Abstract
Genetic mutations of FUS have been linked to many diseases including Amyotrophic Lateral Sclerosis (ALS) and Frontotemporal Lobar Degeneration. A primate specific and polymorphic retrotransposon of the SINE-VNTR-Alu (SVA) family is present upstream of the FUS gene. Here we have demonstrated that this retrotransposon can act as a classical transcriptional regulatory domain in the context of a reporter gene construct both in vitro in the human SK-N-AS neuroblastoma cell line and in vivo in a chick embryo model. We have also demonstrated that the SVA is composed of multiple distinct regulatory domains, one of which is a variable number tandem repeat (VNTR). The ability of the SVA and its component parts to direct reporter gene expression supported a hypothesis that this region could direct differential FUS expression in vivo. The SVA may therefore contribute to the modulation of FUS expression exhibited in and associated with neurological disorders including ALS where FUS regulation may be an important parameter in progression of the disease. As VNTRs are often clinical associates for disease progression we determined the extent of polymorphism within the SVA. In total 2 variants of the SVA were identified based within a central VNTR. Preliminary analysis addressed the association of these SVA variants within a small sporadic ALS cohort but did not reach statistical significance, although we did not include other parameters such as SNPs within the SVA or an environmental factor in this analysis. The latter may be particularly important as the transcriptional and epigenetic properties of the SVA are likely to be directed by the environment of the cell.
Highlights
Genetic variation which alters the primary sequence of a protein has allowed tremendous insight into underlying mechanisms associated with predisposition, progression and severity of diseases
We have demonstrated that a retrotransposon, of the SVA family, 59 of the FUS gene is both polymorphic and a transcriptional regulator domain
The SVA acted as a classical regulatory domain when analysed in reporter gene constructs in vitro and in vivo
Summary
Genetic variation which alters the primary sequence of a protein has allowed tremendous insight into underlying mechanisms associated with predisposition, progression and severity of diseases. Most genetic variation identified in candidate gene and genome wide association studies associated with disease processes is within non coding regions. This has led to a greater analysis and emphasis on the importance of gene-environment interactions in which tissue specific or stimulus inducible challenges target transcriptional regulatory domains to alter mRNA abundance underlying the disease process. A differential response in gene expression to the stimulus could be modulated by the genotype allowing for a Gene x Environment interaction (GxE) in the initiation or progression of conditions such as ALS in which FUS is implicated. We undertook an analysis of the FUS locus to determine potential regions of genomic variation that are candidate domains to direct differential gene expression in response to environmental challenge
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