Rab7 and the CMT2B disease
Rab7 and the CMT2B disease
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DOI：
10.1042/bst0371027
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发表时间：
2009-10-01
影响因子：
3.9
通讯作者：
Bucci, Cecilia
中科院分区：
文献类型：
--
作者：
Cogli, Laura;Piro, Francesco;Bucci, Cecilia
CMT2B（腓骨肌萎缩症 213 型）疾病是一种常染色体显性遗传性轴突神经病。感觉丧失、远端肌肉无力和消瘦、频繁的足部溃疡以及由于频繁感染而导致的脚趾截肢是这种神经病的特征。 rab7 基因中的四个错义突变已被确定为导致该疾病的原因。 Rab7 是 Rab 家族的一种小 G 蛋白，控制内吞途径中的囊泡转运至晚期内体和溶酶体。 CMT2B 相关突变 Rab7 蛋白显示出核苷酸解离速率改变和 GTPase 活性受损。此外，这些突变蛋白在人类细胞中表达时主要以 GTP 结合形式存在，并且能够在 Rab7 耗尽的细胞中挽救 Rab7 功能。因此，这些突变产生了 Rab7 的激活形式，从而导致了疾病的发展。尽管取得了这些结果，我们对 CMT2B 潜在机制的理解仍然存在重要差距。事实上，rab7 基因中的这些突变如何影响特定的外周神经元，导致 CMT2B 中的轴突病理学尚不清楚，鉴于 Rab7 是一种普遍存在的蛋白质，这是一个特别令人费解和具有挑战性的问题。本综述讨论了 CMT2B 可能的分子机制。
The CMT2B (Charcot-Marie-Tooth type 213) disease is an autosomal dominant axonal neuropathy. Sensory loss, distal muscle weakness and wasting, frequent foot ulcers and amputations of the toes due to frequent infections characterize this neuropathy. Four missense mutations in the rab7 gene have been identified as causative of the disease. Rab7 is a small G-protein of the Rab family that controls vesicular transport to late endosomes and lysosomes in the endocytic pathway. The CMT2B-associated mutant Rab7 proteins show altered nucleotide dissociation rates and impaired GTPase activity. in addition, these mutant proteins are predominantly in the GTP-bound form when expressed in human cells and they are able to rescue Rab7 function in Rab7-depleted cells. Thus these mutations generate activated forms of Rab7 that are responsible for the development of the disease. in spite of these results, there are still important gaps in our understanding of the mechanism underlying CMT2B. indeed, how these mutations in the rab7 gene affect specifically peripheral neurons leading to an axonal pathology in CMT2B is not clear, and it is a particularly puzzling and challenging issue in view of the fact that Rab7 is a ubiquitous protein. The present review discusses possible molecular mechanisms underlying CMT2B.