Characterization of a novel zebrafish model of SPEG-related centronuclear myopathy.
Characterization of a novel zebrafish model of SPEG-related centronuclear myopathy.
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DOI：
10.1242/dmm.049437
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发表时间：
2022-05-01
影响因子：
4.3
通讯作者：
Dowling, James J.
中科院分区：
文献类型：
--
作者：
Espinosa, Karla G.;Geissah, Salma;Groom, Linda;Volpatti, Jonathan;Scott, Ian C.;Dirksen, Robert T.;Zhao, Mo;Dowling, James J.
中枢性肌病（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）相关的基因的致病性变异引起。横纹肌富集蛋白激酶（SPEG）中的双等位基因常染色体隐性突变是CNM患者的一个亚组。以前的研究受到组成型Speg基因敲除小鼠围产期致死率的限制。因此，SPEG在骨骼肌发育中的确切生物学作用仍然未知。为了解决这个问题，我们产生了斑马鱼spega、spegb和spega;spegb（speg-DKO）突变系。我们证明了speg-DKO斑马鱼忠实地再现了与CNM相关的多种表型，包括ECC机制的破坏，ECC期间钙稳态的失调和肌肉性能的损害。利用多种CNM基因亚型的斑马鱼模型，我们比较了speg-DKO与mtm 1-KO和DNM 2-S619 L转基因斑马鱼中的新的和已知的疾病标志物。我们观察到结蛋白积累共同的所有CNM亚型，和Dnm 2的speg-DKO和mtm 1-KO斑马鱼的肌肉上调。总之，我们建立了一个新的模型，SPEG相关的CNM，并确定在这个模型中的异常，适合定义疾病的病理机制和评估潜在的治疗。总结：我们创建了一个新的斑马鱼Speg突变的中枢性肌病模型，概括了人类疾病的关键特征，并提供了深入了解疾病的病理机制。
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. Summary: We created a novel zebrafish Speg mutant model of centronuclear myopathy that recapitulates key features of the human disorder and provides insight into pathomechanisms of the disease.
肌质网的末端水箱的连接式面膜的表征。
影响因子：
7.8
作者：
COSTELLO, B;CHADWICK, C;SAITO, A;CHU, A;MAURER, A;FLEISCHER, S
通讯作者：
FLEISCHER, S
SPEG基因突变致中心核肌病一例临床及遗传学分析一例报告及文献复习
影响因子：
2.4
作者：
Zhang G;Xu M;Huang T;Lin W;Chen J;Chen W;Chang X
通讯作者：
Chang X