Genetic etiology of Fronto-Temporal Dementia

在上个财政年度，我们完成了两个项目，这两个项目与解开额颞部痴呆(FTD)的遗传原因直接相关。在第一个项目中，我们使用外显子组测序在一个常染色体显性遗传性肌萎缩侧索硬化症(ALS)意大利家系中鉴定了包含Valosin的蛋白(VCP)基因的编码突变。这与FTD研究直接相关，因为此前已在与包涵体肌病和Pagets病(IBMPFD)相关的额颞部痴呆家族中发现了VCP突变。对210例家族性肌萎缩侧索硬化症病例和尸检证实的肌萎缩侧索硬化症和肌萎缩侧索硬化症-FTD病例进行的VCP筛查发现了另外四个突变，其中包括一例经病理证实的肌萎缩侧索硬化症病例的突变。VCP蛋白是含泛素的自噬小体成熟所必需的，突变型VCP的毒性部分是通过其对TDP-43蛋白的影响而介导的，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。我们的数据拓宽了IBMPFD的表型，包括运动神经元变性，提示VCP突变可能占家族性ALS的1%-2%，并提供了直接涉及运动神经元变性以及额叶皮质区域泛素化/蛋白质降解途径缺陷的证据。此外，我们的工作表明，应用下一代测序技术成功地找到迟发性神经退行性疾病的致病基因是可能的，并提供了进一步的证据，表明ALS和FTD具有共同的遗传病因。这篇论文发表在2010年12月的《神经元》杂志上。 在第二个项目中，我们发表了我们在芬兰对肌萎缩侧索硬化症(和肌萎缩侧索硬化症与FTD相关)的全基因组关联研究结果。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，因为这种疾病谱的发病率是世界上最高的之一，而且芬兰人口的遗传同质性提高了检测风险基因座的能力。我们确定了两个关联峰，它们超过了全基因组的意义。其中一个位于染色体21q22上，对应于SOD1基因的常染色体隐性D90A等位基因。另一个是在染色体9p区域232kb的连锁不平衡区块中检测到的，该区域以前在ALS家系的连锁研究中发现。在这个区域内，我们定义了一个与ALS风险显著增加相关的42-SNP单倍型，该单倍型与最近报道的额颞叶痴呆相关基因座重叠。在93例家族性ALS患者中，9p21基因座的人群归因危险度为37.9%(95%可信区间为27.7~48.1)，D90A纯合子的人群归因危险度为25.5%(16.9~34.1)。这些数据清楚地表明，染色体9p21基因座是芬兰人家族性ALS的主要原因。此外，与最近报道的额颞部痴呆风险单倍型的重叠进一步证明了这两种神经退行性疾病的共同遗传原因。这篇论文发表在2010年10月的《柳叶刀神经学》杂志上。 总之，使用下一代测序和全基因组关联方法，今年已经成功地识别了在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统一为一种疾病红宝石，包括两种主要的迟发性神经退行性疾病。这两项研究中的每一项都使用了大量的研究对象，并利用了NIA神经遗传学实验室提供的测序和基因分型设施。

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.