A mouse model for congenital myasthenic syndrome due to MuSK mutations reveals defects in structure and function of neuromuscular junctions
A mouse model for congenital myasthenic syndrome due to MuSK mutations reveals defects in structure and function of neuromuscular junctions
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DOI：
10.1093/hmg/ddn251
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发表时间：
2008-11-15
影响因子：
3.5
通讯作者：
Witzemann, Veit
中科院分区：
文献类型：
--
作者：
Chevessier, Frederic;Girard, Emmanuelle;Witzemann, Veit
在肌肉特异性酪氨酸激酶受体基因MUSK中，在患有先天性肌无力综合征（CMS）的患者中发现了异等位错义和零突变。我们在麝香(麝香（V789M/V789M）小鼠中产生了一个携带纯合错义突变V789M的小鼠品系，以及第二个与患者基因型相似的半合子品系，其中一个等位基因上有V789M突变，另一个等位基因缺乏激酶结构域（麝香（V789M/-）小鼠）。我们在此报告麝香（V789M/V789M）小鼠在体重、肌肉功能和生存能力方面没有明显的异常表型。成年麝香（V789M/-）小鼠肌肉严重无力，骨盆和肩胛骨萎缩，驼背。麝香（V789M/-）隔膜在直接或神经诱导的刺激下产生较小的力。在神经诱发的肌肉收缩后观察到深刻的强直性衰退，在一系列强直性神经刺激后，疲劳抵抗能力严重受损。电生理测量表明，疲劳性肌肉无力是由于受损的神经传递，观察到的病人患有CMS。成年麝香（V789M/-）小鼠横膈膜终板结构、分布和神经支配模式发生明显变化。因此，麝香中的错义突变V789M作为一种次态突变，导致麝香（V789M/-）突变体的麝香功能不足。这些突变小鼠为阐明MuSK在突触形成、成熟和维持中的作用以及研究MuSK突变引起的CMS的病理生理提供了有价值的模型。
In the muscle-specific tyrosine kinase receptor gene MUSK, a heteroallelic missense and a null mutation were identified in a patient suffering from a congenital myasthenic syndrome (CMS). We generated one mouse line carrying the homozygous missense mutation V789M in musk (musk(V789M/V789M) mice) and a second hemizygous line, resembling the patient genotype, with the V789M mutation on one allele and an allele lacking the kinase domain (musk(V789M/-) mice). We report here that musk(V789M/V789M) mice present no obvious abnormal phenotype regarding weight, muscle function and viability. In contrast, adult musk(V789M/-) mice suffer from severe muscle weakness, exhibit shrinkage of pelvic and scapular regions and hunchback. Musk(V789M/-) diaphragm develops less force upon direct or nerve-induced stimulation. A profound tetanic fade is observed following nerve-evoked muscle contraction, and fatigue resistance is severely impaired upon a train of tetanic nerve stimulations. Electrophysiological measurements indicate that fatigable muscle weakness is due to impaired neurotransmission as observed in a patient suffering from a CMS. The diaphragm of adult musk(V789M/-) mice exhibits pronounced changes in endplate architecture, distribution and innervation pattern. Thus, the missense mutation V789M in MuSK acts as a hypomorphic mutation and leads to insufficiency in MuSK function in musk(V789M/-) mutants. These mutant mice represent valuable models for elucidating the roles of MuSK for synapse formation, maturation and maintenance as well as for studying the pathophysiology of a CMS due to MuSK mutations.