Genetic etiology of Fronto-Temporal Dementia, a dementia related to Alzheimer's disease

额颞叶痴呆（一种与阿尔茨海默病相关的痴呆症）的遗传病因学

• 批准号: 10913164
• 负责人: Bryan Traynor
• 金额: $ 23.24万
• 依托单位: NATIONAL INSTITUTE ON AGING
• 依托单位国家: 美国
• 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/10913164
• 关键词: ALS patients; Accounting; Affect; Age; Alzheimer' s Disease; Alzheimer' s disease related dementia; American; Amyotrophic Lateral Sclerosis; Base Pairing; C9ORF72; Chromosome 9; Clinical; Cost Savings; DNA; Data; Dementia; Disease; Elderly; Epidemiology; European; Family; Frontotemporal Dementia; Genes; Genetic; Genetic Predisposition to Disease; Health Care Costs; Journals; Laboratories; Link; Lobe; Medicine; Molecular; Mutation; National Institute on Aging; Neurodegenerative Disorders; Neuromuscular Diseases; Neurons; New England; Paper; Paralysed; Pathogenesis; Pathologic; Patients; Population; Publications; Publishing; Recording of previous events; Research; Respiratory Failure; Technology; Time; Ubiquitin; United States National Institutes of Health; Variant; Western World; Work; clinical diagnosis; cohort; disease diagnosis; effective therapy; frontotemporal lobar dementia amyotrophic lateral sclerosis; gene therapy; genetic variant; innovation; nervous system disorder; neurogenetics; next generation sequencing; therapeutic target; whole genome

Amyotrophic lateral sclerosis (ALS; Lou Gehrig's 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. Frontotemporal dementia is part of the "Alzheimer's disease and related dementias" spectrum of illness. Overlap between these two clinically distinct neurological diseases has long been recognized, but the molecular basis of this intersection was unknown. In 2011, the Neuromuscular Diseases Research Section (NDRS), 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 on 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. Traynor's 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 patients clinically diagnosed with Alzheimer's disease. 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 diseases. It has already greatly affected 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 2021, we published a paper describing the analysis of whole-genome sequence data for a large cohort of FTD/ALS patients in which we found the HTT repeat expansion to be a rare cause of these diseases. In 2022, we published a review describing the genetic overlap between ALS and FTD. We also published a paper describing mutations in KIF5A as a cause of FTD. In 2023, we published a paper describing the structural variant analysis for a large cohort of FTD/ALS patients. 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 rubric that encompasses two of the major late-onset neurodegenerative diseases.

肌萎缩性侧索硬化症（ALS； Lou Gehrig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。额颞痴呆是“阿尔茨海默氏病和相关痴呆症”疾病谱的一部分。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识别，但是该交叉点的分子基础尚不清楚。 2011年，美国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科（NDRS）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的团体聚集在识别该基因上。 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，该疾病是由六个基准对DNA段引起的，它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，特雷诺（Traynor）博士的小组表明，这种突变是偶发发生的ALS和FTD病例中约8％的缺乏家族病史的原因。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，相同的大型六核苷酸重复扩张是1％的临床诊断患有阿尔茨海默氏病的患者。每年减少的AD案例数量减少1％，每年可节省约10亿美元的医疗保健成本。 C9ORF72六核苷酸重复扩展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，调查和感知方式，并提供了两种临床上不同疾病（ALS和FTD）之间的机械联系。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。 在2021年，我们发表了一篇论文，描述了大量FTD/ALS患者的全基因组序列数据的分析，其中我们发现HTT重复扩张是这些疾病的罕见原因。 在2022年，我们发表了一篇评论，描述了ALS和FTD之间的遗传重叠。我们还发表了一篇论文，将KIF5A中的突变描述为FTD的原因。 2023年，我们发表了一篇论文，描述了大量FTD/ALS患者队列的结构变异分析。 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统一成一个单一的疾病标题，该疾病涵盖了两种主要发作神经退行性疾病。

项目成果

Frontotemporal dementia with a C9ORF72 expansion in a Swedish family: clinical and neuropathological characteristics.

瑞典家庭中 C9ORF72 扩增导致的额颞叶痴呆：临床和神经病理学特征。

• 发表时间: 2013
• 期刊: American journal of neurodegenerative disease
• 作者: LandqvistWaldö,Maria;Gustafson,Lars;Nilsson,Karin;Traynor,BryanJ;Renton,AlanE;Englund,Elisabet;Passant,Ulla
• 通讯作者: Passant,Ulla

Frontotemporal dementia with psychosis, parkinsonism, visuo-spatial dysfunction, upper motor neuron involvement associated to expansion of C9ORF72: a peculiar phenotype?

• DOI: 10.1007/s00415-012-6444-3
• 发表时间: 2012-08
• 期刊: Journal of neurology
• 影响因子: 6
• 作者: Floris G;Borghero G;Cannas A;Di Stefano F;Costantino E;Murru MR;Brunetti M;Restagno G;Traynor BJ;Marrosu MG;Chiò A;Marrosu F
• 通讯作者: Marrosu F

GroupICA dual regression analysis of resting state networks in a behavioral variant of frontotemporal dementia.

• DOI: 10.3389/fnhum.2013.00461
• 发表时间: 2013
• 期刊: Frontiers in human neuroscience
• 影响因子: 2.9
• 作者: Rytty R;Nikkinen J;Paavola L;Abou Elseoud A;Moilanen V;Visuri A;Tervonen O;Renton AE;Traynor BJ;Kiviniemi V;Remes AM
• 通讯作者: Remes AM

Clinical Characteristics of C9ORF72-Linked Frontotemporal Lobar Degeneration.

• DOI: 10.1159/000351859
• 发表时间: 2013
• 期刊: Dementia and geriatric cognitive disorders extra
• 影响因子: 2.3
• 作者: Kaivorinne AL;Bode MK;Paavola L;Tuominen H;Kallio M;Renton AE;Traynor BJ;Moilanen V;Remes AM
• 通讯作者: Remes AM

Screening a UK amyotrophic lateral sclerosis cohort provides evidence of multiple origins of the C9orf72 expansion.

• DOI: 10.1016/j.neurobiolaging.2014.07.037
• 发表时间: 2015-01
• 期刊: Neurobiology of aging
• 影响因子: 4.2
• 作者: Fratta P;Polke JM;Newcombe J;Mizielinska S;Lashley T;Poulter M;Beck J;Preza E;Devoy A;Sidle K;Howard R;Malaspina A;Orrell RW;Clarke J;Lu CH;Mok K;Collins T;Shoaii M;Nanji T;Wray S;Adamson G;Pittman A;Renton AE;Traynor BJ;Sweeney MG;Revesz T;Houlden H;Mead S;Isaacs AM;Fisher EM
• 通讯作者: Fisher EM