Poorkaj P, Tsuang D, Wijsman E, Steinbart E, Garruto R M, Craig U K, Chapman N H, Anderson L, Bird T D, Plato C C, Perl D P, Weiderholt W, Galasko D, Schellenberg G D
Geriatric Research Education Clinical Center, Veterans Affairs Puget Sound Health Care System, Seattle, Washington 98108, USA.
Arch Neurol. 2001 Nov;58(11):1871-8. doi: 10.1001/archneur.58.11.1871.
A Guam variant of amyotrophic lateral sclerosis (ALS-G) and parkinsonism dementia complex (PDC-G) are found in the Chamorro people of Guam. Both disorders have overlapping neuropathologic findings, with neurofibrillary tangles in spinal cord and brain. The cause of ALS-G-PDC-G is unknown, although inheritance and environment appear important. Because neurofibrillary tangles containing tau protein are present in ALS-G-PDC-G, and because mutations in the tau gene (TAU) cause autosomal dominant frontotemporal dementia, TAU was examined as a candidate gene for ALS-G-PDC-G.
TAU was evaluated by DNA sequence analysis in subjects with ALS-G-PDC-G, by linkage analysis of TAU polymorphisms in an extended pedigree from the village of Umatac, and by evaluation of linkage disequilibrium with polymorphic markers flanking and within TAU.
Linkage disequilibrium between ALS-G-PDC-G and the TAU polymorphism CA3662 was observed. For this 2-allele system, PDC and ALS cases were significantly less likely than Guamanian controls to have the 1 allele (4.9% and 2% vs 11.5%, respectively; Fisher exact P =.007). DNA sequence analysis of TAU coding regions did not demonstrate a mutation responsible for ALS-G-PDC-G. Analysis of TAU genotypes in an extended pedigree of subjects from Umatac showed obligate recombinants between TAU and ALS-G-PDC-G. Linkage analysis of the Umatac pedigree indicates that TAU is not the major gene for ALS-G-PDC-G.
The genetic association between ALS-G-PDC-G implicates TAU in the genetic susceptibility to ALS-G-PDC-G. TAU may be a modifying gene increasing risk for ALS-G-PDC-G in the presence of another, as yet, unidentified gene.
在关岛的查莫罗人中发现了关岛型肌萎缩侧索硬化症（ALS - G）和帕金森病痴呆综合征（PDC - G）。这两种疾病具有重叠的神经病理学表现，脊髓和大脑中均存在神经原纤维缠结。尽管遗传和环境因素似乎很重要，但ALS - G - PDC - G的病因尚不清楚。由于ALS - G - PDC - G中存在含tau蛋白的神经原纤维缠结，且tau基因（TAU）的突变会导致常染色体显性额颞叶痴呆，因此将TAU作为ALS - G - PDC - G的候选基因进行了研究。
通过对ALS - G - PDC - G患者进行DNA序列分析、对来自乌马塔克村的一个扩展家系中的TAU多态性进行连锁分析，以及评估TAU侧翼和内部多态性标记的连锁不平衡，来对TAU进行评估。
观察到ALS - G - PDC - G与TAU多态性CA3662之间存在连锁不平衡。对于这个双等位基因系统，PDC和ALS病例携带1等位基因的可能性明显低于关岛对照组（分别为4.9%和2%，而对照组为11.5%；Fisher精确检验P = 0.007）。TAU编码区的DNA序列分析未发现导致ALS - G - PDC - G的突变。对来自乌马塔克的一个扩展家系中的TAU基因型进行分析，结果显示TAU与ALS - G - PDC - G之间存在明确的重组。对乌马塔克家系的连锁分析表明，TAU不是ALS - G - PDC - G的主要基因。
ALS - G - PDC - G之间的遗传关联表明TAU与ALS - G - PDC - G的遗传易感性有关。在存在另一个尚未确定的基因的情况下，TAU可能是一个增加ALS - G - PDC - G风险的修饰基因。
