Rare mutations in SQSTM1 modify susceptibility to frontotemporal lobar degeneration.
Rare mutations in SQSTM1 modify susceptibility to frontotemporal lobar degeneration.
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DOI：
10.1007/s00401-014-1298-7
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发表时间：
2014-09
影响因子：
12.7
通讯作者：
Van Broeckhoven C
中科院分区：
文献类型：
--
作者：
van der Zee J;Van Langenhove T;Kovacs GG;Dillen L;Deschamps W;Engelborghs S;Matěj R;Vandenbulcke M;Sieben A;Dermaut B;Smets K;Van Damme P;Merlin C;Laureys A;Van Den Broeck M;Mattheijssens M;Peeters K;Benussi L;Binetti G;Ghidoni R;Borroni B;Padovani A;Archetti S;Pastor P;Razquin C;Ortega-Cubero S;Hernández I;Boada M;Ruiz A;de Mendonça A;Miltenberger-Miltényi G;do Couto FS;Sorbi S;Nacmias B;Bagnoli S;Graff C;Chiang HH;Thonberg H;Perneczky R;Diehl-Schmid J;Alexopoulos P;Frisoni GB;Bonvicini C;Synofzik M;Maetzler W;vom Hagen JM;Schöls L;Haack TB;Strom TM;Prokisch H;Dols-Icardo O;Clarimón J;Lleó A;Santana I;Almeida MR;Santiago B;Heneka MT;Jessen F;Ramirez A;Sanchez-Valle R;Llado A;Gelpi E;Sarafov S;Tournev I;Jordanova A;Parobkova E;Fabrizi GM;Testi S;Salmon E;Ströbel T;Santens P;Robberecht W;De Jonghe P;Martin JJ;Cras P;Vandenberghe R;De Deyn PP;Cruts M;Sleegers K;Van Broeckhoven C
Sequestosome 1(SQSTM1)基因编码突变与肌萎缩侧索硬化症(ALS)和Paget病有关。在本研究中，我们分析了欧洲早发性痴呆联盟确定的1,808例额颞叶变性(FTLD)患者的扩大队列中SQSTM1编码序列的突变。作为对照数据集，我们对1,625个欧洲对照个体进行了测序，并分析了2,274个德国个体的全外显子序列数据(总n=233,899)。通过对4,332个FTLD和10,240个对照等位基因的荟萃分析，计算了罕见的SQSTM1突变的关联性。我们在FTLD患者中发现了25个编码变体，其中10个尚未描述。对照组中没有15个突变(携带者频率为0.00026)，而其他突变在患者和对照组中都很少见。当将等位基因频率较小的所有变异合并在一起时，计算出患者的总体频率为3.2%。患者和对照组之间的罕见变异关联分析显示，在整个蛋白质上没有差异，但提示SQSTM1UBA域的罕见突变聚集性可能通过使FTLD的风险增加一倍而影响疾病易感性(RR=62.18[95%CI 1.24-3.85]；校正p值=0.042)。详细的组织病理学显示，SQSTM1的突变与广泛的神经元和神经胶质磷酸化TDP-43病理有关。通过这项研究，我们进一步证明了SQSTM1罕见突变在FTLD遗传病因学中的可能作用，并表明，与其他FTLD/ALS基因相比，SQSTM1突变与TDP-43病理相关。本文的在线版本(doi：10.1007/s00401-014-1298-7)包含补充材料，授权用户可以使用。
Mutations in the gene coding for Sequestosome 1 (SQSTM1) have been genetically associated with amyotrophic lateral sclerosis (ALS) and Paget disease of bone. In the present study, we analyzed the SQSTM1 coding sequence for mutations in an extended cohort of 1,808 patients with frontotemporal lobar degeneration (FTLD), ascertained within the European Early-Onset Dementia consortium. As control dataset, we sequenced 1,625 European control individuals and analyzed whole-exome sequence data of 2,274 German individuals (total n = 3,899). Association of rare SQSTM1 mutations was calculated in a meta-analysis of 4,332 FTLD and 10,240 control alleles. We identified 25 coding variants in FTLD patients of which 10 have not been described. Fifteen mutations were absent in the control individuals (carrier frequency <0.00026) whilst the others were rare in both patients and control individuals. When pooling all variants with a minor allele frequency <0.01, an overall frequency of 3.2 % was calculated in patients. Rare variant association analysis between patients and controls showed no difference over the whole protein, but suggested that rare mutations clustering in the UBA domain of SQSTM1 may influence disease susceptibility by doubling the risk for FTLD (RR = 2.18 [95 % CI 1.24–3.85]; corrected p value = 0.042). Detailed histopathology demonstrated that mutations in SQSTM1 associate with widespread neuronal and glial phospho-TDP-43 pathology. With this study, we provide further evidence for a putative role of rare mutations in SQSTM1 in the genetic etiology of FTLD and showed that, comparable to other FTLD/ALS genes, SQSTM1 mutations are associated with TDP-43 pathology. The online version of this article (doi:10.1007/s00401-014-1298-7) contains supplementary material, which is available to authorized users.
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