Novel FUS/TLS Mutations and Pathology in Familial and Sporadic Amyotrophic Lateral Sclerosis
Novel FUS/TLS Mutations and Pathology in Familial and Sporadic Amyotrophic Lateral Sclerosis
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DOI：
10.1001/archneurol.2010.52
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发表时间：
2010-04-01
影响因子：
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通讯作者：
Shaw, Pamela J.
中科院分区：
文献类型：
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作者：
Hewitt, Christopher;Kirby, Janine;Shaw, Pamela J.
目的：确定来自英格兰北部的肌萎缩侧索硬化症（ALS）患者中与FUS/TLS突变相关的临床病理表型的频率。设计：遗传筛选项目，对选定病例的死后组织进行神经病理学检查。所选病例的临床细节也被提出。地点：英格兰北部2所大学教学医院的神经内科。研究人员对42例家族性ALS（FALS）和117例散发性ALS（SALS）患者的15个FUS/TLS外显子进行了测序。外显子14和15随后在431例SALS病例的更大队列中筛选。在293例对照中也筛选了ALS病例中突变的区域。主要观察指标：基因测序色谱仪的评价和中枢神经系统的详细组织病理学分析。结果：6例ALS患者（4例FALS， 2例SALS）共发现4个杂合突变，其中1个为新突变。在对照组中没有发现两种替代，这些病例的神经病理学显示神经元和/或胶质细胞质包涵体对FUS/TLS蛋白呈阳性。其中一例也是首次报道的FUS/TLS突变的SALS病例。在对照病例中也发现了其他2种替代。这些病例的神经病理学显示典型的SALS病理，表明它们可能代表良性多态性。结论：FUS/TLS突变约占筛选的FALS病例的5%。在单个SALS病例中也发现了FUS/TLS突变。然而，在更大的SALS病例队列中对该区域的后续筛查未发现任何额外的突变。
Objective: To determine the frequency of and clinicopathologic phenotypes associated with FUS/TLS mutations in a large cohort of amyotrophic lateral sclerosis (ALS) cases from the north of England.Design: Genetic screening project with neuropathologic examination of postmortem tissue in selected cases. The clinical details of selected cases are also presented.Setting: Neurology departments of 2 university teaching hospitals in the north of England.Participants: The 15 exons of FUS/TLS were sequenced in an initial cohort of 42 familial ALS (FALS) and 117 sporadic ALS( SALS) cases. Exons 14 and 15 were subsequently screened in a larger cohort of 431 SALS cases. Regions mutated in ALS cases were also screened in 293 controls.Main Outcome Measure: Evaluation of gene-sequencing chromatographs and detailed histopathologic analysis of the central nervous system.Results: Four heterozygous mutations, 1 of which is novel, were identified in 6 patients with ALS (4 with FALS and 2 with SALS). Two of the substitutions were not found to be present in controls, and neuropathology in these cases revealed neuronal and/or glial cytoplasmic inclusions positive for the FUS/TLS protein. One of these cases is also the first reported SALS case with an FUS/TLS mutation. The other 2 substitutions identified were also identified in control cases. Neuropathology in these cases revealed typical SALS pathology, suggesting that they are likely to represent benign polymorphisms.Conclusions: FUS/TLS mutations represented approximately 5% of FALS cases screened. A FUS/TLS mutation was also identified in a single SALS case. Subsequent screening of this region in a larger cohort of SALS cases, however, did not reveal any additional mutations.