Genetic Dissection of Neuromuscular Disorders

周围神经病变很常见，约占英国人口的2.5%。当家族遗传时，这种情况通常被称为沙科-玛丽-图斯病（CMT），是最常见的遗传性神经系统疾病之一，每2500人中就有1人患有这种疾病。CMT通常开始于儿童或青少年时期，伴有进行性远端肢体无力，肌肉萎缩和手套和袜子感觉丧失。行走问题和足部畸形很常见，需要脚踝或腿部支撑，手杖和后来的轮椅。许多患者出现疼痛、关节退化、脊柱侧弯和肢体溃疡等并发症。目前还没有有效的治疗方法。CMT本质上可分为影响神经髓鞘的1型（CMT1）和影响神经轴突的2型（CMT2）。CMT的运动形式被称为远端遗传性运动神经病（HMN）和感觉形式的遗传性感觉和自主神经病变（HSAN）。有很多基因一旦有缺陷，就会导致CMT。大多数已经在CMT1中被发现，只有少数基因在其他类型的CMT中被发现。大约40%的CMT患者基因未知。下一代测序技术已经改变了我们识别疾病基因的能力。编码基因外显子的蛋白质突变是大多数人类遗传疾病的原因。我们现在可以使用革命性的富集方法来选择所有的外显子在一个个体（外显子组）中进行测序。在我们的实验室中，我们已经建立了一个有效的外显子组测序管道，非常适合于CMT基因鉴定，在小家庭或非常相似表型的患者群体中。我们提出了一项前所未有的基因发现工作，以识别和表征大部分未知的CMT基因。我们将重点对100个CMT家族进行外显子组测序，分为CMT1、CMT2、远端HMN和HSAN。我们希望鉴定出一些疾病基因，证明这些缺陷，并检查我们的整个CMT患者系列。许多遗传缺陷将需要对其他患者材料（如新鲜血液）进行研究，以证明突变机制。为了进一步分析CMT基因的功能，我们已经建立了一些富有成效的合作。我们期望基因聚集在对周围神经稳态很重要的通路中，当缺陷导致神经变性时。通过识别这些过程，我们希望揭示治疗靶点，这些靶点将成为治疗药物试验的有希望的候选者。

Peripheral neuropathy is common, affecting approximately 2.5% of the UK population. When inherited in a family the condition is usually called Charcot-Marie-Tooth disease (CMT) and is one of the commonest inherited neurological disorders affecting 1 in 2500 people.CMT usually starts in childhood or teenage years with progressive distal limb weakness, muscle wasting and glove and stocking sensory loss. Walking problems and foot deformities are common requiring ankle or leg supports, sticks and later wheelchair use. Many patients develop complications such as pain, degeneration of the joints, scoliosis and limb ulcers. There is no effective treatment available. CMT can essentially be divided into type 1 (CMT1) that affects the nerve myelin sheath or type 2 (CMT2) that affects the nerve axon. The motor form of CMT is called distal hereditary motor neuropathy (HMN) and the sensory form hereditary sensory and autonomic neuropathy (HSAN). There a number of genes that when defective, can cause CMT. The majority have been identified in CMT1, few genes in only a small proportion of cases have been found in the other types of CMT. Around 40% of CMT patients remain genetically unknown.Next generation sequencing technology has transformed our ability to identify disease genes. Mutations in the protein encoding exons of genes account for most of human genetic diseases. We can now use revolutionary enrichment methods to select all the exons to sequence in an individual (exome) using this technology. In our laboratory we have established an effective exome sequencing pipeline which is perfectly suited to CMT gene identification, in small families or groups of patients with very similar phenotypes. We propose an unprecedented gene discovery effort to identify and characterise a large proportion of the unknown CMT genes. We will focus on exome sequencing 100 CMT families, divided between CMT1, CMT2, distal HMN and HSAN. We expect to identify a number of disease genes, prove these defects and examine our entire series of CMT patients. Many genetic defects will require studies on other patient material such as fresh blood to prove the mutation mechanism. To further analyse the function of the CMT genes identified we have established a number of fruitful collaborations. We expect genes to cluster into pathways that are important for peripheral nerve homeostasis and when defective lead to nerve degeneration. Through the identification of these processes we hope to reveal treatment targets that will be promising candidates for therapeutic drug trials.