Genetic etiology of Fronto-Temporal Dementia

额颞叶痴呆的遗传病因学

• 批准号: 7964097
• 负责人: Bryan Traynor
• 金额: $ 11.36万
• 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/7964097
• 关键词: 9p21; Alleles; Amyotrophic Lateral Sclerosis; Atrophic; Autopsy; Brain; Candidate Disease Gene; Chromosomes; Clinical; Cytoplasmic Inclusion; Data; Dementia; Diagnosis; Disease; Epidemiology; Etiology; Genes; Genetic; Genetic Predisposition to Disease; Genotype; Haplotypes; Impaired cognition; Individual; Laboratories; Link; Linkage Disequilibrium Mapping; London; Messenger RNA; Motor Manifestations; Motor Neurons; Mutation; Netherlands; Neurons; PGRN gene; Pathogenesis; Patients; Phenotype; Progranulin; Proteins; Psychiatry; Research Subjects; Risk; Role; Screening procedure; Spinal Cord; Staging; Temporal Lobe; Tissue Extracts; Ubiquitin; Variant; Work; base; cohort; frontal lobe; genetic risk factor; genetic variant; motor neuron degeneration; neurogenetics; protein TDP-43

During the last fiscal year, we have completed two projects that are directly relevant to FTD. First, the progranulin (PGRN) gene was sequenced in 134 Italian sporadic patients and 12 familial cases. Mutations in this gene has been previously identified as a cause of ubiquitin-positive FTD, but the role of this gene in the causation of ALS and ALS-FTD is unclear. Mutational screening revealed a heterozygous change (p.S120Y) in a patient diagnosed with sporadic ALS-FTD. This change was identical to one that we had previously identified in another ALS-FTD patient (cf Schymick et al., J Neurol Neurosurg Psychiatry. 2007; 78:754-6). Haplotype analysis showed a conserved PGRN region among these two subjects consistent with common ancestor allele. This finding confirms that the missence mutation p.S120Y variant causes degeneration of frontal and temporal lobe neurons, as well as motor neurons (i.e. ALS-FTD) in rare cases. In the second project, a large scale two-stage linkage disequilibrium mapping approach was undertaken of the chromosome 9p21 region which has been previously linked to FTD, ALS and ALS-FTD phenotypes. An association of ubiquitin associated protein 1 (UBAP1; OR 1.42 95% CI 1.08-1.88, P=0.013) was identified and then replicated in an additional two independent cohorts from the Netherlands (OR 1.33 95% CI 1.04-1.69, P=0.022), the USA (OR 1.4 95% CI 1.02-1.92, P=0.032), but not in a Spanish cohort (OR 1.45 95% CI 0.97-2.17, P=0.064) or in a cohort from London (OR 0.99 95% CI 0.72-1.37, P=0.989). Quantitative analysis of UBAP1 mRNA extracted from tissue from the Manchester cases demonstrated a significant reduction of expression from the disease-associated haplotype. In addition, a case of familial FTD was identified that demonstrated colocalisation of UBAP1 and TDP-43 in the neuronal cytoplasmic inclusions in the brain of this individual. This data identified UBAP1 as a potential genetic risk factor for FTD. In summary, the current year has been successful in identifying genetic variants important in the pathogenesis of FTD using candidate gene approaches. 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.

在上一个财政年度，我们完成了两个与FTD直接相关的项目。首先，在134例意大利零星患者和12例家族病例中对幼体蛋白（PGRN）基因进行了测序。该基因中的突变先前已被鉴定为泛素阳性FTD的原因，但是该基因在ALS和ALS-FTD因果关系中的作用尚不清楚。突变筛查显示在诊断为零星ALS-FTD的患者中发生了杂合的变化（P.S120Y）。这种变化与我们以前在另一位ALS-FTD患者中发现的变化相同（CF Schymick等，J Neurol Neurol NeurosurgPsychiatry。2007; 78：754-6）。单倍型分析表明，这两个与共同祖先等位基因一致的受试者中有一个保守的PGRN区域。这一发现证实，在极少数情况下，P.S120y的失误突变会导致额叶和颞叶神经元以及运动神经元（即ALS-FTD）的变性。 在第二个项目中，大规模的两阶段连锁不平衡映射方法是对9p21染色体区域进行的，该区域先前已与FTD，ALS和ALS-FTD表型相关。鉴定了泛素相关蛋白1（UBAP1；或1.42 95％CI 1.08-1.88，p = 0.013）的关联，然后在荷兰的另外两个独立队列中复制，然后在荷兰（OR 1.33 95％CI 1.04-1.69，p = 0.022），p = 0.022），p = 0.022），USA（OS 1.4 95％CI 1.02），OS 1.4 95％。不在西班牙队列中（或1.45 95％CI 0.97-2.17，p = 0.064）或伦敦的同伴（或0.99 95％CI 0.72-1.37，p = 0.989）。从曼彻斯特案例中提取的UBAP1 mRNA的定量分析表明，与疾病相关的单倍型的表达显着降低。此外，还确定了一个家族性FTD的一个情况，该病例证明了该个体大脑中神经元细胞质内包含中UBAP1和TDP-43的共定位。该数据将UBAP1确定为FTD的潜在遗传危险因素。 总而言之，本年度在使用候选基因方法中识别在FTD发病机理中重要的遗传变异方面已经成功。两项研究中的每一项都采用了大量研究对象，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。