Lack of C9ORF72 coding mutations supports a gain of function for repeat expansions in amyotrophic lateral sclerosis
Lack of C9ORF72 coding mutations supports a gain of function for repeat expansions in amyotrophic lateral sclerosis
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DOI：
10.1016/j.neurobiolaging.2013.03.006
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发表时间：
2013-09-01
影响因子：
4.2
通讯作者：
Baloh, Robert H.
中科院分区：
文献类型：
--
作者：
Harms, Matthew B.;Cady, Janet;Baloh, Robert H.
C9ORF72基因的六核苷酸重复扩增是家族性和明显散发性肌萎缩侧索硬化症(ALS)和额叶颞叶痴呆(FTD)的常见原因。扩张导致神经退化的机制尚不清楚，但目前的证据支持功能丧失和功能获得的机制。我们在389名ALS患者中使用了C9ORF72基因的池下一代测序来寻找传统的功能丧失突变。尽管发现了罕见的变异，但没有一种可能是致病的，这表明除了重复扩增之外的突变不是ALS的常见原因，并为功能获得机制提供了支持性证据。我们还通过重复启动的PCR基因分型显示，C9ORF72的扩展频率在美国境内因地理区域而异，在中西部地区的频率出人意料地高。最后，我们还通过Southern杂交证明了扩张大小的躯体不稳定，其中最大的扩张发生在脑组织中。(C)2013 Elsevier Inc.保留所有权利。
Hexanucleotide repeat expansions in C9ORF72 are a common cause of familial and apparently sporadic amyotrophic lateral sclerosis (ALS) and frontal temporal dementia (FTD). The mechanism by which expansions cause neurodegeneration is unknown, but current evidence supports both loss-of-function andgain-of-function mechanisms. We used pooled next-generation sequencing of the C9ORF72 gene in 389 ALS patients to look for traditional loss-of-function mutations. Although rare variants were identified, none were likely to be pathogenic, suggesting that mutations other than the repeat expansion are not a common cause of ALS, and providing supportive evidence for a gain-of-function mechanism. We also show by repeat-primed PCR genotyping that the C9ORF72 expansion frequency varies by geographical region within the United States, with an unexpectedly high frequency in the Mid-West. Finally we also show evidence of somatic instability of the expansion size by Southern blot, with the largest expansions occurring in brain tissue. (C) 2013 Elsevier Inc. All rights reserved.