Bibliographic Details
| Title: |
Molecular Analysis of a Congenital Myasthenic Syndrome Due to a Pathogenic Variant Affecting the C-Terminus of ColQ. |
| Authors: |
Barbeau, Susie, Semprez, Fannie, Dobbertin, Alexandre, Merriadec, Laurine, Roussange, Florine, Eymard, Bruno, Sternberg, Damien, Fournier, Emmanuel, Karasoy, Hanice, Martinat, Cécile, Legay, Claire |
| Source: |
International Journal of Molecular Sciences; Nov2023, Vol. 24 Issue 22, p16217, 16p |
| Subject Terms: |
CONGENITAL myasthenic syndromes, MUSCLE weakness, CHOLINERGIC receptors, NEUROMUSCULAR diseases, MYONEURAL junction, MYASTHENIA gravis |
| Abstract: |
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. [ABSTRACT FROM AUTHOR] |
|
Copyright of International Journal of Molecular Sciences is the property of MDPI and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.) |
| Database: |
Complementary Index |
|
Full text is not displayed to guests. |
Login for full access.
|
