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

Julia Pytte, Ryan S. Anderton, Loren L. Flynn, Frances Theunissen, Leanne Jiang, Ianthe Pitout, Ian James, Frank L. Mastaglia, Ann M. Saunders, Richard Bedlack, Teepu Siddique, Nailah Siddique, P. Anthony Akkari

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
Article numbere406
JournalNeurology: Genetics
Volume6
Issue number2
DOIs
StatePublished - 2020

ASJC Scopus subject areas

  • Clinical Neurology
  • Genetics(clinical)

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    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., & Akkari, P. A. (2020). Association of a structural variant within the SQSTM1 gene with amyotrophic lateral sclerosis. Neurology: Genetics, 6(2), [e406]. https://doi.org/10.1212/NXG.0000000000000406