Division of Neuromuscular Medicine, Davee Department of Neurology and Clinical Neurosciences, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA.
Neurology. 2010 Aug 31;75(9):807-14. doi: 10.1212/WNL.0b013e3181f07e0c. Epub 2010 Jul 28.
Amyotrophic lateral sclerosis (ALS) is a progressive paralytic disorder caused by degeneration of motor neurons. Mutations in the FUS gene were identified in patients with familial ALS (FALS) and patients with sporadic ALS (SALS) from a variety of genetic backgrounds. This work further explores the spectrum of FUS mutations in patients with FALS and patients with FALS with features of frontotemporal dementia (FALS/FTD) or parkinsonism and dementia (FALS/PD/DE).
All exons of the FUS gene were sequenced in 476 FALS index cases negative for mutations in SOD1 and TARDBP. A total of 561-726 controls were analyzed for genetic variants observed. Clinical data from patients with FUS mutations were compared to those of patients with known SOD1 and TARDBP mutations.
We identified 17 FUS mutations in 22 FALS families, 2 FALS/FTD families, and 1 FALS/PD/DE family from diverse genetic backgrounds; 11 mutations were novel. There were 4 frameshift, 1 nonsense, and 1 possible alternate splicing mutation. Patients with FUS mutations appeared to have earlier symptom onset, a higher rate of bulbar onset, and shorter duration of symptoms than those with SOD1 mutations.
FUS gene mutations are not an uncommon cause in patients with FALS from diverse genetic backgrounds, and have a prevalence of 5.6% in non-SOD1 and non-TARDBP FALS, and approximately 4.79% in all FALS. The pathogenicity of some of these novel mutations awaits further studies. Patients with FUS mutations manifest earlier symptom onset, a higher rate of bulbar onset, and shorter duration of symptoms.
肌萎缩侧索硬化症（ALS）是一种由运动神经元变性引起的进行性瘫痪性疾病。在来自不同遗传背景的家族性 ALS（FALS）患者和散发性 ALS（SALS）患者中发现了 FUS 基因突变。这项工作进一步探讨了 FALS 患者和具有额颞叶痴呆（FALS/FTD）或帕金森病和痴呆（FALS/PD/DE）特征的 FALS 患者中 FUS 基因突变的谱。
对 476 例 SOD1 和 TARDBP 突变阴性的 FALS 指数病例的 FUS 基因所有外显子进行测序。对观察到的遗传变异进行了总共 561-726 例对照分析。将 FUS 基因突变患者的临床数据与已知 SOD1 和 TARDBP 基因突变患者进行比较。
我们在来自不同遗传背景的 22 个 FALS 家族、2 个 FALS/FTD 家族和 1 个 FALS/PD/DE 家族中发现了 17 个 FUS 突变，其中 11 个是新的。有 4 个移码、1 个无义突变和 1 个可能的选择性剪接突变。与 SOD1 突变患者相比，FUS 突变患者的症状起始年龄更早，球部起始率更高，症状持续时间更短。
FUS 基因突变在来自不同遗传背景的 FALS 患者中并非罕见原因，在非 SOD1 和非 TARDBP FALS 中的患病率为 5.6%，在所有 FALS 中的患病率约为 4.79%。这些新突变的一些致病性有待进一步研究。FUS 突变患者的症状起始年龄更早，球部起始率更高，症状持续时间更短。
