High Frequency of TARDBP Gene Mutations in Italian Patients With Amyotrophic Lateral Sclerosis
High Frequency of TARDBP Gene Mutations in Italian Patients With Amyotrophic Lateral Sclerosis
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DOI：
10.1002/humu.20950
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发表时间：
2009-04-01
期刊：
影响因子：
3.9
通讯作者：
D'Alfonso, S.
中科院分区：
文献类型：
--
作者：
Corrado, Lucia;Ratti, A.;D'Alfonso, S.
最近的研究在肌萎缩侧索硬化症（ALS）患者中鉴定了编码TAR DNA结合蛋白（TDP）-43的TARDBP基因中的罕见错义突变，所述TAR DNA结合蛋白是在受影响的运动神经元（MN）中发现的泛素化包涵体的主要蛋白。本研究的目的是进一步确定666例意大利ALS患者（125例家族性和541例散发性病例）的TARDBP突变谱。在281例患者中对整个编码区进行了测序，而在其余385例病例中仅对外显子6进行了测序。在IS患者中，其中6个是家族性的，我们确定了12个不同的杂合错义突变（9个新的）都位于外显子6，这是缺乏在771匹配的对照。在7名患者中观察到c.1144G>A（p.A382T）变异，因此代表ALS中最常见的TARDBP突变。围绕TARDBP基因的微卫星分析表明，p.A382T是从一个共同的祖先在7例患者中的5继承。总之，与主要来自北方欧洲的个体相比，意大利ALS患者中TARDBP基因突变的频率似乎特别高（2.7% vs. 1%）。对两名携带p.A382T和p.S393L TARDBP突变的患者的淋巴细胞提取物进行Western印迹分析，结果显示存在较低分子量的TDR-43条带，这些条带比在健康对照和TARDBP突变阴性患者中观察到的条带更丰富。总之，本报告有助于证明TARDBP基因在ALS发病机制中的致病作用，并表明突变可能影响蛋白质的稳定性，即使在非神经元组织中。《Mutat》30，688-694，2009年。(C)2009威利-利斯公司
Recent studies identified rare missense mutations in amyotrophic lateral sclerosis (ALS) patients in the TARDBP gene encoding TAR DNA binding protein (TDP)-43, the major protein of the ubiquitinated inclusions l found in affected motor neurons (MNs). The aim of this study was to further define the spectrum of TARDBP mutations in a large cohort of 666 Italian ALS patients (125 familial and 541 sporadic cases). The entire coding region was sequenced in 281 patients, while in the remaining 385 cases only exon 6 was sequenced. In IS patients, of which six are familial, we identified 12 different heterozygous missense mutations (nine novel) all locating to exon 6, which were absent ill 771 matched controls. The c.1144G>A (p.A382T) variation was Observed in seven patients, thus representing the most frequent TARDBP mutation in ALS. Analysis of microsatellites surrounding the TARDBP gene indicated that p.A382T was inherited from a common ancestor in 5 of the 7 patients. Altogether, the frequency of TARDBP gene Mutations appears to be particularly high in Italian ALS patients compared to individuals of mainly Northern European origin (2.7% vs. 1%). Western blot analysis of lymphocyte extracts from two patients carrying the p.A382T and p.S393L TARDBP mutations showed the presence of lower molecular weight TDR-43 bands, which were more abundant than observed in healthy controls and patients negative for TARDBP mutations. In Conclusion, this report contributes to the demonstration of the causative role of the TARDBP gene in ALS pathogenesis and indicates that Mutations may affect the stability of the protein even in nonneuronal tissues. Hum Mutat 30, 688-694, 2009. (C) 2009 Wiley-Liss, Inc.