Abstract：
Centronuclear myopathy (CNM) is a congenital neuromuscular disorder caused by pathogenic variation in genes associated with membrane trafficking and excitation-contraction coupling (ECC). Bi-allelic autosomal-recessive mutations in striated muscle enriched protein kinase (SPEG) account for a subset of CNM patients. Previous research has been limited by the perinatal lethality of constitutive Speg knockout mice. Thus, the precise biological role of SPEG in developing skeletal muscle remains unknown. To address this issue, we generated zebrafish spega, spegb and spega;spegb (speg-DKO) mutant lines. We demonstrated that speg-DKO zebrafish faithfully recapitulate multiple phenotypes associated with CNM, including disruption of the ECC machinery, dysregulation of calcium homeostasis during ECC and impairment of muscle performance. Taking advantage of zebrafish models of multiple CNM genetic subtypes, we compared novel and known disease markers in speg-DKO with mtm1-KO and DNM2-S619L transgenic zebrafish. We observed Desmin accumulation common to all CNM subtypes, and Dnm2 upregulation in muscle of both speg-DKO and mtm1-KO zebrafish. In all, we establish a new model of SPEG-related CNM, and identify abnormalities in this model suitable for defining disease pathomechanisms and evaluating potential therapies. This article has an associated First Person interview with the joint first authors of the paper.
摘要：
中央核肌病（CNM）是一种先天性神经肌肉疾病，由与膜运输和兴奋-收缩偶联（ECC）相关的基因致病变异引起。横纹肌富集蛋白激酶（SPEG）的双等位基因常染色体隐性突变占CNM患者的一部分。先前的研究受到组成型Speg基因敲除小鼠围产期致死性的限制。因此，SPEG在骨骼肌发育中的确切生物学作用尚不清楚.为了解决这个问题，我们产生了斑马鱼，spegb和spega；spegb(speg-DKO)突变系。我们证明speg-DKO斑马鱼忠实地概括了与CNM相关的多种表型，包括ECC机器的中断，ECC期间钙稳态失调和肌肉性能受损。利用斑马鱼模型的多种CNM遗传亚型，我们比较了speg-DKO与mtm1-KO和DNM2-S619L转基因斑马鱼中新型和已知的疾病标志物。我们观察到所有CNM亚型共有的Desmin积累，speg-DKO和mtm1-KO斑马鱼肌肉中的Dnm2上调。总之,我们建立了一个新的与SPEG相关的CNM模型，并在该模型中确定适合定义疾病病理机制和评估潜在治疗的异常。本文与该论文的联合第一作者进行了相关的第一人称访谈。
