Centre for Ageing Brain and Neurodegenerative Disorders, University of Brescia, Brescia, Italy.
Rejuvenation Res. 2010 Oct;13(5):509-17. doi: 10.1089/rej.2010.1017. Epub 2010 Jul 20.
The 43-kD transactive response (TAR)-DNA-binding protein (TARDBP) mutations have been demonstrated to be causative of sporadic and familial forms of amyotrophic lateral sclerosis. More recently, these mutations have been reported in cases of frontotemporal lobar degeneration (FTLD). The aim of this study was to evaluate the role of TARDBP genetic variations in a large sample of consecutive patients with FTLD. A total of 252 FTLD patients were investigated. Each subject had a clinical and neuropsychological evaluation and a brain imaging study. The clinical diagnosis was confirmed by at least 1 year of follow up. The entire TARDBP gene, the intronic flaking regions, and the 5'-untranslated region (5'-UTR) were screened. Six genetic variations were identified in patients with behavioral variant frontotemporal dementia (FTD) and FTD with motor neuron disease phenotypes. Two of these mutations, namely N267S and M359V, lead to amino acid changes within exon 6. We further identified three genetic variations, i.e., Y214Y, IVS-IV + 45C/T, and 5'-UTR G/A, that could potentially affect the normal splicing process as predicted by in silico analyses. None of these genetic variations was found in healthy age-matched controls. Moreover, we identified a previously described benign variant, A66A, in 5 patients. Our study has confirmed and extended the list of pathogenetic mutations in the TARDBP gene in both apparently sporadic and familial FTLD patients. This work further supports the need for TARDBP screening in FTLD. Also intronic splicing that affects mutations should be considered as well.
43kD 转录激活反应（TAR）-DNA 结合蛋白（TARDBP）突变已被证实是散发性和家族性肌萎缩侧索硬化症的致病原因。最近，这些突变也在额颞叶变性（FTLD）病例中被报道。本研究旨在评估 TARDBP 基因突变在大量连续 FTLD 患者中的作用。共研究了 252 例 FTLD 患者。每位患者均进行了临床和神经心理学评估以及脑部影像学研究。临床诊断通过至少 1 年的随访得到确认。对整个 TARDBP 基因、内含子剪接区域和 5'-非翻译区（5'-UTR）进行了筛选。在行为变异额颞叶痴呆（FTD）和具有运动神经元病表型的 FTD 患者中发现了 6 种遗传变异。其中 2 种突变，即 N267S 和 M359V，导致 6 号外显子内的氨基酸变化。我们进一步鉴定了 3 种遗传变异，即 Y214Y、IVS-IV+45C/T 和 5'-UTR G/A，这些变异可能会根据计算机分析预测影响正常剪接过程。这些遗传变异均未在健康年龄匹配的对照组中发现。此外，我们在 5 名患者中发现了先前描述的良性变异 A66A。本研究证实并扩展了 TARDBP 基因在明显散发性和家族性 FTLD 患者中的致病性突变列表。这项工作进一步支持了在 FTLD 中进行 TARDBP 筛查的必要性。还应考虑影响突变的内含子剪接。
