiliation":[{"name":"INSERM\/UEPS UMR 861, Universit\u00e9 Paris Saclay, I-STEM, 91100 Corbeil-Essonnes, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Claire","family":"Legay","sequence":"additional","affiliation":[{"name":"CNRS, Saint P\u00e8res Paris Institute for the Neurosciences (SPPIN), Universit\u00e9 Paris Cit\u00e9, 75270 Paris, France"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,11,11]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"22840","DOI":"10.1074\/jbc.272.36.22840","article-title":"The mammalian gene of acetylcholinesterase-associated collagen","volume":"272","author":"Krejci","year":"1997","journal-title":"J. Biol. Chem."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1476","DOI":"10.1111\/j.1432-1033.2004.04052.x","article-title":"Elements of the C-terminal t peptide of acetylcholinesterase that determine amphiphilicity, homomeric and heteromeric associations, secretion and degradation","volume":"271","author":"Falasca","year":"2004","journal-title":"Eur. J. Biochem."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"104","DOI":"10.1111\/nyas.13595","article-title":"Congenital myasthenic syndromes with acetylcholinesterase deficiency, the pathophysiological mechanisms","volume":"1413","author":"Legay","year":"2018","journal-title":"Ann. N. Y. Acad. Sci."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"523","DOI":"10.1023\/A:1022821306722","article-title":"Trimerization domain of the collagen tail of acetylcholinesterase","volume":"28","author":"Bon","year":"2003","journal-title":"Neurochem. Res."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"505","DOI":"10.1083\/jcb.200307164","article-title":"MuSK is required for anchoring acetylcholinesterase at the neuromuscular junction","volume":"165","author":"Cartaud","year":"2004","journal-title":"J. Cell Biol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"997","DOI":"10.1002\/humu.22325","article-title":"Mutations in the C-terminal domain of ColQ in endplate acetylcholinesterase deficiency compromise ColQ-MuSK interaction","volume":"34","author":"Nakata","year":"2013","journal-title":"Hum. Mutat."},{"key":"ref_7","doi-asserted-by":"crossref","unstructured":"Uyen Dao, T.M., Barbeau, S., Mess\u00e9ant, J., Della-Gaspera, B., Bouceba, T., Semprez, F., Legay, C., and Dobbertin, A. (2023). The collagen ColQ binds to LRP4 and regulates the activation of the Muscle-Specific Kinase-LRP4 receptor complex by agrin at the neuromuscular junction. J. Biol. Chem., 299.","DOI":"10.1016\/j.jbc.2023.104962"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"159","DOI":"10.1146\/annurev-physiol-022516-034255","article-title":"Neuromuscular Junction Formation, Aging and Disorders","volume":"80","author":"Li","year":"2018","journal-title":"Annu. Rev. Physiol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"10997","DOI":"10.1074\/jbc.M305462200","article-title":"Rotundo RLC-terminal heparin-binding domains of collagenic tail subunit are both essential for anchoring acetylcholinesterase at the synapse","volume":"270","author":"Kimbell","year":"2004","journal-title":"J. Biol. Chem."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"3730","DOI":"10.3390\/ijms24043730","article-title":"Clinical and Pathological features of Congenital Myasthenic Syndromes caused by 35 genes\u2014A comprehensive review","volume":"24","author":"Ohno","year":"2023","journal-title":"Int. J. Mol. Sci."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"967","DOI":"10.1086\/302059","article-title":"Mutation in the human acetylcholinesterase-associated collagen gene, COLQ, is responsible for congenital myasthenic syndrome with end-plate acetylcholinesterase deficiency (Type Ic)","volume":"63","author":"Donger","year":"1998","journal-title":"Am. J. Hum. Genet."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"9654","DOI":"10.1073\/pnas.95.16.9654","article-title":"Human endplate acetylcholinesterase deficiency caused by mutations in the collagen-like tail subunit (ColQ) of the asymmetric enzyme","volume":"95","author":"Ohno","year":"1998","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"13","DOI":"10.1523\/JNEUROSCI.4374-09.2010","article-title":"ColQ controls postsynaptic differentiation at the neuromuscular junction","volume":"30","author":"Sigoillot","year":"2010","journal-title":"J. Neurosci."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"2382","DOI":"10.1096\/fj.201500162","article-title":"Neuromuscular junction immaturity and muscle atrophy are hallmarks of the ColQ-deficient mouse, a model of congenital myasthenic syndrome with acetylcholinesterase deficiency","volume":"30","author":"Sigoillot","year":"2016","journal-title":"FASEB J."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"10672","DOI":"10.1523\/JNEUROSCI.19-24-10672.1999","article-title":"Differences in expression of acetylcholinesterase and collagen Q control the distribution and oligomerization of the collagen-tailed forms in fast and slow muscles","volume":"19","author":"Krejci","year":"1999","journal-title":"J. Neurosci."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"1349","DOI":"10.1083\/jcb.144.6.1349","article-title":"Genetic analysis of collagen Q: Roles in acetylcholinesterase and butyrylcholinesterase assembly and in synaptic structure and function","volume":"144","author":"Feng","year":"1999","journal-title":"J. Cell Biol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"102106","DOI":"10.1016\/j.scr.2020.102106","article-title":"Generation of a human induced pluripotent stem cell line (iPSC) from peripheral blood mononuclear cells of a patient with a myasthenic syndrome due to mutation in COLQ","volume":"49","author":"Barbeau","year":"2020","journal-title":"Stem Cell Res."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"599","DOI":"10.1007\/s00439-013-1391-3","article-title":"COOH-terminal collagen Q (COLQ) mutants causing human deficiency of endplate acetylcholinesterase impair the interaction of ColQ with proteins of the basal lamina","volume":"133","author":"Arredondo","year":"2014","journal-title":"Hum. Genet."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"6178","DOI":"10.1093\/emboj\/17.21.6178","article-title":"A four-to-one association between peptide motifs: Four C-terminal domains from cholinesterase assemble with one proline-rich attachment domain (PRAD) in the secretory pathway","volume":"17","author":"Simon","year":"1998","journal-title":"EMBO J."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"3016","DOI":"10.1074\/jbc.272.5.3016","article-title":"Quaternary associations of acetylcholinesterase. II. The polyproline attachment domain of the collagen tail","volume":"272","author":"Bon","year":"1997","journal-title":"J. Biol. Chem."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"20722","DOI":"10.1074\/jbc.M801364200","article-title":"Acetylcholinesterases associates differently with its anchoring proteins ColQ and PRiMA","volume":"283","author":"Noureddine","year":"2008","journal-title":"J. Biol. Chem."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"4519","DOI":"10.1523\/JNEUROSCI.3863-08.2009","article-title":"Targeting of acetylcholinesterase in neurons in vivo: A dual processing function for the proline-rich membrane anchor subunit and the attachment domain on the catalytic subunit","volume":"29","author":"Dobbertin","year":"2009","journal-title":"J. Neurosci."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"747","DOI":"10.1093\/brain\/awm325","article-title":"Clinical and molecular genetic findings in COLQ-mutant congenital myasthenic syndromes","volume":"131","author":"Mihaylova","year":"2008","journal-title":"Brain"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"581097","DOI":"10.3389\/fnmol.2020.581097","article-title":"The Structure, Function, and Physiology of the Fetal and Adult Acetylcholine Receptor in muscle","volume":"13","author":"Cetin","year":"2020","journal-title":"Front. Mol. Neurosci."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"162","DOI":"10.1002\/1531-8249(200002)47:2<162::AID-ANA5>3.0.CO;2-Q","article-title":"The spectrum of mutations causing end-plate acetylchlolinesterase deficiency","volume":"47","author":"Ohno","year":"2000","journal-title":"Ann. Neurol."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"318","DOI":"10.1016\/j.nmd.2011.09.002","article-title":"Long-term follow-up of patients with congenital myasthenic syndrome caused by COLQ mutations","volume":"22","author":"Wargon","year":"2012","journal-title":"Neuromuscul. Disord."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"163","DOI":"10.1016\/0014-5793(93)81155-S","article-title":"Expression of a cDNA encoding the glycolipid-anchored form of rat acetylcholinesterase","volume":"315","author":"Legay","year":"1993","journal-title":"FEBS Lett."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"88","DOI":"10.1016\/0006-2952(61)90145-9","article-title":"A new and rapid colorimetric determination of acetylcholinesterase activity","volume":"7","author":"Ellman","year":"1961","journal-title":"Biochem. Pharmacol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"41","DOI":"10.1093\/hmg\/ddab218","article-title":"CRISPR gene editing in pluripotent stem cells reveals the function of MBNL proteins during human in vitro myogenesis","volume":"31","author":"Cailleret","year":"2021","journal-title":"Hum. Mol. Genet."},{"key":"ref_30","doi-asserted-by":"crossref","unstructured":"Tahraoui-Bories, J., M\u00e9rien, A., Gonz\u00e1lez-Barriga, A., Lain\u00e9, J., Leteur, C., Polv\u00e8che, H., Carteron, A., De Lamotte, J.D., Nicoleau, C., and Polentes, J. (2023). MBNL-dependent impaired development within the neuromuscular system in myotonic dystrophy type 1. Neuropathol. Appl. Neurobiol., 49.","DOI":"10.1111\/nan.12876"}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/24\/22\/16217\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T21:21:41Z","timestamp":1760131301000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/24\/22\/16217"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,11,11]]},"references-count":30,"journal-issue":{"issue":"22","published-online":{"date-parts":[[2023,11]]}},"alternative-id":["ijms242216217"],"URL":"https:\/\/doi.org\/10.3390\/ijms242216217","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,11,11]]}}}