Association of variants in the KIF1A gene with amyotrophic lateral sclerosis.
Association of variants in the KIF1A gene with amyotrophic lateral sclerosis.
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KIF1A 基因变异与肌萎缩侧索硬化症的关联
DOI：
10.1186/s40035-022-00320-2
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发表时间：
2022-10-26
影响因子：
12.6
通讯作者：
Wang, Junling
中科院分区：
文献类型：
--
作者：
Liao, Panlin;Yuan, Yanchun;Liu, Zhen;Hou, Xiaorong;Li, Wanzhen;Wen, Jin;Zhang, Kexuan;Jiao, Bin;Shen, Lu;Jiang, Hong;Guo, Jifeng;Tang, Beisha;Zhang, Zhuohua;Hu, Zhonghua;Wang, Junling
肌萎缩侧索硬化症（ALS）是一种破坏性的进行性神经退行性疾病，影响中枢神经系统和脊髓中的神经元。与许多其他神经退行性疾病一样，ALS的遗传风险因素和发病机制涉及细胞骨架和神经元转运的失调。值得注意的是，感觉和运动神经元疾病，如遗传性感觉和自主神经病变2型（HSAN 2）和痉挛性截瘫30（SPG 30）与ALS共享几个致病基因，以及具有共同的临床表型。KIF 1A编码驱动蛋白3马达，其运输突触前囊泡前体（SVP）和致密核心囊泡，并且已被报道为HSAN 2和SPG 30的致病基因。 在这里，我们分析了941例ALS患者的全外显子组测序数据，以研究KIF 1A与ALS的遗传关联。我们确定了与ALS相关的KIF 1A基因中的罕见损伤变体（RDV），并描述了具有KIF 1A RDV的ALS患者的临床特征。临床上，这些患者往往表现出感觉障碍。有趣的是，这些变体中的大多数位于KIF 1A蛋白的C末端货物结合区。功能检查显示，ALS相关的KIF 1A变体位于C-末端区域优先增强含有RAB 3A，VAMP 2和突触素的SVP的结合。在培养的小鼠皮层神经元中，几种疾病相关的KIF 1A突变体的表达导致RAB 3A或VAMP 2与KIF 1A马达的共定位增强。我们的研究强调了KIF 1A运动介导的转运在ALS发病机制中的重要性，表明KIF 1A在ALS的寡基因情况中起着重要作用。在线版本包含补充材料，可通过10.1186/s40035-022-00320-2获得。
Amyotrophic lateral sclerosis (ALS) is a devastating progressive neurodegenerative disease that affects neurons in the central nervous system and the spinal cord. As in many other neurodegenerative disorders, the genetic risk factors and pathogenesis of ALS involve dysregulation of cytoskeleton and neuronal transport. Notably, sensory and motor neuron diseases such as hereditary sensory and autonomic neuropathy type 2 (HSAN2) and spastic paraplegia 30 (SPG30) share several causative genes with ALS, as well as having common clinical phenotypes. KIF1A encodes a kinesin 3 motor that transports presynaptic vesicle precursors (SVPs) and dense core vesicles and has been reported as a causative gene for HSAN2 and SPG30. Here, we analyzed whole-exome sequencing data from 941 patients with ALS to investigate the genetic association of KIF1A with ALS. We identified rare damage variants (RDVs) in the KIF1A gene associated with ALS and delineated the clinical characteristics of ALS patients with KIF1A RDVs. Clinically, these patients tended to exhibit sensory disturbance. Interestingly, the majority of these variants are located at the C-terminal cargo-binding region of the KIF1A protein. Functional examination revealed that the ALS-associated KIF1A variants located in the C-terminal region preferentially enhanced the binding of SVPs containing RAB3A, VAMP2, and synaptophysin. Expression of several disease-related KIF1A mutants in cultured mouse cortical neurons led to enhanced colocalization of RAB3A or VAMP2 with the KIF1A motor. Our study highlighted the importance of KIF1A motor-mediated transport in the pathogenesis of ALS, indicating KIF1A as an important player in the oligogenic scenario of ALS. The online version contains supplementary material available at 10.1186/s40035-022-00320-2.
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DOI：
10.1093/brain/awx370
发表时间：
2018-03-01
期刊：
Brain : a journal of neurology
影响因子：
--
作者：
Brenner D;Yilmaz R;Müller K;Grehl T;Petri S;Meyer T;Grosskreutz J;Weydt P;Ruf W;Neuwirth C;Weber M;Pinto S;Claeys KG;Schrank B;Jordan B;Knehr A;Günther K;Hübers A;Zeller D;Kubisch C;Jablonka S;Sendtner M;Klopstock T;de Carvalho M;Sperfeld A;Borck G;Volk AE;Dorst J;Weis J;Otto M;Schuster J;Del Tredici K;Braak H;Danzer KM;Freischmidt A;Meitinger T;Strom TM;Ludolph AC;Andersen PM;Weishaupt JH;German ALS network MND-NET
通讯作者：
German ALS network MND-NET
影响因子：
5.3
作者：
Fischer, LR;Culver, DG;Glass, JD
通讯作者：
Glass, JD
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：
8.8
作者：
Baron, Desiree M.;Fenton, Adam R.;Saez-Atienzar, Sara;Giampetruzzi, Anthony;Sreeram, Aparna;Shankaracharya;Keagle, Pamela J.;Doocy, Victoria R.;Smith, Nathan J.;Danielson, Eric W.;Andresano, Megan;McCormack, Mary C.;Garcia, Jaqueline;Bercier, Valerie;Van den Bosch, Ludo;Brent, Jonathan R.;Fallini, Claudia;Traynor, Bryan J.;Holzbaur, Erika L. F.;Landers, John E.
通讯作者：
Landers, John E.
DOI：
10.1083/jcb.201703201
发表时间：
2017-10-02
期刊：
The Journal of cell biology
影响因子：
--
作者：
Huynh W;Vale RD
通讯作者：
Vale RD