Association of Mutations in TBK1 With Sporadic and Familial Amyotrophic Lateral Sclerosis and Frontotemporal Dementia
Association of Mutations in TBK1 With Sporadic and Familial Amyotrophic Lateral Sclerosis and Frontotemporal Dementia
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DOI：
10.1001/jamaneurol.2016.3712
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发表时间：
2017-01-01
期刊：
影响因子：
29
通讯作者：
Andersen, Peter M.
中科院分区：
文献类型：
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作者：
Freischmidt, Axel;Mueller, Kathrin;Andersen, Peter M.
肌萎缩侧索硬化症(ALS)和额颞叶痴呆(FTD)是相关的神经退行性综合征，零星发生或与30多个基因突变的大多数显性遗传有关。一个关键的问题是，所有报告的突变是致病的还是巧合的发现。在这篇综述中，我们分析了新发现的编码坦克结合蛋白1基因的非同义变异的致病性。现有数据表明，导致TBK1蛋白水平下降50%的TBK1突变是致病的。在大多数情况下，突变的TBK1等位基因几乎完全丧失表达是由于功能丧失的突变产生了提前终止密码子，以及无义介导的信使RNA衰退导致突变的信使RNA降解。此外，TBK1蛋白水平降低50%已被证明可导致1种或几种氨基酸的特定框内缺失，这可能是由于突变蛋白的降解增加所致。在ALS或FTD患者中发现的许多TBK1错义突变的评估，由于缺乏证明变异的共分离的数据以及对与神经退行性变相关的TBK1功能的不完全了解而无法进行。这些发现表明，无论突变类型如何，TBK1单倍性不足都是ALS和FTD的致病因素。在没有数据证明共隔离的情况下，评估不会导致单倍体不足的TBK1变体是不可能的。
Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are related neurodegenerative syndromes that occur sporadically or have been associated with mostly dominant inheritance of mutations in more than 30 genes. A critical issue is whether all reported mutations are disease causing or are coincidental findings. In this review we analyze the pathogenicity of nonsynonymous variants in the newly discovered gene encoding TANK-binding kinase 1 (TBK1). The available data suggest that mutations in TBK1 that cause a 50% reduction of TBK1 protein levels are pathogenic. In most cases, the almost complete loss of expression of the mutated TBK1 allele is due to loss-of-function mutations creating a premature termination codon and the degradation of the mutated messenger RNA by nonsense-mediated messenger RNA decay. In addition, TBK1 protein levels reduced by 50% have been proven for specific in-frame deletions of 1 or several amino acids, probably due to increased degradation of the mutated protein. Evaluation of many of the TBK1 missense mutations found in patients with ALS or FTD is prevented by missing data demonstrating cosegregation of the variants and incomplete knowledge about the TBK1 functions relevant for neurodegeneration. These findings suggest that haploinsufficiency of TBK1 is causative for ALS and FTD regardless of the type of mutation. Evaluation of TBK1 variants that do not cause haploinsufficiency is not possible without data demonstrating cosegregation.