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Severe congenital myasthenic syndromes caused by agrin mutations affecting secretion by motoneurons
Acta Neuropathologica ( IF 12.7 ) Pub Date : 2022-08-10 , DOI: 10.1007/s00401-022-02475-8
Arnaud Jacquier 1, 2 , Valérie Risson 1 , Thomas Simonet 1, 2 , Florine Roussange 3 , Nicolas Lacoste 1 , Shams Ribault 1, 4 , Julien Carras 1, 2 , Julian Theuriet 1, 2 , Emmanuelle Girard 1 , Isabelle Grosjean 1 , Laure Le Goff 2 , Stephan Kröger 5 , Julia Meltoranta 5 , Stéphanie Bauché 6 , Damien Sternberg 6, 7 , Emmanuel Fournier 6, 8, 9 , Anna Kostera-Pruszczyk 10 , Emily O'Connor 11 , Bruno Eymard 6, 8 , Hanns Lochmüller 11 , Cécile Martinat 3 , Laurent Schaeffer 1, 2
Affiliation  

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.



中文翻译:

影响运动神经元分泌的聚集蛋白突变引起的严重先天性肌无力综合征

先天性肌无力综合征 (CMS) 的主要特征是肌肉无力和易疲劳,并且可能由神经肌肉接头形成和维持所需的各种基因突变引起。其中,AGRN编码 agrin,一种由运动神经元分泌的必需突触蛋白。我们已经鉴定出在集聚蛋白的 LG2 结构域中具有未表征的 p.R1671Q、p.R1698P 和 p.L1664P 突变的严重 CMS 患者在体外原代运动神经元培养物和体内小鸡脊髓运动神经元中的过度表达表明,突变改变了集聚蛋白的运输,导致其在体细胞和/或轴突中积累。突变体集聚蛋白在培养细胞中的表达表明,集聚蛋白在内质网中的积累与未折叠蛋白反应 (UPR) 的诱导和培养基中的分泌受损有关。有趣的是,对单个集聚蛋白对 AChR 簇形成的特定活性的评估表明,当分泌时,突变集聚蛋白保留了触发 AChR 簇形成的正常能力。为了确认集聚蛋白的积累和分泌缺陷,iPS 细胞来源于患者并分化为运动神经元。患者 iPS 衍生的运动神经元在体细胞中积累了突变体集聚蛋白并增加了 XBP1 mRNA 剪接,表明 UPR 激活。此外,患者 iPS 衍生的运动神经元与肌管的共培养证实了集聚蛋白分泌的缺陷,并揭示了运动神经元存活率的降低。总而言之,我们报告了第一个突变特异性影响运动神经元的集聚蛋白分泌的AGRN基因。有趣的是,携带这些突变的三名患者最初被怀疑患有脊髓性肌萎缩症(SMA)。因此,对于具有 SMA 临床表现但没有SMN1基因突变的患者,值得在AGRN中寻找突变。

更新日期:2022-08-12
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