[SMC] Severe congenital myasthenic syndromes caused by agrin mutations affecting secretion by motoneurons

Répondre
Avatar du membre

Auteur du sujet
RSS-Bot
Ami(e) de Diamant
Ami(e) de Diamant
Messages : 2983
Enregistré le : 31 mai 2020 09:57
3
Zodiaque :
Âge : 20
Contact :
    Linux Chrome

[SMC] Severe congenital myasthenic syndromes caused by agrin mutations affecting secretion by motoneurons

Message par RSS-Bot »


Acta Neuropathol. 2022 Aug 10. doi: 10.1007/s00401-022-02475-8. Online ahead of print.

ABSTRACT

Congenital myasthenic syndromes (CMS) are predominantly characterized by muscle weakness and fatigability and can be caused by a variety of mutations in genes required for neuromuscular junction formation and maintenance. Among them, AGRN encodes agrin, an essential synaptic protein secreted by motoneurons. We have identified severe CMS patients with uncharacterized p.R1671Q, p.R1698P and p.L1664P mutations in the LG2 domain of agrin. Overexpression in primary motoneurons cultures in vitro and in chick spinal motoneurons in vivo revealed that the mutations modified agrin trafficking, leading to its accumulation in the soma and/or in the axon. Expression of mutant agrins in cultured cells demonstrated accumulation of agrin in the endoplasmic reticulum associated with induction of unfolded protein response (UPR) and impaired secretion in the culture medium. Interestingly, evaluation of the specific activity of individual agrins on AChR cluster formation indicated that when secreted, mutant agrins retained a normal capacity to trigger the formation of AChR clusters. To confirm agrin accumulation and secretion defect, iPS cells were derived from a patient and differentiated into motoneurons. Patient iPS-derived motoneurons accumulated mutant agrin in the soma and increased XBP1 mRNA splicing, suggesting UPR activation. Moreover, co-cultures of patient iPS-derived motoneurons with myotubes confirmed the deficit in agrin secretion and revealed a reduction in motoneuron survival. Altogether, we report the first mutations in AGRN gene that specifically affect agrin secretion by motoneurons. Interestingly, the three patients carrying these mutations were initially suspected of spinal muscular atrophy (SMA). Therefore, in the presence of patients with a clinical presentation of SMA but without mutation in the SMN1 gene, it can be worth to look for mutations in AGRN.

PMID:35948834 | DOI:10.1007/s00401-022-02475-8


Source: https://pubmed.ncbi.nlm.nih.gov/3594883 ... 2&v=2.17.7
Si vous appréciez notre travail, merci de nous soutenir un petit don en cliquant ICI

Pour obtenir la traduction en français,
cliquez sur le bouton situé dans la barre des menus en haut de cette page 

Image


Pour les donateurs, si cet article vous intéresse, nous pouvons faire l’acquisition d'un tiré-à-part.
Merci d'en faire la demande sur association.amis-modo@myasthenie.com


Bonne lecture...
Répondre

Retourner vers « Syndrome Myasthénique Congénital -SMC »