SOD1, ANG, TARDBP and FUS mutations in amyotrophic lateral sclerosis: A United States clinical testing lab experience
SOD1, ANG, TARDBP and FUS mutations in amyotrophic lateral sclerosis: A United States clinical testing lab experience
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DOI：
10.3109/17482968.2011.643899
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发表时间：
2012-02-01
影响因子：
--
通讯作者：
Sims, Katherine B.
中科院分区：
文献类型：
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作者：
Brown, Jeffrey A.;Min, Jionghong;Sims, Katherine B.
SOD1、ANG、TARDBP和FUS突变与肌萎缩性侧索硬化症（ALS）有关。我们的目标是将分子遗传学分析扩展到新发现的ALS基因位点，并确定美国大型ALS表型队列中突变的频率、疾病基因的分布和这些基因的变异谱。我们筛选了1220个具有ALS表型的先证者，最初用于SOD1分子遗传分析。对1128例SOD1阴性先证进行ANG筛查，对277例和223例SOD1和ANG阴性样本进行TARDBP和FUS筛查。另外100个先证者专门筛选FUS外显子15。我们在92个先证者中发现了36种不同的SOD1突变，包括3种新的突变。ANG筛选鉴定出三个突变，包括两个新突变，TARDBP筛选鉴定出两个先前报道的TARDBP突变。我们还发现了四种FUS突变，包括报道的一名包体体肌炎患者的FUS框架内缺失，c.430_447del, p.Gly144_Tyr149del，以及两种已知的FUS错义突变。从这项研究中，我们估计美国队列中SOD1、ANG、TARDBP和FUS突变的频率分别为7.5%、0.71%、0.72%和1.9%。总之，我们发现了SOD1、ANG、TARDBP和FUS的新变异，并扩大了FUS相关的临床病理表型。
SOD1, ANG, TARDBP and FUS mutations have been associated with amyotrophic lateral sclerosis (ALS). Our goal was to extend molecular genetic analysis to newly identified ALS genetic loci and to determine the frequency of mutations, distribution of disease genes, and variant spectrum of these genes in a large United States ALS-phenotype cohort. We screened 1220 probands with an ALS phenotype, referred originally for SOD1 molecular genetic analysis. 1128 SOD1-negative probands were screened for ANG, and 277 and 223 SOD1- and ANG-negative samples were screened for TARDBP and FUS, respectively. One hundred additional probands were specifically screened only for FUS exon 15. We identified a total of 36 different SOD1 mutations, including three novel mutations, in 92 probands. ANG screening identified three mutations, including two novel mutations, and TARDBP screening identified two previously reported TARDBP mutations. We also identified four mutations in FUS, including the reported FUS in-frame deletion, c.430_447del, p.Gly144_Tyr149del, in a patient with inclusion body myositis, and two known FUS missense mutations. From this study, we estimate frequencies for SOD1, ANG, TARDBP and FUS mutations, in this United States cohort, to be 7.5%, 0.71%, 0.72% and 1.9%, respectively. In conclusion, we identify novel variants in SOD1, ANG, TARDBP and FUS, and expand the FUS-associated clinicopathologic phenotype.