SQSTM1 Mutations in Familial and Sporadic Amyotrophic Lateral Sclerosis
SQSTM1 Mutations in Familial and Sporadic Amyotrophic Lateral Sclerosis
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DOI：
10.1001/archneurol.2011.250
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发表时间：
2011-11-01
影响因子：
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通讯作者：
Siddique, Teepu
中科院分区：
文献类型：
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作者：
Fecto, Faisal;Yan, Jianhua;Siddique, Teepu
背景资料：SQSTM 1基因编码p62，p62是参与神经变性的主要病理蛋白。目的：检测SQSTM 1突变是否与家族性和散发性肌萎缩侧索硬化（ALS）有关。设计：病例对照研究。设置：学术研究。患者：在一个主要的学术转诊中心对546名家族性（n = 340）或散发性（n = 206）ALS患者进行SQSTM 1突变筛查。我们评估了ALS患者队列中SQSTM 1错义、缺失、沉默和内含子变异的分布。在silico分析的变体进行预测p62的结构和function.Results的改变：我们确定了10个新的SQSTM 1突变（9杂合错义和1缺失）在15例（6与家族性ALS和9散发性ALS）。预测在硅片分析归类为pathogenic.Conclusions的9个错义变异8：使用候选基因识别的基础上事先的生物学知识和罕见的变异的功能预测，我们确定了几个新的SQSTM 1突变ALS患者。我们的研究结果为p62在ALS发病机制中的直接遗传作用提供了证据，并表明调节蛋白降解途径可能是运动神经元变性的重要治疗靶点。
Background: The SQSTM1 gene encodes p62, a major pathologic protein involved in neurodegeneration.Objective: To examine whether SQSTM1 mutations contribute to familial and sporadic amyotrophic lateral sclerosis (ALS).Design: Case-control study.Setting: Academic research.Patients: A cohort of 546 patients with familial (n = 340) or sporadic (n = 206) ALS seen at a major academic referral center were screened for SQSTM1 mutations.Main Outcome Measures: We evaluated the distribution of missense, deletion, silent, and intronic variants in SQSTM1 among our cohort of patients with ALS. In silico analysis of variants was performed to predict alterations in p62 structure and function.Results: We identified 10 novel SQSTM1 mutations (9 heterozygous missense and 1 deletion) in 15 patients (6 with familial ALS and 9 with sporadic ALS). Predictive in silico analysis classified 8 of 9 missense variants as pathogenic.Conclusions: Using candidate gene identification based on prior biological knowledge and the functional prediction of rare variants, we identified several novel SQSTM1 mutations in patients with ALS. Our findings provide evidence of a direct genetic role for p62 in ALS pathogenesis and suggest that regulation of protein degradation pathways may represent an important therapeutic target in motor neuron degeneration.