Luquin Natasha, Yu Bing, Saunderson Rebecca B, Trent Ronald J, Pamphlett Roger
The Stacey Motor Neuron Disease Laboratory, Department of Pathology, The University of Sydney, Sydney, Australia.
Neuromuscul Disord. 2009 Oct;19(10):696-700. doi: 10.1016/j.nmd.2009.07.005. Epub 2009 Aug 19.
All patients with sporadic amyotrophic lateral sclerosis (SALS) have TDP-43 inclusions in their motor neurons, suggesting this protein plays a major role in the disease. Coding mutations in the gene for TDP-43, TARDBP, have been found in only a few patients with SALS. However, the non-coding regulatory regions of TARDBP have not yet been examined in SALS. We therefore sequenced both coding and non-coding regions of TARDBP in 46 tissue-banked SALS brains (brain DNA was used to detect somatic mutations). Non-coding variants (in the promoter or intron 1) were detected in 16 patients (35%) and coding variants in 4 (9%). Two known promoter variants were found more frequently in SALS patients than in controls. Two other variants, found in one patient each but not in controls, have potential regulatory functions. In addition, a novel exon 2 change with predicted functional effects was found in one patient. In summary, variants in the promoter and other non-coding regions of TARDBP may disturb the regulation of this gene in some patients with SALS.
所有散发性肌萎缩侧索硬化症（SALS）患者的运动神经元中都有TDP-43包涵体，这表明该蛋白在该病中起主要作用。仅在少数SALS患者中发现了TDP-43基因（TARDBP）的编码突变。然而，尚未在SALS中研究TARDBP的非编码调控区域。因此，我们对46个保存于组织库中的SALS患者大脑的TARDBP编码区和非编码区进行了测序（使用脑DNA检测体细胞突变）。在16名患者（35%）中检测到非编码变异（在启动子或内含子1中），在4名患者（9%）中检测到编码变异。在SALS患者中发现两种已知的启动子变异的频率高于对照组。另外两个变异分别在一名患者中发现，但对照组中未发现，它们具有潜在的调控功能。此外，在一名患者中发现了一个具有预测功能效应的新的外显子2变化。总之，TARDBP启动子和其他非编码区域的变异可能会干扰一些SALS患者中该基因的调控。
