Poorkaj P, Bird T D, Wijsman E, Nemens E, Garruto R M, Anderson L, Andreadis A, Wiederholt W C, Raskind M, Schellenberg G D
Geriatric Research Education Clinical Center, Veterans Affairs Puget Sound Health Care System, Division of Gerontology, University of Washington, Seattle 98108, USA.
Ann Neurol. 1998 Jun;43(6):815-25. doi: 10.1002/ana.410430617.
Frontotemporal dementia with parkinsonism, chromosome 17 type (FTDP-17), a recently defined disease entity, is clinically characterized by personality changes sometimes associated with psychosis, hyperorality, and diminished speech output, disturbed executive function and nonfluent aphasia, bradykinesia, and rigidity. Neuropathological changes include frontotemporal atrophy often associated with atrophy of the basal ganglia, substantia nigra, and amygdala. Neurofibrillary tangles (NFTs) are seen in some but not all families. Inheritance is autosomal dominant and the gene has been regionally localized to 17q21-22 in a 2- to 4-centimorgan (cM) region flanked by markers D17S800 and D17S791. The gene for tau, the primary component of NFTs, is located in the same region of chromosome 17. Tau was evaluated as a candidate gene. Physical mapping studies place tau within 2 megabases or less of D17S791, but it is probably outside the D17S800-D17S791 FTDP-17 interval. DNA sequence analysis of tau coding regions in affected subjects from two FTDP-17 families revealed nine DNA sequence variants, eight of which were also identified in controls and are thus polymorphisms. A ninth variant (Val279Met) was found in one FTDP-17 family but not in the second FTDP-17 family. Three lines of evidence indicate that the Val279Met change is an FTDP-17 causative mutation. First, the mutation site is highly conserved, and a normal valine is found at this position in all three tau interrepeat sequences and in other microtubule associated protein tau homologues. Second, the mutation co-segregates with the disease in family A. Third, the mutation is not found in normal controls.
17号染色体型额颞叶痴呆伴帕金森综合征（FTDP - 17）是一种最近定义的疾病实体，其临床特征为有时伴有精神病性症状的人格改变、口欲亢进、言语量减少、执行功能障碍和非流畅性失语、运动迟缓及强直。神经病理学改变包括额颞叶萎缩，常伴有基底节、黑质及杏仁核萎缩。部分但并非所有家族中可见神经原纤维缠结（NFTs）。其遗传方式为常染色体显性遗传，基因已被定位到17q21 - 22区域，位于标记D17S800和D17S791两侧2至4厘摩（cM）的区间内。NFTs的主要成分tau蛋白的基因位于17号染色体的同一区域。tau蛋白被评估为候选基因。物理图谱研究表明tau基因位于距D17S791 2兆碱基或更少的范围内，但可能在D17S800 - D17S791 FTDP - 17区间之外。对两个FTDP - 17家族中患病个体的tau编码区进行DNA序列分析，发现了9个DNA序列变异，其中8个在对照中也被鉴定出来，因此属于多态性。第九个变异（Val279Met）在一个FTDP - 17家族中被发现，而在第二个FTDP - 17家族中未被发现。三条证据表明Val279Met改变是FTDP - 17的致病突变。首先，突变位点高度保守，在所有三个tau重复序列以及其他微管相关蛋白tau同源物的该位置均发现正常的缬氨酸。其次，该突变在A家族中与疾病共分离。第三，正常对照中未发现该突变。
