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.

在上一财年，我们完成了两个与 FTD 直接相关的项目。首先，对 134 名意大利散发患者和 12 名家族病例的颗粒体蛋白前体 (PGRN) 基因进行了测序。该基因的突变先前已被确定为泛素阳性 FTD 的原因，但该基因在 ALS 和 ALS-FTD 病因中的作用尚不清楚。突变筛查显示一名诊断为散发性 ALS-FTD 的患者存在杂合性变化 (p.S120Y)。这一变化与我们之前在另一名 ALS-FTD 患者中发现的变化相同（参见 Schymick 等人，J Neurol Neurosurg Psychiatry. 2007；78:754-6）。单倍型分析显示这两个受试者之间存在与共同祖先等位基因一致的保守 PGRN 区域。这一发现证实，错义突变 p.S120Y 变体在极少数情况下会导致额叶和颞叶神经元以及运动神经元（即 ALS-FTD）变性。 在第二个项目中，对染色体 9p21 区域进行了大规模两阶段连锁不平衡作图方法，该区域先前已与 FTD、ALS 和 ALS-FTD 表型相关。鉴定出泛素相关蛋白 1（UBAP1；OR 1.42 95% CI 1.08-1.88，P=0.013）的关联，然后在来自荷兰的另外两个独立队列中进行复制（OR 1.33 95% CI 1.04-1.69，P=0.022） ）、美国​​（OR 1.4 95% CI 1.02-1.92，P=0.032），但不在西班牙队列中（OR 1.45 95% CI 0.97-2.17，P=0.064）或来自伦敦的队列中（OR 0.99 95% CI 0.72-1.37，P=0.989）。对从曼彻斯特病例组织中提取的 UBAP1 mRNA 进行定量分析表明，与疾病相关的单倍型的表达显着减少。此外，还发现了一个家族性 FTD 病例，证明 UBAP1 和 TDP-43 共定位于该个体大脑的神经元细胞质内含物中。该数据将 UBAP1 确定为 FTD 的潜在遗传风险因素。 总之，今年利用候选基因方法成功识别了 FTD 发病机制中重要的遗传变异。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。