Genomic Studies in Charcot-Marie-Tooth Disease

描述（由申请人提供）：大约有2000万美国人患上周围神经病变，每年仅医疗保险的费用就超过35亿美元。对这些疾病的了解很少，治疗方法也仅限于不存在.周围神经病变的遗传形式提供了一个独特的机会窗口，以确定和解剖的关键基因和途径。事实上，这些遗传性神经病，被称为腓骨肌萎缩症（CMT），是神经病学中最常见的遗传性疾病，每2500人中就有1人受到影响。尽管在CMT的基因鉴定方面取得了令人印象深刻的成功，但对于可以说是最重要的轴突亚型，只有约30%的遗传原因被确定。传统的基因鉴定方法依赖于大的谱系，对于解决这个问题变得越来越无效。新的高通量测序技术现在是可用的，其允许有效分析整个基因组或其高度信息化的替代物，例如外显子组，编码外显子的整个集合。在最先进的Hussman人类基因组学研究所人类分子基因组学中心主任Zuchner博士的领导下，我们最近发表了多代系谱的第一个外显子组测序研究和CMT的第一个外显子组研究，现在已经发表了几个用这种方法鉴定的新基因。我们完全期望这项技术将大大增加解决不适合经典连锁分析的相对较小的CMT家族的致病基因。Michael Shy博士是该国最大的CMT诊所的主任，也是NINDS/ORD资助的遗传性神经病罕见病临床研究中心（RDCRC）和MDA/CMTA资助的北美数据库和北美CMT网络的PI。因此，我们可以接触到世界各地的CMT患者，并在本资助中提出了一种大胆的方法，涉及高通量基因组技术的应用，这将导致在几年内发现相当数量的基因。此外，我们还在多个生物系统（酵母、斑马鱼、哺乳动物细胞培养物）中通过创新的功能设计追求遗传结果，这些系统有助于更高通量的研究。我们组建了一支由临床医生、分子和统计遗传学家、生物信息学家和分子生物学家组成的跨学科团队，以成功应用这些高度复杂的技术。所有的数据将提供给公众访问的数据库奠定了基础，为未来的周围神经病变基因库。只有通过确定CMT的遗传原因，我们才能够研究编码蛋白的功能并开发合理的治疗干预方法。重要的是，相关的轴突神经病变，如糖尿病性神经病变，药物诱导的神经病变和运动和感觉神经元的退行性疾病将大大受益于这些研究的结果。

DESCRIPTION (provided by applicant): Approximately 20 million Americans develop peripheral neuropathy with annual costs to Medicare alone in excess of $3.5 billion. These diseases are poorly understood and therapeutic options are limited to non- existent. The hereditary forms of peripheral neuropathies present a unique window of opportunity to identify and dissect the key genes and pathways. In fact, these hereditary neuropathies, known as Charcot-Marie- Tooth disease (CMT), represent the most common inherited disorders in Neurology with 1/2500 individuals affected. Despite impressive success in gene identification in CMT, only ~30% of the genetic causes have been identified for the arguably most important, axonal subtype. Classic methods for gene identification, which depend on large pedigrees, become increasingly ineffective to resolve this problem. New high- throughput sequencing technology is now available that permits for the efficient analysis of whole genomes or highly informative proxies thereof, such as the exome, the entire collection of coding exons. Under the lead of Dr. Zuchner, Director of the Center for Human Molecular Genomics at the state-of-the-art Hussman Institute for Human Genomics, we have recently published the first exome sequencing study of a multigenerational pedigree and the first exome study on CMT and have now published several new genes identified with this method. We fully expect that this technology will add tremendously to resolving causative genes in relatively small CMT families not suitable for classic linkage analysis. The second PI of this proposal, Dr. Michael Shy, is Director of the largest CMT Clinic in the country as well as the PI of the NINDS/ORD funded Rare Disease Clinical Research Center (RDCRC) for genetic neuropathies and the MDA/CMTA funded North American Database and the North American CMT Network. Consequently, we have access to CMT patients throughout the world and propose in this grant a bold approach involving the application of high- throughput genomic technologies that will lead to the discovery of a considerable number of genes in a few years time. In addition we are pursuing genetic results with an innovative functional design in multiple biological systems, yeast, zebrafish, mammalian cell culture, that lend themselves to higher throughput studies. We have assembled an interdisciplinary team of clinicians, molecular and statistical geneticists, bioinformaticians, and molecular biologists to successfully apply these highly complex technologies. All data will be made available to publicly accessible databases laying the foundation for a future genomic repository for peripheral neuropathies. It is only by identifying the genetic causes of CMT that we will be able to study the function of encoded proteins and develop rational approaches to therapeutic intervention. Importantly, related axonal neuropathies, such as diabetic neuropathy, drug-induced neuropathies and degenerative diseases of motor and sensory neurons will greatly benefit from the results of such studies.