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

我们的团队刚刚发现了一种导致Charcot-Marie-Tooth(CMT)病的新基因突变。多发性肌萎缩侧索硬化症是一种临床和遗传多样性的人类周围神经病家族。CMT神经病是最常见的遗传性周围神经病，大约每2500人中就有1人受到影响。这是已知的最常见的人类遗传病，由50个或更多基因引起。CMT具有巨大的经济意义，因为许多受影响的个人的养老金终生无效，需要持续的医疗和辅助医疗支持。我们发现的新突变是CMT的一种变异形式，并影响到被称为PH结构域的重要区域中的Dynamin 2蛋白。Dy2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)，它也是细胞增殖等其他功能所必需的。PH域是DYN2的一部分，它允许它在需要时移动到细胞的适当部分，但目前尚不清楚该突变是否破坏了DYN2的这一功能。由于Dy2具有多种细胞功能，目前尚不清楚它可能导致这种疾病的原因。我们的目标是通过揭示动力素的许多功能中的哪些主要受到影响，来理解这种突变为什么会导致周围神经退化。我们希望在RME如何与神经元变性联系方面揭示一个新的概念。在之前的研究中，我们开发了第一批与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物，作为修复受损PH结构域的候选药物。更好地了解dy2和内吞作用对于理解CMT和最终开发治疗方法是至关重要的。

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.