TBK1 is associated with ALS and ALS-FTD in Sardinian patients.
TBK1 is associated with ALS and ALS-FTD in Sardinian patients.
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DOI：
10.1016/j.neurobiolaging.2016.03.028
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发表时间：
2016-07
影响因子：
4.2
通讯作者：
ITALSGEN and SARDINALS Consortia
中科院分区：
文献类型：
--
作者：
Borghero G;Pugliatti M;Marrosu F;Marrosu MG;Murru MR;Floris G;Cannas A;Occhineri P;Cau TB;Loi D;Ticca A;Traccis S;Manera U;Canosa A;Moglia C;Calvo A;Barberis M;Brunetti M;Gibbs JR;Renton AE;Errichiello E;Zoledziewska M;Mulas A;Qian Y;Din J;Pliner HA;Traynor BJ;Chiò A;ITALSGEN and SARDINALS Consortia
最近，TANK 结合激酶 1 (TBK1) 基因突变被确定为伴有或不伴有额颞叶痴呆的肌萎缩侧索硬化症 (ALS) 的原因。我们评估了一群撒丁岛血统的 ALS 患者中 TBK1 突变的频率和临床特征。全外显子组测序在Hiseq2000平台(Illumina)上进行。基因组分析工具包用于根据人类基因组 (UCSC hg19) 比对和编码变体。通过桑格序列证实突变。在我们对 186 名撒丁岛 ALS 病例的筛查中，我们发现 3 名 (1.6%) 患者携带 3 种不同的新型遗传变异：非同义 SNV c.1150C>T 导致外显子 9 中的 p.Arg384Thr 变化；非同义 SNV c.1331G>A 导致外显子 11 中的 p.Arg444Gln 发生变化；以及该基因外显子 20 处的移码删除 c.2070delG (p.Met690fs)，导致在 693 密码子处终止。后者患者还携带 SQSTM1 基因的错义突变 c.98C>T，导致第 33 位精氨酸被缬氨酸取代（p.Arg33Val）。根据计算机预测，所有变体都被发现是有害的。所有病例显然都是散发性的，其中一例表现出与 ALS 相关的额颞叶痴呆。在 2 个由 6780 名种族匹配的对照组成的队列中未发现这些突变。我们发现 TBK1 突变占撒丁岛 ALS 病例的 1.6%。我们的数据支持 TBK1 是一种新型 ALS 基因的观点，为最初的描述提供了补充的重要证据。
Recently, mutations in the TANK-binding kinase 1 (TBK1) gene were identified as a cause for amyotrophic lateral sclerosis (ALS) with or without comorbid frontotemporal dementia. We have assessed the frequency and clinical characteristics of TBK1 mutations in a cohort of ALS patients of Sardinian ancestry. Whole-exome sequencing was performed on Hiseq2000 platform (Illumina). Genome analysis Toolkit was used to align and to code variants according to Human Genome (UCSC hg19). Mutation was confirmed with Sanger sequence. In our screening of 186 Sardinian ALS cases, we found 3 (1.6%) patients carrying 3 distinct novel genetic variants: a nonsynonymous SNV c.1150C>T leading to a p.Arg384Thr change in exon 9; a nonsynonymous SNV c.1331G>A causes a p.Arg444Gln change in exon 11; and a frameshift deletion c.2070delG (p.Met690fs) at the exon 20 of the gene leading to a stop at 693 codon. The latter patients also carried missense mutation c.98C>T of the SQSTM1 gene causing a substitution of an arginine with a valine at the position 33 (p.Arg33Val). All variants were found to be deleterious according to in silico predictions. All cases were apparently sporadic and one of them showed frontotemporal dementia associated to ALS. These mutations were not found in 2 cohorts of 6780 ethnic-matched controls. We have found that TBK1 mutations account for 1.6% of Sardinian ALS cases. Our data support the notion that TBK1 is a novel ALS gene, providing important evidence complementary to the first descriptions.
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DOI：
10.1126/science.aaa3650
发表时间：
2015-03-27
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Cirulli ET;Lasseigne BN;Petrovski S;Sapp PC;Dion PA;Leblond CS;Couthouis J;Lu YF;Wang Q;Krueger BJ;Ren Z;Keebler J;Han Y;Levy SE;Boone BE;Wimbish JR;Waite LL;Jones AL;Carulli JP;Day-Williams AG;Staropoli JF;Xin WW;Chesi A;Raphael AR;McKenna-Yasek D;Cady J;Vianney de Jong JM;Kenna KP;Smith BN;Topp S;Miller J;Gkazi A;FALS Sequencing Consortium;Al-Chalabi A;van den Berg LH;Veldink J;Silani V;Ticozzi N;Shaw CE;Baloh RH;Appel S;Simpson E;Lagier-Tourenne C;Pulst SM;Gibson S;Trojanowski JQ;Elman L;McCluskey L;Grossman M;Shneider NA;Chung WK;Ravits JM;Glass JD;Sims KB;Van Deerlin VM;Maniatis T;Hayes SD;Ordureau A;Swarup S;Landers J;Baas F;Allen AS;Bedlack RS;Harper JW;Gitler AD;Rouleau GA;Brown R;Harms MB;Cooper GM;Harris T;Myers RM;Goldstein DB
通讯作者：
Goldstein DB
影响因子：
25
作者：
Renton AE;Chiò A;Traynor BJ
通讯作者：
Traynor BJ
影响因子：
9.9
作者：
Chio, Adriano;Calvo, Andrea;Restagno, Gabriella
通讯作者：
Restagno, Gabriella
影响因子：
--
作者：
Fecto, Faisal;Yan, Jianhua;Siddique, Teepu
通讯作者：
Siddique, Teepu
影响因子：
14.9
作者：
Wang K;Li M;Hakonarson H
通讯作者：
Hakonarson H