Genetic analysis of VCP and WASH complex genes in a German cohort of sporadic ALS-FTD patients
Genetic analysis of VCP and WASH complex genes in a German cohort of sporadic ALS-FTD patients
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DOI：
10.1016/j.neurobiolaging.2017.04.023
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发表时间：
2017-08-01
影响因子：
4.2
通讯作者：
Clemen，Christoph S.
中科院分区：
文献类型：
--
作者：
Tuerk，Matthias;Schroeder，Rolf;Clemen，Christoph S.
人类含缬氨酸蛋白p97 （VCP）和Wiskott-Aldrich综合征蛋白及SCAR同源（WASH）复合基因的突变可引起运动神经元和认知功能障碍。在这里，我们分析了一组因VCP和WASH复合基因突变而患有散发性肌萎缩侧索硬化症和额颞叶变性合并症（ALS/FTD）的德国患者。对43例散发性ALS/FTD患者进行了新一代VCP、WASH1、FAM21C、CCDC53、SWIP、strumpellin、肌肉z线α - 1 (CAPZA1) F-actin封盖蛋白和CAPZB基因的平板测序。随后的分析包括Sanger测序、计算机分析、实时PCR和CCDC53免疫印迹。我们发现1例患者在CAPZA1中携带杂合变异C . 26c >T，预计会导致p.Ser9Leu，另1例患者在CCDC53中携带杂合起始密码子变异C . 2t >C。硅分析预测了CAPZα1 n端结构的变化，这可能会干扰CAPZα:CAPZβ二聚化。虽然CCDC53的翻译起始密码子发生了突变，但实时PCR和免疫印迹均未发现CCDC53单倍体不足或CCDC53蛋白种类异常的证据。此外，后来在该患者中发现了一种致病的C9orf72重复扩增突变。因此，除了一种推定的致病性杂合c.26C>T CAPZA1变异外，我们的遗传分析未发现VCP和其余WASH复合物亚基的突变。
Mutations of the human valosin-containing protein, p97 (VCP) and Wiskott-Aldrich syndrome protein and SCAR homolog (WASH) complex genes cause motor neuron and cognitive impairment disorders. Here, we analyzed a cohort of German patients with sporadic amyotrophic lateral sclerosis and frontotemporal lobar degeneration comorbidity (ALS/FTD) for VCP and WASH complex gene mutations. Next-generation panel sequencing of VCP, WASH1, FAM21C, CCDC53, SWIP, strumpellin, F-actin capping protein of muscle Z-line alfa 1 (CAPZA1), and CAPZB genes was performed in 43 sporadic ALS/FTD patients. Subsequent analyses included Sanger sequencing, in silico analyses, real-time PCR, and CCDC53 immunoblotting. We identified 1 patient with the heterozygous variant c.26C>T in CAPZA1, predicted to result in p.Ser9Leu, and a second with the heterozygous start codon variant c.2T>C in CCDC53. In silico analysis predicted structural changes in the N-terminus of CAPZα1, which may interfere with CAPZα:CAPZβ dimerization. Though the translation initiation codon of CCDC53 is mutated, real-time PCR and immunoblotting did neither reveal any evidence for a CCDC53 haploinsufficiency nor for aberrant CCDC53 protein species. Moreover, a disease-causing C9orf72 repeat expansion mutation was later on identified in this patient. Thus, with the exception of a putatively pathogenic heterozygous c.26C>T CAPZA1 variant, our genetic analysis did not reveal mutations in VCP and the remaining WASH complex subunits.