Characterization of molecular mechanisms underlying the axonal Charcot-Marie-Tooth neuropathy caused by MORC2 mutations
Characterization of molecular mechanisms underlying the axonal Charcot-Marie-Tooth neuropathy caused by MORC2 mutations
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DOI：
10.1093/hmg/ddz006
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发表时间：
2019-05-15
影响因子：
3.5
通讯作者：
Espinos, Carmen
中科院分区：
文献类型：
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作者：
Sancho, Paula;Bartesaghi, Luca;Espinos, Carmen
MORC2基因突变导致2Z型Charcot-Marie-Tooth(CMT)神经病的轴突形式。到目前为止，已有31个家系被描述为MORC2突变，表明该基因经常涉及轴索性CMT病例。虽然遗传学数据清楚地确定了MORC2在CMT2Z中的致病作用，但其突变对神经生物学的影响及其在患者中的表型后果仍有待阐明。我们发现MORC2的全长形式在胚胎和成年人类神经组织中都高度表达，并且Morc2的表达在发育中和成熟的小鼠神经系统中都受到动态调节。为了确定最常见的MORC2突变p.S87L和p.R252W的影响，我们使用了几种体外细胞培养范例。这两个突变都会导致患者来源的成纤维细胞以及在啮齿动物感觉神经元中表达时的转录变化。在表达MORC2 p.S87L突变的神经元中，这些变化更加明显，并伴随着轴突形态的异常，这与更严重的临床表型有关。这些数据提供了对突变的MORC2介导的表型的神经元特异性的洞察，并强调了神经细胞模型对研究CMT2Z的病理生理学的重要性。
Mutations in MORC2 lead to an axonal form of Charcot-Marie-Tooth (CMT) neuropathy type 2Z. To date, 31 families have been described with mutations in MORC2, indicating that this gene is frequently involved in axonal CMT cases. While the genetic data clearly establish the causative role of MORC2 in CMT2Z, the impact of its mutations on neuronal biology and their phenotypic consequences in patients remains to be clarified. We show that the full-length form of MORC2 is highly expressed in both embryonic and adult human neural tissues and that Morc2 expression is dynamically regulated in both the developing and the maturing murine nervous system. To determine the effect of the most common MORC2 mutations, p.S87L and p.R252W, we used several in vitro cell culture paradigms. Both mutations induced transcriptional changes in patient-derived fibroblasts and when expressed in rodent sensory neurons. These changes were more pronounced and accompanied by abnormal axonal morphology, in neurons expressing the MORC2 p.S87L mutation, which is associated with a more severe clinical phenotype. These data provide insight into the neuronal specificity of the mutated MORC2-mediated phenotype and highlight the importance of neuronal cell models to study the pathophysiology of CMT2Z.