SQSTM1/p62 variants in 486 patients with familial ALS from Germany and Sweden.

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.

• Authors: Rüstem Yilmaz, Kathrin Müller, David Brenner, Alexander E Volk, Guntram Borck, Andreas Hermann, Thomas Meitinger, Tim M Strom, Karin M Danzer, Albert C Ludolph, Peter M Andersen, Jochen H Weishaupt, German ALS Network MND-NET
• Journal: Neurobiology of aging (Neurobiol Aging) Vol. 87 Pg. 139.e9-139.e15 (03 2020) ISSN: 1558-1497 [Electronic] United States
• PMID: 31859009 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2019 Elsevier Inc. All rights reserved.

Chemical References

• SQSTM1 protein, human
• Sequestosome-1 Protein

Topics

• Amyotrophic Lateral Sclerosis (genetics)
• Female
• Genetic Variation
• Germany
• Humans
• Male
• Sequestosome-1 Protein (genetics)
• Sweden