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Association of a structural variant within the SQSTM1 gene with amyotrophic lateral sclerosis

Pytte, J., Anderton, R.S., Flynn, L.L., Theunissen, F., Jiang, L., Pitout, I., James, I., Mastaglia, F.L., Saunders, A.M., Bedlack, R., Siddique, T., Siddique, N. and Akkari, P.A. (2020) Association of a structural variant within the SQSTM1 gene with amyotrophic lateral sclerosis. Neurology Genetics, 6 (2). Art. e406.

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Objective As 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).

Methods A 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.

Results A 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).

Conclusions This disease association highlights the importance and implications of further investigation into SVs that may provide new targets for cohort stratification and therapeutic development.

Item Type: Journal Article
Murdoch Affiliation(s): Centre for Molecular Medicine and Innovative Therapeutics
Institute for Immunology and Infectious Diseases
Publisher: Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology
Copyright: © 2020 American Academy of Neurology
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