Myoclonus dystonia syndrome (MDS) is an inherited movement disorder, and most MDS-related mutations have so far been found in the ε-sarcoglycan (SGCE) coding gene. By generating SGCE-knockout (KO) and human 237 C > T mutation knock-in (KI) mice, we showed here that both KO and KI mice exerted typical movement defects similar to those of MDS patients. SGCE promoted filopodia development in vitro and inhibited excitatory synapse formation both in vivo and in vitro. Loss of function of SGCE leading to excessive excitatory synapses that may ultimately contribute to MDS pathology. Indeed, using a zebrafish MDS model, we found that among 1700 screened chemical compounds, Vigabatrin was the most potent in readily reversing MDS symptoms of mouse disease models. Our study strengthens the notion that mutations of SGCE lead to MDS and most likely, SGCE functions to brake synaptogenesis in the CNS.

肌阵挛性肌张力障碍综合征 (MDS) 是一种遗传性运动障碍，迄今为止，大多数与 MDS 相关的突变都存在于 ε-肌聚糖 (SGCE) 编码基因中。通过生成 SGCE 敲除 (KO) 和人类 237 C > T 突变敲入 (KI) 小鼠，我们在这里展示了 KO 和 KI 小鼠都表现出与 MDS 患者相似的典型运动缺陷。SGCE在体外促进丝状伪足发育并在体内和体外抑制兴奋性突触形成. SGCE 功能丧失导致过度兴奋性突触，最终可能导致 MDS 病理。事实上，使用斑马鱼 MDS 模型，我们发现在 1700 种筛选的化合物中，氨己烯酸在容易逆转小鼠疾病模型的 MDS 症状方面是最有效的。我们的研究强化了 SGCE 突变导致 MDS 的观点，并且最有可能的是，SGCE 的功能是阻止 CNS 中的突触发生。