Mutations in the MORC2 gene cause axonal Charcot-Marie-Tooth disease
Mutations in the MORC2 gene cause axonal Charcot-Marie-Tooth disease
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DOI：
10.1093/brain/awv311
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发表时间：
2016-01-01
期刊：
影响因子：
14.5
通讯作者：
Espinos, Carmen
中科院分区：
文献类型：
--
作者：
Sevilla, Teresa;Lupo, Vincenzo;Espinos, Carmen
腓骨肌萎缩症 (CMT) 是一种具有广泛遗传异质性的复杂疾病。在这里，我们提出了一种新的轴突腓骨肌萎缩症，与微睾症家族 CW 型锌指 2 (MORC2) 基因相关。在具有常染色体显性分离的家族中进行全外显子组测序，鉴定出新的 MORC2 p。 4 名患者的 R190W 发生变化。我们的轴突腓骨肌萎缩症临床系列中的进一步突变筛查发现了另外两例散发病例，其中一名患者也携带相同的 MORC2 p。 R190W 突变和另一名携带 MORC2 p 的患者。 S25L突变。遗传和计算机研究有力地支持了这些序列变异的致病性。表型是可变的，包括先天性或婴儿期发病的患者，以及其他在第二个十年开始出现症状的患者。发病早期的患者出现类似脊髓性肌萎缩症的症状，而发病较晚的患者最初的症状是痉挛、远端无力和感觉障碍。虚弱和萎缩以随机和不对称的方式进展，并累及肢带肌肉，导致成年后严重丧失工作能力。感觉丧失总是很明显，并且与疾病的严重程度成正比。电生理学研究与不对称轴突运动和感觉神经病一致，而针肌电图相当频繁地记录到肌束颤动和肌颤动。腓肠神经活检显示有髓鞘纤维明显多灶性损耗，伴有一些再生簇和偶尔出现的小洋葱球。 Morc2 在小鼠周围神经的轴突和雪旺细胞中表达。 MORC2 在生物过程中的不同作用已被描述。由于腓骨肌萎缩症基因的沉默与 DNA 损伤反应相关，因此很容易推测该通路的失调可能与 MORC2 神经病中观察到的轴突变性有关，从而为腓骨肌萎缩症的一长串病因增添了一种新的致病机制。
Charcot-Marie-Tooth disease (CMT) is a complex disorder with wide genetic heterogeneity. Here we present a new axonal Charcot-Marie-Tooth disease form, associated with the gene microrchidia family CW-type zinc finger 2 (MORC2). Whole-exome sequencing in a family with autosomal dominant segregation identified the novel MORC2 p. R190W change in four patients. Further mutational screening in our axonal Charcot-Marie-Tooth disease clinical series detected two additional sporadic cases, one patient who also carried the same MORC2 p. R190W mutation and another patient that harboured a MORC2 p. S25L mutation. Genetic and in silico studies strongly supported the pathogenicity of these sequence variants. The phenotype was variable and included patients with congenital or infantile onset, as well as others whose symptoms started in the second decade. The patients with early onset developed a spinal muscular atrophy-like picture, whereas in the later onset cases, the initial symptoms were cramps, distal weakness and sensory impairment. Weakness and atrophy progressed in a random and asymmetric fashion and involved limb girdle muscles, leading to a severe incapacity in adulthood. Sensory loss was always prominent and proportional to disease severity. Electrophysiological studies were consistent with an asymmetric axonal motor and sensory neuropathy, while fasciculations and myokymia were recorded rather frequently by needle electromyography. Sural nerve biopsy revealed pronounced multifocal depletion of myelinated fibres with some regenerative clusters and occasional small onion bulbs. Morc2 is expressed in both axons and Schwann cells of mouse peripheral nerve. Different roles in biological processes have been described for MORC2. As the silencing of Charcot-Marie-Tooth disease genes have been associated with DNA damage response, it is tempting to speculate that a deregulation of this pathway may be linked to the axonal degeneration observed in MORC2 neuropathy, thus adding a new pathogenic mechanism to the long list of causes of Charcot-Marie-Tooth disease.