De novo truncating FUS gene mutation as a cause of sporadic amyotrophic lateral sclerosis.
De novo truncating FUS gene mutation as a cause of sporadic amyotrophic lateral sclerosis.
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DOI：
10.1002/humu.21241
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发表时间：
2010-05
期刊：
影响因子：
3.9
通讯作者：
Rademakers, Rosa
中科院分区：
文献类型：
--
作者：
DeJesus-Hernandez, Mariely;Kocerha, Jannet;Finch, NiCole;Crook, Richard;Baker, Matt;Desaro, Pamela;Johnston, Amelia;Rutherford, Nicola;Wojtas, Aleksandra;Kennelly, Kathleen;Wszolek, Zbigniew K.;Graff-Radford, Neill;Boylan, Kevin;Rademakers, Rosa
关键词：
肌萎缩侧索硬化症(ALS)的基因突变是肌萎缩侧索硬化症(ALS)的新病因，强调了ALS的遗传异质性。对在梅奥诊所确诊的99例散发性ALS患者和17例家族性ALS患者的超氧化物歧化酶(SOD)、TAR DNA结合蛋白43(TARDBP)和FUS基因进行了序列测定。我们在99名散发性ALS患者中的2名(2.0%)中发现了两个新的FUS突变，并确定了1个FUS突变的从头发生。在家族性患者中，我们发现了三个(17.6%)SOD1突变，而FUS和TARDBP突变被排除在外。新的FUS突变(g.10747A>；G；IVS13-2A>；G)影响FUS内含子13的剪接受体位点，并导致FUS外显子14的跳跃，导致FUS的C端截断(p.G466VfsX14)。亚细胞定位研究表明，与野生型FUS相比，FUS在细胞质中的定位显著增加，而正常核表达减少。我们进一步在FUS外显子12(p.S402 P411delinsGGGG)中发现了一个新的框内插入/缺失突变，该突变被预测为扩展了一个保守的多甘氨酸基序。我们的发现扩展了导致ALS的FUS突变谱，并描述了FUS中的第一个从头突变。
Mutations in the gene encoding fused in sarcoma (FUS) were recently identified as a novel cause of amyotrophic lateral sclerosis (ALS), emphasizing the genetic heterogeneity of ALS. We sequenced the genes encoding superoxide dismutase (SOD1), TAR DNA-binding protein 43 (TARDBP) and FUS in 99 sporadic and 17 familial ALS patients ascertained at Mayo Clinic. We identified two novel mutations in FUS in two out of 99 (2.0%) sporadic ALS patients and established the de novo occurrence of one FUS mutation. In familial patients, we identified three (17.6%) SOD1 mutations, while FUS and TARDBP mutations were excluded. The de novo FUS mutation (g.10747A>G; IVS13-2A>G) affects the splice-acceptor site of FUS intron 13 and was shown to induce skipping of FUS exon 14 leading to the C-terminal truncation of FUS (p.G466VfsX14). Subcellular localization studies showed a dramatic increase in the cytoplasmic localization of FUS and a reduction of normal nuclear expression in cells transfected with truncated compared to wild-type FUS. We further identified a novel in-frame insertion/deletion mutation in FUS exon 12 (p.S402 P411delinsGGGG) which is predicted to expand a conserved poly-glycine motif. Our findings extend the mutation spectrum in FUS leading to ALS and describe the first de novo mutation in FUS.
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影响因子：
4.2
作者：
Chio, Adriano;Restagno, Gabriella;Brunetti, Maura;Ossola, Irene;Calvo, Andrea;Mora, Gabriele;Sabatelli, Mario;Monsurro, Maria Rosaria;Battistini, Stefania;Mandrioli, Jessica;Salvi, Fabrizio;Spataro, Rossella;Schymick, Jennifer;Traynor, Bryan J.;La Bella, Vincenzo
通讯作者：
La Bella, Vincenzo
影响因子：
--
作者：
Andersson MK;Ståhlberg A;Arvidsson Y;Olofsson A;Semb H;Stenman G;Nilsson O;Aman P
通讯作者：
Aman P
影响因子：
56.9
作者：
Kwiatkowski, T. J., Jr.;Bosco, D. A.;Brown, R. H., Jr.
通讯作者：
Brown, R. H., Jr.
DOI：
10.1016/j.vascn.2008.10.003
发表时间：
2009-01-01
影响因子：
1.9
作者：
Beekman, Johanna M.;Reischl, Joachim;Heubach, Juergen F.
通讯作者：
Heubach, Juergen F.
DOI：
10.1093/bfgp/ell015
发表时间：
2006-03-01
期刊：
Briefings in Functional Genomics & Proteomics
影响因子：
--
作者：
Law, Warren J.;Cann, Kendra L.;Hicks, Geoffrey G.
通讯作者：
Hicks, Geoffrey G.