TARDBP (TDP-43) sequence analysis in patients with familial and sporadic ALS: identification of two novel mutations
TARDBP (TDP-43) sequence analysis in patients with familial and sporadic ALS: identification of two novel mutations
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DOI：
10.1111/j.1468-1331.2009.02574.x
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发表时间：
2009-06-01
影响因子：
5.1
通讯作者：
Comi, G. P.
中科院分区：
文献类型：
--
作者：
Del Bo, R.;Ghezzi, S.;Comi, G. P.
越来越多的证据表明TAR DNA结合蛋白43（TDP-43）在神经变性中的直接作用。最近在家族性和散发性肌萎缩侧索硬化症（ALS）病例中报告了编码TDP-43的TARDBP基因突变，为了进一步确定TARDBP突变的谱和频率，我们对314例ALS患者（主要是意大利患者）的TARDBP基因进行了分析，包括16名非SOD 1家族性ALS患者，我们在5名无关ALS患者中发现了4个杂合错义突变（1.6%）。其中两个突变（p.G348C和p.A382T）在来自不同地理来源（分别为比利时和意大利）的常染色体显性遗传家族的携带者中检测到。比利时家系显示，在五代内有几个受影响的成员，并具有可变的临床特征。在两个散发病例中发现了两个新的突变（p.G294V和p.G295S）。五名携带TARDBP突变的ALS患者的鉴定扩展了TARDBP突变的范围，并支持TDP-43在运动神经元疾病中的病理作用。我们的研究结果提供的证据表明，TARDBP突变在意大利散发性ALS患者中并不常见（1%）;然而，结合文献，我们的数据进一步支持TARDBP突变是家族性ALS的相关原因。
Increasing evidence suggests a direct role of the TAR DNA-binding protein 43 (TDP-43) in neurodegeneration. Mutations in the TARDBP gene, which codes for TDP-43, have been recently reported in familial and sporadic amyotrophic lateral sclerosis (ALS) cases.To further define the spectrum and frequency of TARDBP mutations, we present genetic analysis data on TARDBP in 314 ALS mainly Italian patients, including 16 subjects with non-SOD1 familial ALS.We identified four heterozygous missense mutations in five unrelated ALS patients (1.6%). Two of these mutations (p.G348C and p.A382T) were detected in carriers coming from families with an autosomal dominant transmission of different geographic origin (Belgian and Italian, respectively). The Belgian pedigree showed several affected members within five generations and with variable clinical features. Two novel mutations (p.G294V and p.G295S) were identified in two sporadic cases.The identification of five ALS patients carrying TARDBP alterations extends the spectrum of TARDBP mutations and supports the pathological role of TDP-43 in motor neurone disease. Our findings provide evidence that TARDBP mutations are not frequent in Italian sporadic ALS patients (1%); however, combined with the literature, our data further support TARDBP mutations as a relevant cause of familial ALS.