Genetic Dissection of Neuromuscular Disorders

周围神经病变是常见的，影响约2.5%的英国人口。当在家族中遗传时，该病症通常被称为Charcot-Marie-Tooth病（CMT），并且是影响1/2500人的最常见的遗传性神经系统疾病之一。CMT通常在儿童或青少年时期开始，伴有进行性远端肢体无力、肌肉萎缩以及手套和长袜感觉丧失。行走问题和足部畸形是常见的，需要脚踝或腿部支撑，棍棒和后来的轮椅使用。许多患者出现并发症，如疼痛、关节退化、脊柱侧凸和肢体溃疡。目前尚无有效的治疗方法。CMT基本上可以分为影响神经髓鞘的1型（CMT 1）或影响神经轴突的2型（CMT 2）。CMT的运动形式称为远端遗传性运动神经病（HMN），感觉形式称为遗传性感觉和自主神经病（HSAN）。有一些基因，当有缺陷时，可以导致CMT。大多数已在CMT 1中鉴定，在其他类型的CMT中仅在一小部分病例中发现了少数基因。大约40%的CMT患者的基因仍然未知。下一代测序技术已经改变了我们识别疾病基因的能力。基因编码蛋白外显子的突变是人类遗传性疾病的主要原因。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序列在一个人（外显子组）使用这项技术。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，非常适合在具有非常相似表型的小家庭或患者群体中进行CMT基因鉴定。我们提出了一个前所未有的基因发现的努力，以确定和测序的未知CMT基因的很大一部分。我们将专注于外显子组测序100 CMT家族，分为CMT 1，CMT 2，远端HMN和HSAN。我们希望能够识别出一些疾病基因，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。我们预期基因会聚集成对周围神经稳态很重要的通路，当有缺陷时会导致神经退化。通过对这些过程的识别，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.