title: Copy Number Variations in Amyotrophic Lateral Sclerosis: Piecing the Mosaic Tiles Together through a Systems Biology Approach.
abstract: 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.
authors.affiliation: Institute of Neurological Sciences (ISN), National Research Council (CNR), Via Paolo Gaifami, 18, 95126, Catania, Italy.
authors.forename: Giovanna
authors.initials: G
authors.lastname: Morello
authors.affiliation: Institute of Neurological Sciences (ISN), National Research Council (CNR), Via Paolo Gaifami, 18, 95126, Catania, Italy.
authors.forename: Maria
authors.initials: M
authors.lastname: Guarnaccia
authors.affiliation: Institute of Neurological Sciences (ISN), National Research Council (CNR), Via Paolo Gaifami, 18, 95126, Catania, Italy.
authors.forename: Antonio Gianmaria
authors.initials: AG
authors.lastname: Spampinato
authors.affiliation: 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.
authors.forename: Valentina
authors.initials: V
authors.lastname: La Cognata
authors.affiliation: Department of Biomedical and Biotechnological Sciences, Section of Human Anatomy and Histology, University of Catania, Catania, Italy.
authors.forename: Velia
authors.initials: V
authors.lastname: D'Agata
authors.affiliation: Institute of Neurological Sciences (ISN), National Research Council (CNR), Via Paolo Gaifami, 18, 95126, Catania, Italy. sebastiano.cavallaro@cnr.it.
authors.forename: Sebastiano
authors.initials: S
authors.lastname: Cavallaro
mesh_terms: D000690:Amyotrophic Lateral Sclerosis / Q000235:genetics*; D056915:DNA Copy Number Variations; D020022:Genetic Predisposition to Disease; D015894:Genome, Human; D006801:Humans; D020641:Polymorphism, Single Nucleotide; D049490:Systems Biology
keywords: Amyotrophic lateral sclerosis (ALS); Copy number variations (CNVs); Genomics; Systems biology