title: An evaluation of a SVA retrotransposon in the FUS promoter as a transcriptional regulator and its association to ALS.
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.
authors.affiliation: Department of Molecular and Clinical Pharmacology, Institute of Translational Medicine, The University of Liverpool, Liverpool, United Kingdom.
authors.forename: Abigail L
authors.initials: AL
authors.lastname: Savage
authors.affiliation: Department of Molecular and Clinical Pharmacology, Institute of Translational Medicine, The University of Liverpool, Liverpool, United Kingdom.
authors.forename: Thomas P
authors.initials: TP
authors.lastname: Wilm
authors.forename: Kejhal
authors.initials: K
authors.lastname: Khursheed
authors.affiliation: Clinical Neuroscience, Institute of Psychiatry, King's College London, London, United Kingdom.
authors.forename: Aleksey
authors.initials: A
authors.lastname: Shatunov
authors.affiliation: School of Clinical and Experimental Medicine, College of Medicine and Dentistry, University of Birmingham, Birmingham, United Kingdom; and Neurosciences Division, University Hospital Birmingham NHS Foundation Trust, Birmingham, West Midlands, United Kingdom.
authors.forename: Karen E
authors.initials: KE
authors.lastname: Morrison
authors.affiliation: Academic Unit of Neurology, Department of Neuroscience, Sheffield Institute for Translational Research, University of Sheffield, Sheffield, South Yorkshire, United Kingdom.
authors.forename: Pamela J
authors.initials: PJ
authors.lastname: Shaw
authors.affiliation: Clinical Neuroscience, Institute of Psychiatry, King's College London, London, United Kingdom.
authors.forename: Christopher E
authors.initials: CE
authors.lastname: Shaw
authors.affiliation: Clinical Neuroscience, Institute of Psychiatry, King's College London, London, United Kingdom.
authors.forename: Bradley
authors.initials: B
authors.lastname: Smith
authors.affiliation: MRC Social Genetic and Developmental Psychiatry Research Centre, Institute of Psychiatry, King's College London, London, United Kingdom; National Institute for Health Research Biomedical Research, Centre for Mental Health, South London, United Kingdom; and Maudsley NHS Foundation Trust and Institute of Psychiatry, King's College London, London, United Kingdom.
authors.forename: Gerome
authors.initials: G
authors.lastname: Breen
authors.affiliation: Clinical Neuroscience, Institute of Psychiatry, King's College London, London, United Kingdom.
authors.forename: Ammar
authors.initials: A
authors.lastname: Al-Chalabi
authors.affiliation: Department of Cellular and Molecular Physiology, Institute of Translational Medicine, The University of Liverpool, Liverpool, United Kingdom.
authors.forename: Diana
authors.initials: D
authors.lastname: Moss
authors.affiliation: Department of Molecular and Clinical Pharmacology, Institute of Translational Medicine, The University of Liverpool, Liverpool, United Kingdom.
authors.forename: Vivien J
authors.initials: VJ
authors.lastname: Bubb
authors.affiliation: Department of Molecular and Clinical Pharmacology, Institute of Translational Medicine, The University of Liverpool, Liverpool, United Kingdom.
authors.forename: John P
authors.initials: JP
authors.lastname: Quinn
mesh_terms: D000690:Amyotrophic Lateral Sclerosis / Q000235:genetics*; D000818:Animals; D001483:Base Sequence; D016022:Case-Control Studies; D045744:Cell Line, Tumor; D002642:Chick Embryo; D056726:Genetic Association Studies; D006801:Humans; D018598:Minisatellite Repeats; D011401:Promoter Regions, Genetic; D034702:RNA-Binding Protein FUS / Q000235:genetics*; D050436:Regulatory Elements, Transcriptional; D018626:Retroelements; D017422:Sequence Analysis, DNA; D014158:Transcription, Genetic
chemical_list: D034702:RNA-Binding Protein FUS; D018626:Retroelements