Genetic etiology of Fronto-Temporal Dementia

额颞叶痴呆的遗传病因学

基本信息

批准号：
8736653
负责人：
Bryan Traynor
金额：
$ 34.2万
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/8736653
关键词：
Accounting Affect Age Alzheimer&apos s Disease American Amyotrophic Lateral Sclerosis Base Pairing C9ORF72 Chromosomes, Human, Pair 9 Clinical Cost Savings DNA Data Dementia Disease Elderly Epidemiology European Family Frontotemporal Dementia Genes Genetic Genetic Predisposition to Disease Genotype Health Care Costs Journals Laboratories Link Medicine Molecular Mutation National Institute on Aging Neurodegenerative Disorders Neuromuscular Diseases Neurons New England Paralysed Pathogenesis Patients Population Publications Publishing Recording of previous events Research Research Subjects Respiratory Failure Technology Temporal Lobe Time Ubiquitin United States National Institutes of Health Western World base cohort disease diagnosis effective therapy gene therapy genetic variant innovation nervous system disorder neurogenetics next generation sequencing 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. In summary, we have been successful in identifying genetic variants important in the pathogenesis of FTD using next generation sequencing. Our data also helps to unify FTD and ALS into a single disease rubic that encompasses two of the major late-onset neurodegenerative diseases. Each of the two studies employed large cohorts of research subjects, and utilized the sequencing and genotyping facilities available within the Laboratory of Neurogenetics, NIA.

肌萎缩性侧索硬化症（ALS； Lou Gehrigs病）是一种致命的神经退行性疾病，可导致快速进行性瘫痪和呼吸衰竭。 ALS是西方世界中第三大常见的神经退行性疾病，目前尚无有效的疗法。额颞痴呆（FTD）是65岁以下人群中最常见的痴呆形式。长期以来，这两种临床上不同的神经系统疾病之间的重叠已被认识到，但是该交叉点的分子基础尚不清楚。最近，国家衰老研究所的神经遗传学实验室的一部分，神经肌肉疾病研究部门（NDRU）确定了ALS和FTD的主要遗传原因。为此，Traynor博士（NDRU的负责人）组织了一个全球的财团，将以前曾是竞争对手集中精力努力识别该基因的竞争对手组合在一起。 NIH可用的下一代测序技术使这成为可能。这种创新的方法奏效了，他的小组在2011年9月在神经元期间发表了染色体9连接的ALS/FTD的原因。在这些情况下，该疾病是由六个基对DNA的六个基对DNA引起的，该疾病在病理上一遍又一遍地重复，多达几千次。这种所谓的大型六核苷酸重复破坏了位于9号染色体上的C9ORF72基因。这是迄今为止确定的ALS和FTD的最常见遗传原因，约占欧洲和北美人口中ALS和FTD的所有家族案例的大约40％。此外，Traynors Group博士表明，这种突变是偶发发生的ALS和FTD病例的8％是缺乏家族病史的情况。这代表了这些疾病的零星形式首次确定共同的遗传原因。在《新英格兰医学杂志》上的另一份出版物中，他们还表明，同样的大型六核苷酸重复扩张是阿尔茨海默氏病病例的1％。每年减少的AD案例数量减少1％，约占医疗保健成本约10亿美元。 C9ORF72六核苷酸重复扩张的发现是我们对神经退行性疾病的理解。它已经极大地影响了这些疾病的诊断，研究和感知，并在两种临床上不同的疾病ALS和FTD之间提供了机械联系。它还为旨在改善疾病的基因疗法工作提供了一个独特的治疗靶标，并且此类努力已经在进行中。总而言之，我们已经成功地鉴定了使用下一代测序在FTD发病机理中重要的遗传变异。我们的数据还有助于将FTD和ALS统一成单个疾病Rubic，其中包括两种主要发作的神经退行性疾病。两项研究中的每一项都采用了大量研究对象，并利用了NIA神经遗传学实验室内可用的测序和基因分型设施。