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Molecular Analysis of a Congenital Myasthenic Syndrome Due to a Pathogenic Variant Affecting the C-Terminus of ColQ

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...

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Autores principales: Barbeau, Susie, Semprez, Fannie, Dobbertin, Alexandre, Merriadec, Laurine, Roussange, Florine, Eymard, Bruno, Sternberg, Damien, Fournier, Emmanuel, Karasoy, Hanice, Martinat, Cécile, Legay, Claire
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10671321/
https://www.ncbi.nlm.nih.gov/pubmed/38003406
http://dx.doi.org/10.3390/ijms242216217
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author Barbeau, Susie
Semprez, Fannie
Dobbertin, Alexandre
Merriadec, Laurine
Roussange, Florine
Eymard, Bruno
Sternberg, Damien
Fournier, Emmanuel
Karasoy, Hanice
Martinat, Cécile
Legay, Claire
author_facet Barbeau, Susie
Semprez, Fannie
Dobbertin, Alexandre
Merriadec, Laurine
Roussange, Florine
Eymard, Bruno
Sternberg, Damien
Fournier, Emmanuel
Karasoy, Hanice
Martinat, Cécile
Legay, Claire
author_sort Barbeau, Susie
collection PubMed
description 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 > 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.
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spelling pubmed-106713212023-11-11 Molecular Analysis of a Congenital Myasthenic Syndrome Due to a Pathogenic Variant Affecting the C-Terminus of ColQ Barbeau, Susie Semprez, Fannie Dobbertin, Alexandre Merriadec, Laurine Roussange, Florine Eymard, Bruno Sternberg, Damien Fournier, Emmanuel Karasoy, Hanice Martinat, Cécile Legay, Claire Int J Mol Sci Article 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 > 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. MDPI 2023-11-11 /pmc/articles/PMC10671321/ /pubmed/38003406 http://dx.doi.org/10.3390/ijms242216217 Text en © 2023 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Barbeau, Susie
Semprez, Fannie
Dobbertin, Alexandre
Merriadec, Laurine
Roussange, Florine
Eymard, Bruno
Sternberg, Damien
Fournier, Emmanuel
Karasoy, Hanice
Martinat, Cécile
Legay, Claire
Molecular Analysis of a Congenital Myasthenic Syndrome Due to a Pathogenic Variant Affecting the C-Terminus of ColQ
title Molecular Analysis of a Congenital Myasthenic Syndrome Due to a Pathogenic Variant Affecting the C-Terminus of ColQ
title_full Molecular Analysis of a Congenital Myasthenic Syndrome Due to a Pathogenic Variant Affecting the C-Terminus of ColQ
title_fullStr Molecular Analysis of a Congenital Myasthenic Syndrome Due to a Pathogenic Variant Affecting the C-Terminus of ColQ
title_full_unstemmed Molecular Analysis of a Congenital Myasthenic Syndrome Due to a Pathogenic Variant Affecting the C-Terminus of ColQ
title_short Molecular Analysis of a Congenital Myasthenic Syndrome Due to a Pathogenic Variant Affecting the C-Terminus of ColQ
title_sort molecular analysis of a congenital myasthenic syndrome due to a pathogenic variant affecting the c-terminus of colq
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10671321/
https://www.ncbi.nlm.nih.gov/pubmed/38003406
http://dx.doi.org/10.3390/ijms242216217
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