Institute of Neurological Sciences (ISN), National Research Council (CNR), Via Paolo Gaifami, 18, 95126, Catania, Italy.
Department of Biomedical and Biotechnological Sciences, Section of Human Anatomy and Histology, University of Catania, Catania, Italy.
Mol Neurobiol. 2018 Feb;55(2):1299-1322. doi: 10.1007/s12035-017-0393-x. Epub 2017 Jan 24.
Amyotrophic lateral sclerosis (ALS) is a devastating and still untreatable motor neuron disease. Despite the molecular mechanisms underlying ALS pathogenesis that are still far from being understood, several studies have suggested the importance of a genetic contribution in both familial and sporadic forms of the disease. In addition to single-nucleotide polymorphisms (SNPs), which account for only a limited number of ALS cases, a consistent number of common and rare copy number variations (CNVs) have been associated to ALS. Most of the CNV-based association studies use a traditional candidate-gene approach that is inadequate for uncovering the genetic architectures of complex traits like ALS. The emergent paradigm of "systems biology" may offer a new perspective to better interpret the wide spectrum of CNVs in ALS, enabling the characterization of the complex network of gene products underlying ALS pathogenesis. In this review, we will explore the landscape of CNVs in ALS, putting specific emphasis on the functional impact of common CNV regions and genes consistently associated with increased risk of developing disease. In addition, we will discuss the potential contribution of multiple rare CNVs in ALS pathogenesis, focusing our attention on the complex mechanisms by which these proteins might impact, individually or in combination, the genetic susceptibility of ALS. The comprehensive detection and functional characterization of common and rare candidate risk CNVs in ALS susceptibility may bring new pieces into the intricate mosaic of ALS pathogenesis, providing interesting and important implications for a more precise molecular biomarker-assisted diagnosis and more effective and personalized treatments.
肌萎缩侧索硬化症（ALS）是一种破坏性的、仍无法治疗的运动神经元疾病。尽管 ALS 发病机制的分子机制仍远未被理解，但有几项研究表明，遗传因素在家族性和散发性疾病中都很重要。除了单核苷酸多态性（SNP），它们只占 ALS 病例的有限数量外，大量常见和罕见的拷贝数变异（CNV）也与 ALS 相关。大多数基于 CNV 的关联研究使用传统的候选基因方法，这种方法不足以揭示 ALS 等复杂特征的遗传结构。新兴的“系统生物学”范式可能为更好地解释 ALS 中的广泛 CNV 提供新的视角，使 ALS 发病机制的复杂基因产物网络的特征化成为可能。在这篇综述中，我们将探讨 ALS 中的 CNV 景观，特别强调与疾病风险增加一致相关的常见 CNV 区域和基因的功能影响。此外，我们还将讨论多个罕见 CNV 在 ALS 发病机制中的潜在贡献，重点关注这些蛋白质可能以个体或组合的方式影响 ALS 遗传易感性的复杂机制。对 ALS 易感性中常见和罕见候选风险 CNV 的全面检测和功能特征分析，可能会为 ALS 发病机制的复杂镶嵌提供新的内容，为更精确的分子生物标志物辅助诊断和更有效、个性化的治疗提供有趣和重要的意义。
