Hot-spot KIF5A mutations cause familial ALS.
Hot-spot KIF5A mutations cause familial ALS.
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DOI：
10.1093/brain/awx370
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发表时间：
2018-03-01
期刊：
影响因子：
--
通讯作者：
German ALS network MND-NET
中科院分区：
文献类型：
--
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
Brenner等人表明，驱动蛋白-5A（KIF 5A）的C-末端热点中的突变可引起经典的ALS表型。使用患者来源的细胞系的实验表明，单倍不足的分子遗传机制。这强调了细胞内转运过程与ALS的相关性，并且对于临床遗传诊断和咨询很重要。在驱动蛋白家族成员5A（KIF 5A）基因的N-末端马达或卷曲螺旋结构域中的杂合错义突变引起单基因痉挛性截瘫（HSP 10）和Charcot-Marie-Tooth病2型（CMT 2）。此外，在KIF 5A的C-末端结构域中的杂合从头移码突变与新生儿顽固性肌阵挛（一种神经发育综合征）相关。这些发现，以及许多与肌萎缩侧索硬化症相关的疾病基因破坏细胞骨架功能和细胞内转运的观察，使我们假设KIF 5A突变也是肌萎缩侧索硬化症的原因。我们对426名家族性肌萎缩侧索硬化症患者和6137名对照者进行了全外显子组测序和罕见变异分析，检测到肌萎缩侧索硬化症中KIF 5A剪接位点突变的富集（2/426，对照组为0/6137; P = 4.2 × 10−3），均位于蛋白质C末端的热点，预计会影响27号外显子的剪接。此外，我们还显示了两个典型的剪接位点突变在两个家庭中与肌萎缩侧索硬化症的共分离。对KIF 5A剪接位点突变患者的淋巴母细胞系的研究显示突变体RNA表达缺失，并提示单倍不足是最可能的潜在分子机制。此外，位于外显子27剪接供体上游的蛋白质C末端的罕见非同义错义突变（预测p.Arg1007Gly）的mRNA测序显示，由于供体位点的废除，相应患者来源的细胞系中存在KIF 5A前体mRNA剪接缺陷。最后，非同义单核苷酸变异rs 113247976（对照组中次要等位基因频率= 1.00%，n = 6137），也位于C-末端区域[p.（Pro 986 Leu）在家族性肌萎缩侧索硬化症患者中显著富集（次要等位基因频率= 3.40%; P = 1.28 × 10−7）。我们的研究表明，KIF 5A的C-末端热点特异性突变可导致经典的肌萎缩侧索硬化症表型，并强调肌萎缩侧索硬化症发病机制中的细胞内转运过程的参与。
Brenner et al. show that mutations in a C-terminal hotspot of kinesin-5A (KIF5A) can cause a classical ALS phenotype. Experiments using patient-derived cell lines suggest haploinsufficiency as the molecular genetic mechanism. This underlines the relevance of intracellular transport processes for ALS, and is important for clinico-genetic diagnosis and counselling. Heterozygous missense mutations in the N-terminal motor or coiled-coil domains of the kinesin family member 5A (KIF5A) gene cause monogenic spastic paraplegia (HSP10) and Charcot-Marie-Tooth disease type 2 (CMT2). Moreover, heterozygous de novo frame-shift mutations in the C-terminal domain of KIF5A are associated with neonatal intractable myoclonus, a neurodevelopmental syndrome. These findings, together with the observation that many of the disease genes associated with amyotrophic lateral sclerosis disrupt cytoskeletal function and intracellular transport, led us to hypothesize that mutations in KIF5A are also a cause of amyotrophic lateral sclerosis. Using whole exome sequencing followed by rare variant analysis of 426 patients with familial amyotrophic lateral sclerosis and 6137 control subjects, we detected an enrichment of KIF5A splice-site mutations in amyotrophic lateral sclerosis (2/426 compared to 0/6137 in controls; P = 4.2 × 10−3), both located in a hot-spot in the C-terminus of the protein and predicted to affect splicing exon 27. We additionally show co-segregation with amyotrophic lateral sclerosis of two canonical splice-site mutations in two families. Investigation of lymphoblast cell lines from patients with KIF5A splice-site mutations revealed the loss of mutant RNA expression and suggested haploinsufficiency as the most probable underlying molecular mechanism. Furthermore, mRNA sequencing of a rare non-synonymous missense mutation (predicting p.Arg1007Gly) located in the C-terminus of the protein shortly upstream of the splice donor of exon 27 revealed defective KIF5A pre-mRNA splicing in respective patient-derived cell lines owing to abrogation of the donor site. Finally, the non-synonymous single nucleotide variant rs113247976 (minor allele frequency = 1.00% in controls, n = 6137), also located in the C-terminal region [p.(Pro986Leu) in exon 26], was significantly enriched in familial amyotrophic lateral sclerosis patients (minor allele frequency = 3.40%; P = 1.28 × 10−7). Our study demonstrates that mutations located specifically in a C-terminal hotspot of KIF5A can cause a classical amyotrophic lateral sclerosis phenotype, and underline the involvement of intracellular transport processes in amyotrophic lateral sclerosis pathogenesis.
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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：
12.3
作者：
Celniker SE;Wheeler DA;Kronmiller B;Carlson JW;Halpern A;Patel S;Adams M;Champe M;Dugan SP;Frise E;Hodgson A;George RA;Hoskins RA;Laverty T;Muzny DM;Nelson CR;Pacleb JM;Park S;Pfeiffer BD;Richards S;Sodergren EJ;Svirskas R;Tabor PE;Wan K;Stapleton M;Sutton GG;Venter C;Weinstock G;Scherer SE;Myers EW;Gibbs RA;Rubin GM
通讯作者：
Rubin GM
影响因子：
4.4
作者：
Kaji, Seiji;Kawarai, Toshitaka;Kaji, Ryuji
通讯作者：
Kaji, Ryuji
影响因子：
9.9
作者：
Liu, Yo-Tsen;Laura, Matilde;Houlden, Henry
通讯作者：
Houlden, Henry
影响因子：
16.6
作者：
McLaughlin RL;Schijven D;van Rheenen W;van Eijk KR;O'Brien M;Kahn RS;Ophoff RA;Goris A;Bradley DG;Al-Chalabi A;van den Berg LH;Luykx JJ;Hardiman O;Veldink JH;Project MinE GWAS Consortium;Schizophrenia Working Group of the Psychiatric Genomics Consortium
通讯作者：
Schizophrenia Working Group of the Psychiatric Genomics Consortium