Lemke G
Molecular Neurobiology Laboratory, Salk Institute, La Jolla, California 92037.
Glia. 1993 Apr;7(4):263-71. doi: 10.1002/glia.440070402.
Recent molecular genetic studies have provided new insights into the structure and function of 2 of the major integral membrane proteins of myelin--the proteolipid protein (PLP) and protein zero (P0)--and have uncovered a third such protein--PMP22/gas3. The rumpshaker mouse has been shown to carry a point mutation in the PLP gene that uncouples a deleterious effect on CNS myelin assembly, which these mice exhibit, from oligodendrocyte degeneration and cell death, which they do not. The developmental importance of the P0 protein in PNS myelination has been dramatically demonstrated by the analysis of loss-of-function mutations engineered through the expression of antisense RNA and through the insertional inactivation of the P0 gene by homologous recombination in embryonic stem cells and the generation of P0-deficient mice. The cloned promoter of the P0 gene has been shown to drive quantitative, Schwann cell-specific expression of heterologous genes in transgenic mice. The PMP22/gas3 gene, previously cloned from fibroblast cell lines, has been found to encode an axonally regulated Schwann cell protein that is assembled into PNS myelin. Importantly, this gene appears to be the target of mutations that result in the Trembler alleles in mice, and in Charcot-Marie-Tooth disease Type 1a, the most common inherited peripheral neuropathy in humans.
最近的分子遗传学研究为髓磷脂的两种主要整合膜蛋白——蛋白脂蛋白（PLP）和零蛋白（P0）的结构与功能提供了新的见解，并发现了第三种此类蛋白——PMP22/gas3。已证明摇臀小鼠的PLP基因存在一个点突变，该突变将这些小鼠所表现出的对中枢神经系统髓磷脂组装的有害影响与它们并未出现的少突胶质细胞变性和细胞死亡分离开来。通过对反义RNA表达所构建的功能丧失突变体进行分析，以及通过胚胎干细胞中的同源重组对P0基因进行插入失活并生成P0缺陷小鼠，显著证明了P0蛋白在周围神经系统髓鞘形成中的发育重要性。已证明P0基因的克隆启动子可驱动转基因小鼠中异源基因的定量、施万细胞特异性表达。先前从成纤维细胞系中克隆的PMP22/gas3基因，已发现其编码一种轴突调节的施万细胞蛋白，该蛋白组装到周围神经系统髓磷脂中。重要的是，该基因似乎是导致小鼠震颤等位基因以及人类最常见的遗传性周围神经病1A型（夏科-马里-图斯病）的突变靶点。
