Suter U, Nave K A
Department of Biology, Swiss Federal Institute of Technology, ETH-Hönggerberg, Zürich, Switzerland.
Ann N Y Acad Sci. 1999 Sep 14;883:247-53.
We have generated several PMP22 animal mutants with altered PMP22 gene dosage. A moderate increase in the number of PMP22 genes led to hypomyelination comparable to CMT1A, whereas high copy numbers of transgenic PMP22 resulted in phenotypes resembling more severe forms of hereditary motor and sensory neuropathies. In contrast, eliminating one of the two normal PMP22 genes by gene targeting caused unstable focal hypermyelination (tomacula) similar to the pathology in HNPP. A related but more severe phenotype was observed in mice that lack PMP22 completely. Detailed analysis of the different PMP22 mutants revealed, in addition to the obvious myelinopathy, distal axonopathy as a characteristic feature. We conclude that the maintenance of axons might be a promising target for therapeutic interventions in these demyelinating hereditary neuropathies. Furthermore, our results strongly support the concept that PMP22-related neuropathies (and most likely also other forms of inherited motor and sensory neuropathies) should be viewed as the consequence of impaired neuron-Schwann cell interactions that are likely already to be operative during development. Such considerations should be taken into account in the design of potential novel treatment strategies.
我们已经培育出了几种PMP22基因剂量改变的动物突变体。PMP22基因数量适度增加会导致髓鞘形成减少，程度与CMT1A相当，而转基因PMP22的高拷贝数则会导致类似于更严重形式的遗传性运动和感觉神经病的表型。相比之下，通过基因靶向消除两个正常PMP22基因中的一个会导致不稳定的局灶性髓鞘过度形成（腊肠体），类似于HNPP中的病理情况。在完全缺乏PMP22的小鼠中观察到了一种相关但更严重的表型。对不同PMP22突变体的详细分析表明，除了明显的髓鞘病变外，远端轴索性神经病也是一个特征性表现。我们得出结论，轴突的维持可能是这些脱髓鞘性遗传性神经病治疗干预的一个有前景的靶点。此外，我们的结果有力地支持了这样一种观点，即PMP22相关的神经病（很可能还有其他形式的遗传性运动和感觉神经病）应被视为神经元-施万细胞相互作用受损的结果，这种相互作用在发育过程中可能已经起作用。在设计潜在的新治疗策略时应考虑到这些因素。
