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先天性肌无力综合征由于 MUSK 突变表明 MuSK 磷酸化水平对于调节突触结构至关重要。

Congenital myasthenic syndrome due to mutations in MUSK suggests that the level of MuSK phosphorylation is crucial for governing synaptic structure.

机构信息

Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford, UK.

Neurosciences Group, The John Radcliffe Hospital, Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, UK.

出版信息

Hum Mutat. 2020 Mar;41(3):619-631. doi: 10.1002/humu.23949. Epub 2019 Nov 25.

DOI:10.1002/humu.23949
PMID:31765060
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC7028094/
Abstract

MUSK encodes the muscle-specific receptor tyrosine kinase (MuSK), a key component of the agrin-LRP4-MuSK-DOK7 signaling pathway, which is essential for the formation and maintenance of highly specialized synapses between motor neurons and muscle fibers. We report a patient with severe early-onset congenital myasthenic syndrome and two novel missense mutations in MUSK (p.C317R and p.A617V). Functional studies show that MUSK p.C317R, located at the frizzled-like cysteine-rich domain of MuSK, disrupts an integral part of MuSK architecture resulting in ablated MuSK phosphorylation and acetylcholine receptor (AChR) cluster formation. MUSK p.A617V, located at the kinase domain of MuSK, enhances MuSK phosphorylation resulting in anomalous AChR cluster formation. The identification and evidence for pathogenicity of MUSK mutations supported the initiation of treatment with β2-adrenergic agonists with a dramatic improvement of muscle strength in the patient. This work suggests uncharacterized mechanisms in which control of the precise level of MuSK phosphorylation is crucial in governing synaptic structure.

摘要

MUSK 编码肌肉特异性受体酪氨酸激酶 (MuSK)，是神经递质乙酰胆碱受体 (AChR) 形成和稳定所必需的神经-肌肉接头形成和维持的关键成分。我们报道了一名严重的早发性先天性肌无力综合征患者，以及 MUSK 中的两个新的错义突变（p.C317R 和 p.A617V）。功能研究表明，MUSK p.C317R 位于 MuSK 的卷曲样富含半胱氨酸结构域，破坏了 MuSK 结构的重要部分，导致 MuSK 磷酸化和 AChR 簇形成被破坏。MUSK p.A617V 位于 MuSK 的激酶结构域，增强 MuSK 磷酸化，导致异常的 AChR 簇形成。MUSK 突变的鉴定和致病性证据支持了使用β2 肾上腺素能激动剂治疗的启动，患者的肌肉力量有了显著改善。这项工作表明，在调节突触结构方面，MuSK 磷酸化的精确水平的控制存在未被描述的机制。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/71dc/7028094/65cfaedbd1f6/HUMU-41-619-g008.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/71dc/7028094/565993d791c8/HUMU-41-619-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/71dc/7028094/f8edd87b6055/HUMU-41-619-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/71dc/7028094/9f97daa6e76e/HUMU-41-619-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/71dc/7028094/2f71f7a81797/HUMU-41-619-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/71dc/7028094/48e0a4b70a59/HUMU-41-619-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/71dc/7028094/2e840ea37e74/HUMU-41-619-g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/71dc/7028094/d0b5166e71b5/HUMU-41-619-g007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/71dc/7028094/65cfaedbd1f6/HUMU-41-619-g008.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/71dc/7028094/565993d791c8/HUMU-41-619-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/71dc/7028094/f8edd87b6055/HUMU-41-619-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/71dc/7028094/9f97daa6e76e/HUMU-41-619-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/71dc/7028094/2f71f7a81797/HUMU-41-619-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/71dc/7028094/48e0a4b70a59/HUMU-41-619-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/71dc/7028094/2e840ea37e74/HUMU-41-619-g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/71dc/7028094/d0b5166e71b5/HUMU-41-619-g007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/71dc/7028094/65cfaedbd1f6/HUMU-41-619-g008.jpg

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