Genetic etiology of Fronto-Temporal Dementia

额颞叶痴呆的遗传病因学

• 批准号: 8335972
• 负责人: Bryan Traynor
• 金额: $ 20.95万
• 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/8335972
• 关键词: 9p21; Accounting; Affect; Aging; Alleles; Alzheimer' s Disease; Amyotrophic Lateral Sclerosis; Atrophic; Autophagosome; Autopsy; Chromosomes; Clinical; Code; Data; Defect; Degradation Pathway; Dementia; Disease; Elderly; Epidemiology; Familial Amyotrophic Lateral Sclerosis; Family; Family Study; Finland; Frontotemporal Dementia; Genes; Genetic; Genetic Predisposition to Disease; Genotype; Haplotypes; Impaired cognition; Incidence; Inclusion Bodies; Inherited; Laboratories; Linkage Disequilibrium; Location; Mediating; Motor Manifestations; Motor Neurons; Mutation; Myopathy; Neurodegenerative Disorders; Neurology; Neurons; Paget' s Disease; Paper; Pathogenesis; Patients; Phenotype; Population; Population Attributable Risks; Proteins; Publishing; Reporting; Research; Research Subjects; Risk; SOD1 gene; Screening procedure; Spinal Cord; Staging; Techniques; Temporal Lobe; Toxic effect; Ubiquitin; Ubiquitination; Work; age related; base; cohort; exome; frontal lobe; genetic variant; genome wide association study; genome-wide; motor neuron degeneration; mutant; neurogenetics; next generation; protein TDP-43; protein degradation; valosin-containing protein

During the last fiscal year, we have completed two projects that are directly relevant to unraveling the genetic causes of frontotemporal dementia (FTD). In the first project, we used exome sequencing to identify a coding mutation in the valosin-containing protein (VCP) gene in an Italian family with autosomal dominantly inherited amyotrophic lateral sclerosis (ALS). This is directly relevant to FTD research, as mutations in VCP have previously been identified in families with Frontotemporal Dementia associated with Inclusion Body Myopathy and Pagets disease (IBMPFD). Screening of VCP in a cohort of 210 familial ALS cases and autopsy-proven ALS and ALS-FTD cases identified four additional mutations including a mutation in a pathologically proven case of ALS. VCP protein is essential for maturation of ubiquitin-containing autophagosomes, and mutant VCP toxicity is partially mediated through its effect on TDP-43 protein, a major constituent of ubiquitin inclusions that neuropathologically characterize ALS. Our data broaden the phenotype of IBMPFD to include motor neuron degeneration, suggest that VCP mutations may account for ∼1%-2% of familial ALS, and provide evidence directly implicating defects in the ubiquitination/protein degradation pathway in motor neuron degeneration, as well as frontal cortical regions. Furthermore, our work shows that it is possible to apply next generation sequencing techniques to successfully find causative genes in late-onset neurodegenerative diseases of aging, and provides further evidence that ALS and FTD share a common genetic etiology. This paper was published in Neuron in December 2010. In the second project, we published the results of our genome-wide association study of ALS (and ALS associated with FTD) in Finland. Finland is an ideal location for a genome-wide association study of these age-related neurodegenerative diseases because the incidence of this disease spectrum is one of the highest in the world, and because the genetic homogeneity of the Finnish population enhances the ability to detect risk loci. We identified two association peaks that exceeded genome-wide significance. One was located on chromosome 21q22, which corresponds to the autosomal recessive D90A allele of the SOD1 gene. The other was detected in a 232kb block of linkage disequilibrium in a region of chromosome 9p that was previously identified in linkage studies of families with ALS. Within this region, we defined a 42-SNP haplotype that was associated with significantly increased risk of ALS, and which overlapped with an association locus recently reported for frontotemporal dementia. For the 93 patients with familial ALS, the population attributable risk for the chromosome 9p21 locus was 37.9% (95% CI 27.7-48.1) and that for D90A homozygosity was 25.5% (16.9-34.1). These data clearly show that the chromosome 9p21 locus is a major cause of familial ALS in the Finnish population. Furthermore, the overlap with the risk haplotype recently reported for frontotemporal dementia provides further evidence of a shared genetic cause for these two neurodegenerative diseases. This paper was published in Lancet Neurology in October 2010. In summary, the current year has been successful in identifying genetic variants important in the pathogenesis of FTD using next generation sequencing and genome-wide association approaches. 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.

在上一财年，我们完成了两个与揭示额颞叶痴呆 (FTD) 遗传原因直接相关的项目。在第一个项目中，我们使用外显子组测序来鉴定一个患有常染色体显性遗传性肌萎缩侧索硬化症（ALS）的意大利家族的含缬洛辛蛋白（VCP）基因的编码突变。这与 FTD 研究直接相关，因为之前已在与包涵体肌病和佩吉茨病 (IBMPFD) 相关的额颞叶痴呆家族中发现了 VCP 突变。在 210 例家族性 ALS 病例以及尸检证实的 ALS 和 ALS-FTD 病例中进行 VCP 筛查，发现了四种额外的突变，其中包括病理证实的 ALS 病例中的突变。 VCP 蛋白对于含泛素的自噬体的成熟至关重要，突变型 VCP 毒性部分是通过其对 TDP-43 蛋白的影响介导的，TDP-43 蛋白是泛素包涵体的主要成分，是 ALS 的神经病理学特征。我们的数据扩大了 IBMPFD 的表型，将运动神经元变性包括在内，表明 VCP 突变可能占家族性 ALS 的 1%-2%，并提供了直接暗示运动神经元变性中泛素化/蛋白质降解途径缺陷的证据。作为额叶皮质区域。此外，我们的工作表明，应用下一代测序技术可以成功找到老年迟发性神经退行性疾病的致病基因，并进一步证明 ALS 和 FTD 具有共同的遗传病因。该论文于 2010 年 12 月发表在 Neuron 上。 在第二个项目中，我们发表了芬兰 ALS（以及与 FTD 相关的 ALS）全基因组关联研究的结果。芬兰是对这些与年龄相关的神经退行性疾病进行全基因组关联研究的理想地点，因为这种疾病谱是世界上发病率最高的国家之一，而且芬兰人口的遗传同质性增强了检测风险的能力基因座。我们确定了两个超出全基因组显着性的关联峰。其中一个位于染色体 21q22，对应于 SOD1 基因的常染色体隐性 D90A 等位基因。另一个是在 9p 染色体区域的 232kb 连锁不平衡块中检测到的，该区域先前在 ALS 家族的连锁研究中被发现。在该区域内，我们定义了一个 42-SNP 单倍型，该单倍型与 ALS 风险显着增加相关，并且与最近报道的额颞叶痴呆的关联位点重叠。对于 93 名家族性 ALS 患者，染色体 9p21 基因座的人群归因风险为 37.9%（95% CI 27.7-48.1），D90A 纯合性的人群归因风险为 25.5%（16.9-34.1）。这些数据清楚地表明，染色体 9p21 位点是芬兰人群中家族性 ALS 的主要原因。此外，与最近报道的额颞叶痴呆风险单倍型的重叠进一步证明这两种神经退行性疾病具有共同的遗传原因。该论文于2010年10月发表在《柳叶刀神经病学》杂志上。 总之，今年利用下一代测序和全基因组关联方法成功识别了 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 统一为单一疾病红字，涵盖两种主要的迟发性神经退行性疾病。这两项研究均采用了大量研究对象，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。