Consequences of Dynamin 2 PH Domain Dysfunction in Charcot-Marie-Tooth Neuropathy

我们的团队刚刚发现了一种新的基因突变，它会导致CMT病。CMT是一种临床和遗传多样化的人类周围神经病变家族。CMT神经病变是最常见的遗传性周围神经病变，约1 / 2500。它是已知的最常见的人类遗传疾病，由50个或更多的基因引起。CMT具有重大的经济意义，因为许多受影响的个人领取终身无效养恤金，需要持续的医疗和辅助医疗支助。我们发现的新突变是CMT的一种变体形式，它影响了一个叫做PH结构域的重要区域的蛋白动力蛋白2。Dyn2的正常功能是从细胞膜上回收激活的激素和生长因子受体（呼叫者受体介导的内吞作用或RME），它也需要其他功能，如细胞增殖。PH结构域是Dyn2的一部分，它允许它在需要完成工作时移动到细胞的适当部分，但目前尚不清楚突变是否会破坏Dyn2的这一功能。由于Dyn2具有多种细胞功能，目前尚不清楚它为什么会导致这种疾病。我们的目标是通过揭示动力蛋白的哪些功能主要受到影响，来理解为什么这种突变会导致周围神经退化。我们希望揭示RME与神经元退化之间的联系的新概念。在之前的研究中，我们开发了第一种与PH结构域相互作用的药物。我们现在将充分开发这些药物，并合成与PH结构域相互作用的新药，作为修复受损PH结构域的候选药物。更好地了解Dyn2和内吞作用对于理解CMT和最终开发治疗方法至关重要。

Our team has just discovered a new gene mutation that causes Charcot-Marie-Tooth (CMT) disease. CMT is a clinically and genetically diverse family of human peripheral neuropathies. CMT neuropathy is the most common inherited peripheral neuropathy, affecting approximately 1 in 2500. It is the most common human genetic disorder known and is caused by fifty or more genes. CMT is of large economic significance since many of the affected individuals are on lifetime invalid pensions and require continual medical and paramedical support. The new mutation we discovered is in a variant form of CMT and affects the protein dynamin 2, in an important region called the PH domain. The normal function of Dyn2 is to retrieve activated receptors for hormones and growth factors from the membrane of cells (caller receptor mediated endocytosis or RME) and it is also required for other functions like cell proliferation. The PH domain is the part of Dyn2 that allows it to move to the appropriate part of the cell when needed to do its job, but it is not known whether the mutation disrupts this function of Dyn2. Since Dyn2 has multiple cellular functions, it is not understood why it might cause the disease. Our goal is to understand why this mutation causes peripheral nerves to degenerate, by revealing which of dynamin's many functions are primarily affected. We expect to uncover a new concept in how RME links to neuronal degeneration. In previous studies we developed the first drugs that interact with PH domains. We will now fully develop these, and synthesise new drugs that interact with the PH domain, as candidates to effect some repair of the damaged PH domain. A better understanding of Dyn2 and endocytosis is crucial to understanding both CMT and ultimately for developing therapies.