Orthmann-Murphy Jennifer L, Enriquez Alan D, Abrams Charles K, Scherer Steven S
Department of Neurology, University of Pennsylvania School of Medicine, Room 464 Stemmler Hall, 3450 Hamilton Walk, Philadelphia, PA 19104-6077, USA.
Mol Cell Neurosci. 2007 Apr;34(4):629-41. doi: 10.1016/j.mcn.2007.01.010. Epub 2007 Jan 25.
Recessive mutations in GJA12/Cx47, the gene encoding the gap junction protein connexin47 (Cx47), cause Pelizaeus-Merzbacher-like disease (PMLD), which is characterized by severe CNS dysmyelination. Three missense PMLD mutations, P87S, Y269D and M283T, were expressed in communication-incompetent HeLa cells, and in each case the mutant proteins appeared to at least partially accumulate in the ER. Cells expressing each mutant did not pass Lucifer Yellow or neurobiotin in scrape loading assays, in contrast to robust transfer in cells expressing wild type Cx47. Dual whole-cell patch clamping of transfected Neuro2A cells demonstrated that none of the mutants formed functional channels, in contrast to wild type Cx47. Immunostaining sections of primate brains demonstrated that oligodendrocytes express Cx47, which is primarily localized to their cell bodies. Thus, the Cx47 mutants associated with PMLD likely disrupt the gap junction coupling between astrocytes and oligodendrocytes.
编码缝隙连接蛋白连接蛋白47（Cx47）的基因GJA12/Cx47中的隐性突变会导致佩利措伊斯-默茨巴赫样病（PMLD），其特征是严重的中枢神经系统髓鞘形成异常。三种错义PMLD突变，即P87S、Y269D和M283T，在无通讯能力的HeLa细胞中表达，在每种情况下，突变蛋白似乎至少部分积聚在内质网中。与表达野生型Cx47的细胞中荧光黄或神经生物素的强劲转移相反，表达每种突变体的细胞在刮擦加载试验中均未传递荧光黄或神经生物素。对转染的Neuro2A细胞进行双全细胞膜片钳记录表明，与野生型Cx47相反，没有一个突变体形成功能性通道。灵长类动物脑切片的免疫染色显示，少突胶质细胞表达Cx47，其主要定位于细胞体。因此，与PMLD相关的Cx47突变体可能破坏星形胶质细胞和少突胶质细胞之间的缝隙连接偶联。
