Exome sequencing in amyotrophic lateral sclerosis identifies risk genes and pathways

By Elizabeth T. Cirulli, Brittany N. Lasseigne, S. Petrovski, P. Sapp, P. Dion, C. Leblond, Julien Couthouis, Yi-Fan Lu, Quanli Wang, Brian J. Krueger and 61 more. Science, 2015

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New players in Lou Gehrig's disease Amyotrophic lateral sclerosis (ALS), often referred to as “Lou Gehrig's disease,” is a progressive neurodegenerative disease that affects nerve cells in the brain and the spinal cord. Cirulli et al. sequenced the expressed genes of nearly 3000 ALS patients and compared them with those of more than 6000 controls (see the Perspective by Singleton and Traynor). They identified several proteins that were linked to disease in patients. One such protein, TBK1, is implicated in innate immunity and autophagy and may represent a therapeutic target. Science, this issue p. 1436; see also p. 1422 Analysis of the expressed genes of nearly 2900 patients with amyotrophic lateral sclerosis and about 6400 controls reveals a disease predisposition–associated gene. [Also see Perspective by Singleton and Traynor] Amyotrophic lateral sclerosis (ALS) is a devastating neurological disease with no effective treatment. We report the results of a moderate-scale sequencing study aimed at increasing the number of genes known to contribute to predisposition for ALS. We performed whole-exome sequencing of 2869 ALS patients and 6405 controls. Several known ALS genes were found to be associated, and TBK1 (the gene encoding TANK-binding kinase 1) was identified as an ALS gene. TBK1 is known to bind to and phosphorylate a number of proteins involved in innate immunity and autophagy, including optineurin (OPTN) and p62 (SQSTM1/sequestosome), both of which have also been implicated in ALS. These observations reveal a key role of the autophagic pathway in ALS and suggest specific targets for therapeutic intervention.

Subfields: Epidemiology, Genetics, Neurology

View Paper: https://www.semanticscholar.org/paper/4414a1e13595c8ff7bdc861c5725836bc11d76e0

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Citations in the corpus

Deciphering the Molecular Signals of PINK1/Parkin Mitophagy. (2016, background): “Interestingly, mutations in TBK1 were also recently identified to cause ALS [53,54] while TBK1 gene duplications have been linked with glaucoma [55].”
Amyotrophic lateral sclerosis: a clinical review (2020, background): “Mutations in TBK1 are most probably the fifth most common cause of autosomal dominant ALS, responsible for about 1% of patients [28,29] but up to 10% of patients with ALS-FTD [30].”
Autophagy and Neurodegeneration: Pathogenic Mechanisms and Therapeutic Opportunities. (2017, positive): “Disruption of the ESCRT machinery through mutations in charged multivesicular body protein 2B (CHMP2B) have been associated with both ALS and Frontotemporal Dementia, a neurodegenerative disease thought to be on a spectrum with ALS.”
Molecular mechanisms and physiological functions of mitophagy (2021, positive): “Mutations in several autophagy-related proteins including optineurin, which acts downstream of PINK1/ Parkin-mediated mitophagy, have been linked to ALS (Maruyama et al , 2010; Cirulli et al , 2015).”
The Intolerance of Regulatory Sequence to Genetic Variation Predicts Gene Dosage Sensitivity (2015, background): “Another important goal of this work is to illustrate that in addition to traditional phylogenetic signatures of important noncoding sequence, we can use signatures from human standing variation to help define boundaries of noncoding sequence that when considered as a unit might show an excess of mut”