1. SQSTM1/p62 variants in 486 patients with familial ALS from Germany and Sweden.
- Author
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Yilmaz, Rüstem, Müller, Kathrin, Brenner, David, Volk, Alexander E., Borck, Guntram, Hermann, Andreas, Meitinger, Thomas, Strom, Tim M., Danzer, Karin M., Ludolph, Albert C., Andersen, Peter M., and Weishaupt, Jochen H.
- Subjects
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AMYOTROPHIC lateral sclerosis , *PROTEOLYSIS , *MOTOR neuron diseases - Abstract
Several studies reported amyotrophic lateral sclerosis (ALS)-linked mutations in TBK1 , OPTN , VCP , UBQLN2 , and SQSTM1 genes encoding proteins involved in autophagy. SQSTM1 was originally identified by a candidate gene approach because it encodes p62, a multifunctional protein involved in protein degradation both through proteasomal regulation and autophagy. Both p62 and optineurin (encoded by OPTN) are direct interaction partners and substrates of TBK1, and these 3 proteins form the core of a genetic and functional network that may connect autophagy with ALS. Considering the molecular and conceptual relevance of the TBK1 / OPTN / SQSTM1 "triangle," we here performed a targeted screen for SQSTM1 variants in 486 patients with familial ALS from Germany and Sweden by analyzing whole-exome sequencing data. We report 9 novel and 5 previously reported rare variants in SQSTM1 and discuss the current evidence for SQSTM1 as a primary disease gene for ALS. We conclude that the evidence for causality remains vague for SQSTM1 and is weaker than for the other autophagy genes, for example, TBK1 and OPTN. • Fourteen rare variants were found in SQSTM1 in our familial ALS patient cohort. • Nine variants were novel, whereas 5 were previously reported. • The variant c.98C>T (p.Ala33Val) did not cosegregate with the disease. • Rare SQSTM1 variants were not enriched in patients in comparison to the controls. [ABSTRACT FROM AUTHOR]
- Published
- 2020
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