Genetic etiology of Fronto-Temporal Dementia

在上一个财政年度，我们完成了两个项目，这是直接相关的解开额颞叶痴呆症（FTD）的遗传原因。在第一个项目中，我们使用外显子组测序，以确定一个编码突变的valosin-containing蛋白（VCP）基因在意大利家庭与常染色体显性遗传性肌萎缩侧索硬化症（ALS）。这与FTD研究直接相关，因为之前已在与包涵体肌病和佩吉特病（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病例和尸检证实的ALS和ALS-FTD病例的队列中筛查VCP，发现了4个额外的突变，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是必不可少的，并且突变的VCP毒性部分地通过其对TDP-43蛋白的作用介导，TDP-43蛋白是神经病理学表征ALS的泛素包涵体的主要成分。我们的数据扩大了IBMPFD的表型，包括运动神经元变性，表明VCP突变可能占家族性ALS的1%-2%，并提供证据直接暗示运动神经元变性中的泛素化/蛋白质降解途径缺陷，以及额叶皮质区域。此外，我们的工作表明，有可能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，并进一步证明ALS和FTD具有共同的遗传病因。这篇论文于2010年12月发表在Neuron上。 在第二个项目中，我们在芬兰发表了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有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增强了检测风险位点的能力。我们确定了两个超过全基因组显著性的关联峰。一个位于染色体21 q22，对应于SOD 1基因的常染色体隐性D90 A等位基因。另一个在染色体9 p的一个区域中检测到232 kb的连锁不平衡块，该区域先前在ALS家族的连锁研究中被确定。在这个区域内，我们定义了一个42-SNP单倍型，该单倍型与ALS风险显著增加相关，并且与最近报道的额颞叶痴呆相关位点重叠。在93例家族性ALS患者中，染色体9 p21位点的群体归因危险度为37.9%（95% CI 27.7-48.1），D90 A纯合性的群体归因危险度为25.5%（16.9-34.1）。这些数据清楚地表明，染色体9 p21位点是芬兰人群中家族性ALS的主要原因。此外，最近报道的额颞叶痴呆症的风险单倍型的重叠提供了这两种神经退行性疾病的共同遗传原因的进一步证据。这篇论文发表在2010年10月的《柳叶刀神经病学》上。 总之，本年度使用下一代测序和全基因组关联方法成功鉴定了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统一为一种单一的疾病，包括两种主要的迟发性神经退行性疾病。这两项研究都采用了大量的研究对象，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。

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.