LRP4 third β-propeller domain mutations cause novel congenital myasthenia by compromising agrin-mediated MuSK signaling in a position-specific manner
LRP4 third β-propeller domain mutations cause novel congenital myasthenia by compromising agrin-mediated MuSK signaling in a position-specific manner
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DOI：
10.1093/hmg/ddt578
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发表时间：
2014-04-01
影响因子：
3.5
通讯作者：
Ohno, Kinji
中科院分区：
文献类型：
--
作者：
Ohkawara, Bisei;Cabrera-Serrano, Macarena;Ohno, Kinji
先天性肌无力综合征（CMS）是一种异质性疾病，其中神经肌肉传递的安全范围受到一种或多种特定机制的影响。在CMS患者中使用桑格和外显子组测序，我们确定了两个异等位基因突变，p.Glu1233 Lys和p.Arg1277 His，在LRP 4编码突触后低密度脂蛋白受体相关蛋白4。LRP 4表达于神经肌肉接头的突触后膜表面，是神经分泌的聚集蛋白的受体，并且聚集蛋白结合的LRP 4激活MuSK。与Dok-7协同激活的MuSK刺激rapsyn集中并锚AChR在突触后膜上，并与参与神经肌肉接头组装和维持的其他蛋白质相互作用。LRP 4还作为Wnt/β-连环蛋白信号传导的抑制剂发挥作用。LRP 4中鉴定的突变位于其第3 β-螺旋桨结构域的边缘，并降低LRP 4对MuSK和聚集蛋白的结合亲和力。LRP 4第3 β-螺旋桨结构域的突变先前被报道会损害Wnt信号传导并导致骨疾病，包括Cenani-Lenz并指综合征和硬化症-2。通过分析LRP 4第3 β-螺旋桨结构域中天然存在的和人工引入的突变，我们表明该结构域的边缘调节MuSK信号传导，而其中央空腔控制Wnt信号传导。我们的结论是，LRP 4是一个新的CMS疾病基因，LRP 4的第3 β螺旋桨结构域介导的两个信号通路中的位置特异性的方式。
Congenital myasthenic syndromes (CMS) are heterogeneous disorders in which the safety margin of neuromuscular transmission is compromised by one or more specific mechanisms. Using Sanger and exome sequencing in a CMS patient, we identified two heteroallelic mutations, p.Glu1233Lys and p.Arg1277His, in LRP4 coding for the postsynaptic low-density lipoprotein receptor-related protein 4. LRP4, expressed on the surface of the postsynaptic membrane of the neuromuscular junction, is a receptor for neurally secreted agrin, and LRP4 bound by agrin activates MuSK. Activated MuSK in concert with Dok-7 stimulates rapsyn to concentrate and anchor AChR on the postsynaptic membrane and interacts with other proteins implicated in the assembly and maintenance of the neuromuscular junction. LRP4 also functions as an inhibitor of Wnt/beta-catenin signaling. The identified mutations in LRP4 are located at the edge of its 3rd beta-propeller domain and decrease binding affinity of LRP4 for both MuSK and agrin. Mutations in the LRP4 3rd beta-propeller domain were previously reported to impair Wnt signaling and cause bone diseases including Cenani-Lenz syndactyly syndrome and sclerosteosis-2. By analyzing naturally occurring and artificially introduced mutations in the LRP4 3rd beta-propeller domain, we show that the edge of the domain regulates the MuSK signaling whereas its central cavity governs Wnt signaling. We conclude that LRP4 is a new CMS disease gene and that the 3rd beta propeller domain of LRP4 mediates the two signaling pathways in a position-specific manner.