Pathogenic Huntingtin Repeat Expansions in Patients with Frontotemporal Dementia and Amyotrophic Lateral Sclerosis.
Pathogenic Huntingtin Repeat Expansions in Patients with Frontotemporal Dementia and Amyotrophic Lateral Sclerosis.
复制标题
DOI：
10.1016/j.neuron.2020.11.005
复制
发表时间：
2021-02-03
期刊：
影响因子：
16.2
通讯作者：
Traynor BJ
中科院分区：
文献类型：
--
作者：
Dewan R;Chia R;Ding J;Hickman RA;Stein TD;Abramzon Y;Ahmed S;Sabir MS;Portley MK;Tucci A;Ibáñez K;Shankaracharya FNU;Keagle P;Rossi G;Caroppo P;Tagliavini F;Waldo ML;Johansson PM;Nilsson CF;American Genome Center (TAGC);FALS Sequencing Consortium;Genomics England Research Consortium;International ALS/FTD Genomics Consortium (iAFGC);International FTD Genetics Consortium (IFGC);International LBD Genomics Consortium (iLBDGC);NYGC ALS Consortium;PROSPECT Consortium;Rowe JB;Benussi L;Binetti G;Ghidoni R;Jabbari E;Viollet C;Glass JD;Singleton AB;Silani V;Ross OA;Ryten M;Torkamani A;Tanaka T;Ferrucci L;Resnick SM;Pickering-Brown S;Brady CB;Kowal N;Hardy JA;Van Deerlin V;Vonsattel JP;Harms MB;Morris HR;Ferrari R;Landers JE;Chiò A;Gibbs JR;Dalgard CL;Scholz SW;Traynor BJ
我们通过分析2,442例额颞叶痴呆(FTD)和肌萎缩侧索硬化症(ALS)患者、2,599例路易体痴呆(LBD)患者和3,158名神经健康受试者的全基因组序列数据，研究了重复扩张在额颞叶痴呆(FTD)和肌萎缩侧索硬化症(ALS)发病机制中的作用。在3例(0.12%)单纯股骨头萎缩性侧索硬化症/肌萎缩侧索硬化症患者中发现了亨廷顿蛋白基因的致病扩增(范围从40到CAG重复)，但在LBD或健康队列中没有出现。我们在3674名FTD/ALS患者的独立集合中重复了我们的发现。两名患者的死后评估显示FTD/ALS的经典TDP-43病理，以及额叶皮质中Huntingtin阳性的、泛素阳性的聚集体。这两个病例都没有表现出亨廷顿病的新纹状体萎缩。我们的发现揭示了HTT重复扩增与FTD/ALS综合征的病因学关系，并提示应考虑对FTD/ALS患者进行HTT重复扩增的基因筛查。利用大规模全基因组测序，Dewan等人在诊断为FTD/ALS神经退行性疾病的患者中确定了致病HTT重复序列的扩张。尸检证实了FTD/ALS中预期的TDP-43病理，并显示额叶皮质内有多聚谷氨酰胺包涵体，但没有纹状体变性。这些数据拓宽了HTT重复扩增所产生的表型。
We examined the role of repeat expansions in the pathogenesis of frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS) by analyzing whole-genome sequence data from 2,442 FTD/ALS patients, 2,599 Lewy body dementia (LBD) patients, and 3,158 neurologically healthy subjects. Pathogenic expansions (range: 40 to 64 CAG repeats) in the huntingtin (HTT) gene were found in three (0.12%) patients diagnosed with pure FTD/ALS syndromes, but were not present in the LBD or healthy cohorts. We replicated our findings in an independent collection of 3,674 FTD/ALS patients. Postmortem evaluations of two patients revealed the classical TDP-43 pathology of FTD/ALS, as well as huntingtin-positive, ubiquitin-positive aggregates in the frontal cortex. The neostriatal atrophy that pathologically defines Huntington’s disease was absent in both cases. Our findings reveal an etiological relationship between HTT repeat expansions and FTD/ALS syndromes, and indicate that genetic screening of FTD/ALS patients for HTT repeat expansions should be considered. Using large-scale whole-genome sequencing, Dewan et al identifies pathogenic HTT repeat expansions in patients diagnosed with FTD/ALS neurodegenerative disorders. Autopsies confirm the TDP-43 pathology expected in FTD/ALS and show polyglutamine inclusions within the frontal cortices, but no striatal degeneration. These data broaden the phenotype resulting from HTT repeat expansions.
登录
查看更多内容
影响因子：
9.2
作者：
Chang CC;Chow CC;Tellier LC;Vattikuti S;Purcell SM;Lee JJ
通讯作者：
Lee JJ
影响因子：
16.6
作者：
Arthur KC;Calvo A;Price TR;Geiger JT;Chiò A;Traynor BJ
通讯作者：
Traynor BJ
影响因子：
11.1
作者：
Ciosi, Marc;Maxwell, Alastair;Monckton, Darren G.
通讯作者：
Monckton, Darren G.
影响因子：
64.8
作者：
LASPADA, AR;WILSON, EM;FISCHBECK, KH
通讯作者：
FISCHBECK, KH
影响因子：
8.6
作者：
Kanai, Kazuaki;Kuwabara, Satoshi;Hattori, Takamichi
通讯作者：
Hattori, Takamichi