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

被引:10
|
作者
Pytte, Julia [1 ,2 ]
Anderton, Ryan S. [1 ,2 ,3 ,4 ]
Flynn, Loren [1 ,2 ,5 ]
Theunissen, Frances [1 ,2 ]
Jiang, Leanne [2 ]
Pitout, Ianthe [2 ,5 ]
James, Ian [6 ]
Mastaglia, Frank L. [1 ,2 ]
Saunders, Ann M. [8 ]
Bedlack, Richard [7 ,9 ]
Siddique, Teepu [10 ,11 ,12 ,13 ]
Siddique, Nailah [10 ,11 ,12 ,13 ]
Akkari, P. Anthony [1 ,2 ,5 ]
机构
[1] Univ Western Australia, Ctr Neuromuscular & Neurol Disorders, Crawley, Australia
[2] Perron Inst Neurol & Translat Sci, Nedlands, WA, Australia
[3] Univ Notre Dame Australia, Sch Hlth Sci, Fremantle, WA, Australia
[4] Univ Notre Dame Australia, Inst Hlth Res, Fremantle, WA, Australia
[5] Murdoch Univ, Ctr Mol Med & Innovat Therapeut, Murdoch, WA, Australia
[6] Murdoch Univ, Inst Immunol & Infect Dis, Murdoch, WA, Australia
[7] Duke Univ, Sch Med, Dept Neurol, Durham, NC USA
[8] Zinfandel Pharmaceut Inc, Durham, NC USA
[9] Duke Univ, ALS Clin, Durham, NC USA
[10] Northwestern Univ, Feinberg Sch Med, Les Turner ALS Ctr, Dept Neurol, Chicago, IL 60611 USA
[11] Northwestern Univ, Feinberg Sch Med, Les Turner ALS Ctr, Dept Pathol, Chicago, IL 60611 USA
[12] Northwestern Univ, Feinberg Sch Med, Les Turner ALS Ctr, Dept Cell & Mol Biol, Chicago, IL 60611 USA
[13] Northwestern Univ, Interdept Neurosci Program, Chicago, IL 60611 USA
关键词
UBIQUITIN-LIKE PROTEINS; ALZHEIMERS-DISEASE; HEXANUCLEOTIDE REPEAT; MUTATIONS; ALS; AUTOPHAGY; C9ORF72; EXPANSION; TOMM40; LINKS;
D O I
10.1212/NXG.0000000000000406
中图分类号
Q3 [遗传学];
学科分类号
071007 ; 090102 ;
摘要
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.
引用
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页数:7
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