PMP22 overexpression causes dysmyelination in mice
PMP22 overexpression causes dysmyelination in mice
复制标题
DOI：
10.1093/brain/awf230
复制
发表时间：
2002-10-01
期刊：
影响因子：
14.5
通讯作者：
Fontés, M
中科院分区：
文献类型：
--
作者：
Robaglia-Schlupp, A;Pizant, J;Fontés, M
腓骨肌萎缩症 (CMT) 病是人类最常见的遗传性周围神经病。其患病率约为 2500 分之一。CMT1A 亚型以常染色体显性性状传播。估计 75% 的患者受到影响。这种疾病已被证明与 17 号染色体短臂 1.5 Mb 区域的重复有关，其中 PMP22 基因已被定位。我们通过将含有外周髓磷脂蛋白 22 (PMP22) 及其侧翼控制元件的人 YAC 插入小鼠基因组中，构建了 CMT1A 小鼠模型。我们描述了 C22 系（YAC 的 7 个拷贝，PMP22 过表达的 2.1 倍）在髓鞘形成过程中的行为。电子显微镜、形态测定、电生理学、神经传导以及正常和病理雪旺细胞中特定标记物（例如 Krox20）的表达表明，PMP22 过度表达会导致轴突髓鞘形成缺陷。最大的轴突受影响最严重。仅观察到少数脱髓鞘/髓鞘再生过程。此外，PMP22 过度表达可能会在髓鞘形成之前增强成纤维细胞的胶原合成，这表明雪旺细胞以外的结构也受到 PMP22 过度表达的影响。传统上，CMT1A 被认为是由正常髓鞘形成阶段后的脱髓鞘过程引起的，但我们的数据表明，髓鞘形成障碍应被视为该疾病的主要因素。
Charcot-Marie-Tooth (CMT) disease is the most frequent hereditary peripheral neuropathy in humans. Its prevalence is about one in 2500. A subform, CMT1A, is transmitted as an autosomal dominant trait. An estimated 75% of patients are affected. This disorder has been shown to be associated with the,duplication of a 1.5 Mb region of the short arm of chromosome 17, in which the PMP22 gene has been mapped. We have constructed a murine model of CMT1A by inserting into the murine genome a human YAC containing peripheral myelin protein 22 (PMP22) and its flanking controlling elements. We describe the behaviour of the C22 line (seven copies of YAC, 2.1 times PMP22 overexpression) during the myelination process. Electron microscopy, morphometry, electrophysiology, nerve conduction and expression of specific markers (e.g. Krox20) in normal and pathological Schwann cells demonstrated that PMP22 overexpression leads to a defect in the myelination of axons. The largest axons are the most affected. Only a few demyelination/remyelination processes were observed. Moreover, PMP22 overexpression probably enhances collagen synthesis by fibroblasts, before myelination, demonstrating that structures other than Schwann cells are affected by PMP22 overexpression. Classically, CMT1A was thought to be induced by a demyelination process following a phase of normal myelination, yet our data suggest that dysmyelination should be considered as a major factor for the disease.