Genetic etiology of Amyotrophic Lateral Sclerosis

肌萎缩侧索硬化症的遗传病因学

基本信息

批准号：
8736652
负责人：
Bryan Traynor
金额：
$ 56.32万
依托单位：
NATIONAL INSTITUTE ON AGING
依托单位国家：
美国
项目类别：
财政年份：
资助国家：
美国
起止时间：
至
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/8736652
关键词：
Accounting Age Aging Alzheimer&apos s Disease American Amyotrophic Lateral Sclerosis Base Pairing C9ORF72 Canada Chromosomes, Human, Pair 9 Cost Savings DNA Data Dementia Development Diagnosis Disease Disease Progression Elderly European Familial Amyotrophic Lateral Sclerosis Family Finland Frontotemporal Dementia Genes Genetic Genetic Predisposition to Disease Genotype Germany Health Care Costs International Israel Italy Journals Laboratories Light Link London Medicine Molecular Motor Mutation National Institute on Aging Nerve Degeneration Neurodegenerative Disorders Neuromuscular Diseases Neurons New England Paralysed Pathogenesis Pathway interactions Population Publications Publishing Recording of previous events Recruitment Activity Research Research Subjects Respiratory Failure Role Sampling Technology Therapeutic Agents Time United States National Institutes of Health Universities Western World age related base cohort college disease diagnosis effective therapy exome sequencing gene discovery gene therapy genetic variant genome wide association study innovation interest motor neuron degeneration nervous system disorder neurogenetics next generation sequencing novel therapeutics therapeutic target working group

项目摘要

Amyotrophic lateral sclerosis (ALS; Lou Gehrigs disease) is a fatal neurodegenerative disorder that leads to rapidly progressive paralysis and respiratory failure. ALS is the third most common neurodegenerative disease in the Western World, and there are currently no effective therapies. Frontotemporal dementia (FTD) is the most common form of dementia in the population under the age of 65. An overlap between these two clinically distinct neurological diseases has long been recognized, but the molecular basis of this intersection was unknown. Recently, the Neuromuscular Diseases Research Unit (NDRU), a part of the Laboratory of Neurogenetics at the National Institute on Aging, identified the major genetic cause of both ALS and FTD. To do this, Dr. Traynor (chief of NDRU) organized a worldwide consortium, bringing together groups that had previously been competitors to focus their efforts towards identifying this gene. This was made possible by the next generation sequencing technologies available at the NIH. This innovative approach worked, and his group published the cause of chromosome 9-linked ALS/FTD in the journal Neuron in September 2011. In these cases, the disease is caused by a six base pair segment of DNA that is pathologically repeated over and over again, up to several thousand times. This so-called large hexanucleotide repeat disrupts the C9ORF72 gene located on chromosome 9. This is the most common genetic cause of both ALS and FTD identified to date, accounting for approximately 40% of all familial cases of ALS and FTD in European and North American populations. Further, Dr. Traynors group has shown that this mutation underlies about 8% of cases of sporadically occurring ALS and FTD that lack a family history. This represents the first time that a common genetic cause has been identified for the sporadic form of these diseases. In a separate publication in The New England Journal of Medicine, they have also shown that the same large hexanucleotide repeat expansion underlies 1% of Alzheimers disease cases. A one percent reduction in the number of AD cases would represent approximately $1 billion in healthcare cost savings annually. The discovery of the C9ORF72 hexanucleotide repeat expansion is a landmark discovery in our understanding of neurodegenerative disease. It has already greatly effected how these diseases are diagnosed, investigated and perceived, and provides a mechanistic link between two clinically distinct disorders, ALS and FTD. It also provides a distinct therapeutic target for gene therapy efforts aimed at ameliorating the disease, and such efforts are already well underway. Ongoing projects in the laboratory include: (1) exome sequencing of additional familial ALS samples to look for causative genes underlying motor neuron degeneration. DNA for these cases were obtained from our collaborators, Adriano Chio (Italy), Michael Sendtner (Germany), Ekaterina Rogaeva (Canada), and Vivian Drory (Israel), as well as our own efforts to recruit subjects locally and nationally; (2) Large scale genome-wide association study. To achieve this, we have reached out to other laboratories interested in studying this locus, and formed an international consortium involving the University College London, the University of Turin, and the University of Helsinki in Finland. In summary, the current year has been incredibly successful in identifying genetic variants important in the pathogenesis of ALS using next generation sequencing technologies. Each of these studies employed large cohorts of research subjects, and utilized the sequencing and genotyping facilities available within the Laboratory of Neurogenetics, NIA. By understanding the cellular mechanisms underlying late-onset motor neurodegeneration, we also hope to shed light on the role of aging in the CNS and in age-related decline in mobility.

肌萎缩侧索硬化症（ALS；卢伽雷氏病）是一种致命的神经退行性疾病，会导致快速进行性瘫痪和呼吸衰竭。 ALS 是西方世界第三大常见的神经退行性疾病，目前尚无有效的治疗方法。额颞叶痴呆 (FTD) 是 65 岁以下人群中最常见的痴呆形式。人们早已认识到这两种临床上不同的神经系统疾病之间存在重叠，但这种交叉的分子基础尚不清楚。最近，国家衰老研究所神经遗传学实验室下属的神经肌肉疾病研究中心 (NDRU) 确定了 ALS 和 FTD 的主要遗传原因。为此，Traynor 博士（NDRU 主席）组织了一个全球联盟，将以前的竞争对手聚集在一起，集中精力识别该基因。美国国立卫生研究院 (NIH) 提供的下一代测序技术使这成为可能。这种创新方法奏效了，他的团队于 2011 年 9 月在《Neuron》杂志上发表了 9 号染色体连锁的 ALS/FTD 的病因。在这些病例中，这种疾病是由 DNA 的一个六碱基对片段引起的，该片段在病理上一遍又一遍地重复再次，多达数千次。这种所谓的大六核苷酸重复破坏了位于 9 号染色体上的 C9ORF72 基因。这是迄今为止发现的 ALS 和 FTD 最常见的遗传原因，约占欧洲和北美所有 ALS 和 FTD 家族病例的 40%人口。此外，Traynors 博士小组还表明，这种突变是约 8% 的无家族史的偶发性 ALS 和 FTD 病例的基础。这是首次确定这些散发性疾病的共同遗传原因。在《新英格兰医学杂志》的另一篇文章中，他们还表明，相同的大六核苷酸重复扩增是 1% 的阿尔茨海默病病例的基础。 AD 病例数量减少 1% 意味着每年可节省约 10 亿美元的医疗费用。 C9ORF72 六核苷酸重复扩增的发现是我们理解神经退行性疾病的一个里程碑式的发现。它已经极大地影响了这些疾病的诊断、研究和感知方式，并提供了两种临床上不同的疾病（ALS 和 FTD）之间的机制联系。它还为旨在改善疾病的基因治疗努力提供了独特的治疗靶点，并且此类努力已经在顺利进行中。实验室正在进行的项目包括：(1) 对其他家族性 ALS 样本进行外显子组测序，以寻找运动神经元变性的致病基因。这些病例的 DNA 是从我们的合作者 Adriano Chio（意大利）、Michael Sendtner（德国）、Ekaterina Rogaeva（加拿大）和 Vivian Drory（以色列）以及我们自己在当地和全国招募受试者的努力获得的； (2)大规模全基因组关联研究。为了实现这一目标，我们已经联系了其他有兴趣研究该基因座的实验室，并组建了一个由伦敦大学学院、都灵大学和芬兰赫尔辛基大学组成的国际联盟。总之，今年利用下一代测序技术在识别 ALS 发病机制中重要的遗传变异方面取得了令人难以置信的成功。这些研究中的每一项都采用了大量的研究对象，并利用了 NIA 神经遗传学实验室内提供的测序和基因分型设施。通过了解迟发性运动神经变性的细胞机制，我们还希望阐明衰老在中枢神经系统中的作用以及与年龄相关的活动能力下降。