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研究揭示Dok7先天性肌无力的发病机制和治疗手段
2021-06-27 15:58

近日,美国纽约大学Steven J. Burden、Shohei Koide等研究人员合作揭示Dok7先天性肌无力的发病机制和治疗手段。该项研究成果于2021年6月23日在线发表在《自然》杂志上。

研究人员表示,先天性肌无力(CM)是一种破坏性的神经肌肉疾病,DOK7(一种对形成和维持神经肌肉突触至关重要的衔接蛋白)突变是CM的主要原因。最常见的致病突变(DOK71124_1127 dup)会截断DOK7并导致两个酪氨酸残基丢失,这些残基被磷酸化并募集CRK蛋白,这对于将乙酰胆碱受体锚定在突触上很重要。

研究人员报道了这种常见形式的CM小鼠模型(Dok7CM小鼠)以及在两个酪氨酸残基中具有点突变的小鼠(Dok72YF)。研究人员表明,Dok7CM小鼠在导致新生儿致死的神经肌肉突触形成方面存在严重缺陷。出乎意料的是,这些缺陷是由于肌肉特异性激酶(MUSK)的磷酸化和激活严重不足,而不是DOK7酪氨酸磷酸化的不足。研究人员开发了针对MUSK的激动剂抗体,并表明这些抗体可以恢复神经肌肉突触的形成并预防Dok7CM小鼠的新生致死率和迟发性疾病。

这些发现为DOK7 CM和由AGRIN、LRP4或MUSK突变引起的其他形式CM确定了一种意想不到的疾病原因和潜在治疗方法,并说明了靶向治疗挽救先天性致死率的潜力。 

附:英文原文

Title: Mechanism of disease and therapeutic rescue of Dok7 congenital myasthenia

Author: Julien Oury, Wei Zhang, Nadia Leloup, Akiko Koide, Alexis D. Corrado, Gayatri Ketavarapu, Takamitsu Hattori, Shohei Koide, Steven J. Burden

Issue&Volume: 2021-06-23

Abstract: Congenital myasthenia (CM) is a devastating neuromuscular disease, and mutations in DOK7, an adaptor protein that is crucial for forming and maintaining neuromuscular synapses, are a major cause of CM1,2. The most common disease-causing mutation (DOK71124_1127 dup) truncates DOK7 and leads to the loss of two tyrosine residues that are phosphorylated and recruit CRK proteins, which are important for anchoring acetylcholine receptors at synapses. Here we describe a mouse model of this common form of CM (Dok7CM mice) and a mouse with point mutations in the two tyrosine residues (Dok72YF). We show that Dok7CM mice had severe deficits in neuromuscular synapse formation that caused neonatal lethality. Unexpectedly, these deficits were due to a severe deficiency in phosphorylation and activation of muscle-specific kinase (MUSK) rather than a deficiency in DOK7 tyrosine phosphorylation. We developed agonist antibodies against MUSK and show that these antibodies restored neuromuscular synapse formation and prevented neonatal lethality and late-onset disease in Dok7CM mice. These findings identify an unexpected cause for disease and a potential therapy for both DOK7 CM and other forms of CM caused by mutations in AGRIN, LRP4 or MUSK, and illustrate the potential of targeted therapy to rescue congenital lethality. In a mouse model of congenital myasthenia caused by mutations in the Dok7 gene, agonist antibodies against MUSK restore synaptic function and survival.

DOI: 10.1038/s41586-021-03672-3

Source: https://www.nature.com/articles/s41586-021-03672-3

Nature:《自然》,创刊于1869年。隶属于施普林格·自然出版集团,最新IF:43.07
官方网址:http://www.nature.com/
投稿链接:http://www.nature.com/authors/submit_manuscript.html


本期文章:《自然》:Online/在线发表

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