A mutation causes MuSK reduced sensitivity to agrin and congenital myasthenia.
A mutation causes MuSK reduced sensitivity to agrin and congenital myasthenia.
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DOI：
10.1371/journal.pone.0053826
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发表时间：
2013
期刊：
影响因子：
3.7
通讯作者：
Hantaï D
中科院分区：
文献类型：
--
作者：
Ben Ammar A;Soltanzadeh P;Bauché S;Richard P;Goillot E;Herbst R;Gaudon K;Huzé C;Schaeffer L;Yamanashi Y;Higuchi O;Taly A;Koenig J;Leroy JP;Hentati F;Najmabadi H;Kahrizi K;Ilkhani M;Fardeau M;Eymard B;Hantaï D
先天性肌无力综合征 (CMS) 是一组影响神经肌肉传递的异质遗传性疾病。集聚蛋白/肌肉特异性激酶 (MuSK) 通路对于神经肌肉接头 (NMJ) 的正常发育和维护至关重要。我们在此报告一名伊朗患者，他因患有先天性波动性双侧对称性上睑下垂、向上凝视麻痹和缓慢进行性肌肉无力导致无法行走而被诊断为 CMS。对患者的遗传分析显示，MUSK 编码序列中存在纯合错义突变 c.2503A>G，导致 p.Met835Val 替换。该突变遗传自两个根据血缘关系为杂合子的父母。对三角肌活检的免疫细胞化学和电子显微镜研究显示，NMJ 的突触前和突触后元件发生了巨大变化。这些变化诱导了天然 NMJ 的去神经支配/神经再支配过程，并通过适应性机制形成新形成的异位 NMJ。还注意到异常的轴突生长、神经末梢分支减少和节点轴突发芽。小鼠模型中突变 MuSK 的体内电穿孔显示，NMJ 杂乱无章，轴突生长异常，再现了与患者活检标本中观察到的相似表型。体外实验表明，该突变改变了集聚蛋白依赖性乙酰胆碱受体聚集，导致 MuSK 的组成型激活及其集聚蛋白和 Dok-7 依赖性磷酸化的减少。
Congenital myasthenic syndromes (CMSs) are a heterogeneous group of genetic disorders affecting neuromuscular transmission. The agrin/muscle-specific kinase (MuSK) pathway is critical for proper development and maintenance of the neuromuscular junction (NMJ). We report here an Iranian patient in whom CMS was diagnosed since he presented with congenital and fluctuating bilateral symmetric ptosis, upward gaze palsy and slowly progressive muscle weakness leading to loss of ambulation. Genetic analysis of the patient revealed a homozygous missense mutation c.2503A>G in the coding sequence of MUSK leading to the p.Met835Val substitution. The mutation was inherited from the two parents who were heterozygous according to the notion of consanguinity. Immunocytochemical and electron microscopy studies of biopsied deltoid muscle showed dramatic changes in pre- and post-synaptic elements of the NMJs. These changes induced a process of denervation/reinnervation in native NMJs and the formation, by an adaptive mechanism, of newly formed and ectopic NMJs. Aberrant axonal outgrowth, decreased nerve terminal ramification and nodal axonal sprouting were also noted. In vivo electroporation of the mutated MuSK in a mouse model showed disorganized NMJs and aberrant axonal growth reproducing a phenotype similar to that observed in the patient’s biopsy specimen. In vitro experiments showed that the mutation alters agrin-dependent acetylcholine receptor aggregation, causes a constitutive activation of MuSK and a decrease in its agrin- and Dok-7-dependent phosphorylation.
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影响因子：
3.4
作者：
Apel, Peter J.;Ma, Jianjun;Callahan, Michael;Northam, Casey N.;Alton, Timothy B.;Sonntag, William E.;Li, Zhongyu
通讯作者：
Li, Zhongyu
影响因子：
56.9
作者：
Beeson, David;Higuchi, Osamu;Yamanashi, Yuji
通讯作者：
Yamanashi, Yuji
影响因子：
4.2
作者：
Do Thi, N A;Bourre, J M;Piciotti, M
通讯作者：
Piciotti, M
DOI：
10.1073/pnas.88.12.5096
发表时间：
1991-06-01
影响因子：
11.1
作者：
JAT, PS;NOBLE, MD;KIOUSSIS, D
通讯作者：
KIOUSSIS, D
DOI：
10.1083/jcb.125.4.893
发表时间：
1994-05
期刊：
The Journal of cell biology
影响因子：
--
作者：
Caroni P;Schneider C;Kiefer MC;Zapf J
通讯作者：
Zapf J