Journal article
Association of a structural variant within the SQSTM1 gene with amyotrophic lateral sclerosis
Neurology Genetics, Vol.6(2), Art. e406
2020
Abstract
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.
Details
- Title
- Association of a structural variant within the SQSTM1 gene with amyotrophic lateral sclerosis
- Authors/Creators
- J. Pytte (Author/Creator) - Centre for Neuromuscular & Neurological DisordersR.S. Anderton (Author/Creator) - School of Health SciencesL.L. Flynn (Author/Creator) - Murdoch UniversityF. Theunissen (Author/Creator) - Centre for Neuromuscular & Neurological DisordersL. Jiang (Author/Creator) - Centre for Neuromuscular & Neurological DisordersI. Pitout (Author/Creator) - Murdoch UniversityI. James (Author/Creator) - Murdoch UniversityF.L. Mastaglia (Author/Creator) - Centre for Neuromuscular & Neurological DisordersA.M. Saunders (Author/Creator) - Zinfandel Pharmaceuticals, IncR. Bedlack (Author/Creator) - Duke UniversityT. Siddique (Author/Creator) - Northwestern UniversityN. Siddique (Author/Creator) - Northwestern UniversityP.A. Akkari (Author/Creator)
- Publication Details
- Neurology Genetics, Vol.6(2), Art. e406
- Publisher
- Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology
- Identifiers
- 991005541020607891
- Copyright
- © 2020 American Academy of Neurology
- Murdoch Affiliation
- Centre for Molecular Medicine and Innovative Therapeutics; Institute for Immunology and Infectious Diseases
- Language
- English
- Resource Type
- Journal article
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- Collaboration types
- Domestic collaboration
- International collaboration
- Citation topics
- 1 Clinical & Life Sciences
- 1.52 Neurodegenerative Diseases
- 1.52.765 ALS Mechanisms
- Web Of Science research areas
- Clinical Neurology
- Genetics & Heredity
- ESI research areas
- Neuroscience & Behavior