No abstract

ObjectiveAs structural variations may underpin susceptibility to complex neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS), the objective of this study was to investigate a structural variant (SV) within sequestosome 1 (SQSTM1). MethodsA candidate insertion/deletion variant within intron 5 of the SQSTM1 gene was identified using a previously established SV evaluation algorithm and chosen according to its subsequent theoretical effect on gene expression. The variant was systematically assessed through PCR, polyacrylamide gel fractionation, Sanger sequencing, and reverse transcriptase PCR. ResultsA reliable and robust assay confirmed the polymorphic nature of this variant and that the variant may influence SQSTM1 transcript levels. In a North American cohort of patients with familial ALS (fALS) and sporadic ALS (sALS) (n = 403) and age-matched healthy controls (n = 562), we subsequently showed that the SQSTM1 variant is associated with fALS (p = 0.0036), particularly in familial superoxide dismutase 1 mutation positive patients (p = 0.0005), but not with patients with sALS (p = 0.97). ConclusionsThis disease association highlights the importance and implications of further investigation into SVs that may provide new targets for cohort stratification and therapeutic development. sclerosis gene with amyotrophic lateral SQSTM1 Association of a structural variant within theThis information is current as of February 27, 2020 Services Updated Information & http://ng.neurology.org/content/6/2/e406.full.html including high resolution figures, can be found at: References http://ng.neurology.org/content/6/2/e406.full.html##ref-list-1 This article cites 38 articles, 4 of which you can access for free at: Subspecialty Collections http://ng.neurology.org//cgi/collection/association_studies_in_genetics Association studies in genetics http://ng.neurology.org//cgi/collection/amyotrophic_lateral_sclerosis_ Amyotrophic lateral sclerosis http://ng.neurology.org//cgi/collection/all_neuromuscular_disease All Neuromuscular Disease http://ng.neurology.org//cgi/collection/all_genetics All Genetics following collection(s): This article, along with others on similar topics, appears in the Permissions & Licensing http://ng.neurology.org/misc/about.xhtml#permissions its entirety can be found online at: Information about reproducing this article in parts (figures,tables) or in Reprints http://ng.neurology.org/misc/addir.xhtml#reprintsus Information about ordering reprints can be found online: reserved. Online