PDF(Pubmed)
Abstract：
BACKGROUND: MAPT is a causative gene in frontotemporal dementia with parkinsonism linked to chromosome 17 (FTDP-17), a hereditary degenerative disease with various clinical manifestations, including progressive supranuclear palsy, corticobasal syndrome, Parkinson\'s disease, and frontotemporal dementia.
OBJECTIVE: To analyze genetically, biochemically, and pathologically multiple members of two families who exhibited various phenotypes of the disease.
METHODS: Genetic analysis included linkage analysis, homozygosity haplotyping, and exome sequencing. We conducted tau protein microtubule polymerization assay, heparin-induced tau aggregation, and western blotting with brain lysate from an autopsy case. We also evaluated abnormal tau aggregation by using anti-tau antibody and PM-PBB3.
RESULTS: We identified a variant, c.896_897insACA, p.K298_H299insQ, in the MAPT gene of affected patients. Similar to previous reports, most patients presented with atypical parkinsonism. Biochemical analysis revealed that the mutant tau protein had a reduced ability to polymerize microtubules and formed abnormal fibrous aggregates. Pathological study revealed frontotemporal lobe atrophy, midbrain atrophy, depigmentation of the substantia nigra, and four-repeat tau-positive inclusions in the hippocampus, brainstem, and spinal cord neurons. The inclusion bodies also stained positively with PM-PBB3.
CONCLUSIONS: This study confirmed that the insACA mutation caused FTDP-17. The affected patients showed symptoms resembling Parkinson\'s disease initially and symptoms of progressive supranuclear palsy later. Despite the initial clinical diagnosis of frontotemporal dementia in the autopsy case, the spread of lesions could explain the process of progressive supranuclear palsy. The study of more cases in the future will help clarify the common pathogenesis of MAPT mutations or specific pathogeneses of each mutation.
OBJECTIVE: To analyze genetically, biochemically, and pathologically multiple members of two families who exhibited various phenotypes of the disease.
METHODS: Genetic analysis included linkage analysis, homozygosity haplotyping, and exome sequencing. We conducted tau protein microtubule polymerization assay, heparin-induced tau aggregation, and western blotting with brain lysate from an autopsy case. We also evaluated abnormal tau aggregation by using anti-tau antibody and PM-PBB3.
RESULTS: We identified a variant, c.896_897insACA, p.K298_H299insQ, in the MAPT gene of affected patients. Similar to previous reports, most patients presented with atypical parkinsonism. Biochemical analysis revealed that the mutant tau protein had a reduced ability to polymerize microtubules and formed abnormal fibrous aggregates. Pathological study revealed frontotemporal lobe atrophy, midbrain atrophy, depigmentation of the substantia nigra, and four-repeat tau-positive inclusions in the hippocampus, brainstem, and spinal cord neurons. The inclusion bodies also stained positively with PM-PBB3.
CONCLUSIONS: This study confirmed that the insACA mutation caused FTDP-17. The affected patients showed symptoms resembling Parkinson\'s disease initially and symptoms of progressive supranuclear palsy later. Despite the initial clinical diagnosis of frontotemporal dementia in the autopsy case, the spread of lesions could explain the process of progressive supranuclear palsy. The study of more cases in the future will help clarify the common pathogenesis of MAPT mutations or specific pathogeneses of each mutation.
摘要：
背景：MAPT是与染色体17（FTDP-17）相关的额颞叶痴呆伴帕金森病的致病基因，具有各种临床表现的遗传性退行性疾病，包括进行性核上性麻痹,皮质基底综合征,帕金森病,和额颞叶痴呆.
目的：分析基因，生物化学，和病理上表现出各种疾病表型的两个家庭的多个成员。
方法：遗传分析包括连锁分析，纯合性单倍型，和外显子组测序。我们进行了tau蛋白微管聚合试验，肝素诱导的tau聚集，用尸检病例的大脑裂解物进行蛋白质印迹.我们还通过使用抗tau抗体和PM-PBB3评估了异常tau聚集。
结果：我们确定了一个变体，c.896_897insACA，p.K298_H299insQ,在受影响患者的MAPT基因中。与以前的报道类似，大多数患者表现为非典型帕金森病。生化分析表明，突变型tau蛋白聚合微管的能力降低，并形成异常的纤维聚集体。病理研究显示额颞叶萎缩，中脑萎缩,黑质的脱色,和海马中的四次重复tau阳性包涵体，脑干,和脊髓神经元。包涵体也用PM-PBB3阳性染色。
结论：本研究证实insACA突变导致FTDP-17。受影响的患者最初表现出类似帕金森氏病的症状，后来表现出进行性核上性麻痹的症状。尽管在尸检病例中初步诊断为额颞叶痴呆，病变的扩散可以解释进行性核上性麻痹的过程。未来对更多病例的研究将有助于阐明MAPT突变的共同发病机制或各突变的具体发病机制。
目的：分析基因，生物化学，和病理上表现出各种疾病表型的两个家庭的多个成员。
方法：遗传分析包括连锁分析，纯合性单倍型，和外显子组测序。我们进行了tau蛋白微管聚合试验，肝素诱导的tau聚集，用尸检病例的大脑裂解物进行蛋白质印迹.我们还通过使用抗tau抗体和PM-PBB3评估了异常tau聚集。
结果：我们确定了一个变体，c.896_897insACA，p.K298_H299insQ,在受影响患者的MAPT基因中。与以前的报道类似，大多数患者表现为非典型帕金森病。生化分析表明，突变型tau蛋白聚合微管的能力降低，并形成异常的纤维聚集体。病理研究显示额颞叶萎缩，中脑萎缩,黑质的脱色,和海马中的四次重复tau阳性包涵体，脑干,和脊髓神经元。包涵体也用PM-PBB3阳性染色。
结论：本研究证实insACA突变导致FTDP-17。受影响的患者最初表现出类似帕金森氏病的症状，后来表现出进行性核上性麻痹的症状。尽管在尸检病例中初步诊断为额颞叶痴呆，病变的扩散可以解释进行性核上性麻痹的过程。未来对更多病例的研究将有助于阐明MAPT突变的共同发病机制或各突变的具体发病机制。
