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。额颞叶痴呆是“阿尔茨海默病和相关痴呆”疾病谱的一部分。这两种临床上不同的神经系统疾病之间的重叠早已被认识到，但这种交叉的分子基础尚不清楚。 2011 年，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科 (NDRS) 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 的六碱基对片段引起的，该片段在病理上反复重复反复进行，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，Traynor 博士的研究小组还表明，约 8% 的无家族史的偶发性 ALS 和 FTD 病例都是由这种突变引起的。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，1% 的临床诊断患有阿尔茨海默病的患者也存在同样的大六核苷酸重复扩增。 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。 2021 年，我们发表了一篇论文，描述了对一大群 FTD/ALS 患者的全基因组序列数据的分析，其中我们发现 HTT 重复扩展是这些疾病的罕见原因。 2022 年，我们发表了一篇综述，描述了 ALS 和 FTD 之间的基因重叠。我们还发表了一篇论文，描述了 KIF5A 突变是 FTD 的一个原因。 2023 年，我们发表了一篇论文，描述了一大群 FTD/ALS 患者的结构变异分析。 总之，我们已经使用新一代测序成功地识别了 FTD 发病机制中重要的遗传变异。我们的数据还有助于将 FTD 和 ALS 统一为一个疾病分类，涵盖两种主要的迟发性神经退行性疾病。

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

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

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