State of play in amyotrophic lateral sclerosis genetics

By A. Renton, A. Chiò, B. Traynor. Nature Neuroscience, 2013

1,511 citations recorded by the source corpus.

Considerable progress has been made in unraveling the genetic etiology of amyotrophic lateral sclerosis (ALS), the most common form of adult-onset motor neuron disease and the third most common neurodegenerative disease overall. Here we review genes implicated in the pathogenesis of motor neuron degeneration and how this new information is changing the way we think about this fatal disorder. Specifically, we summarize current literature of the major genes underlying ALS, SOD1, TARDBP, FUS, OPTN, VCP, UBQLN2, C9ORF72 and PFN1, and evaluate the information being gleaned from genome-wide association studies. We also outline emerging themes in ALS research, such as next-generation sequencing approaches to identify de novo mutations, the genetic convergence of familial and sporadic ALS, the proposed oligogenic basis for the disease, and how each new genetic discovery is broadening the phenotype associated with the clinical entity we know as ALS.

Subfields: Genetics, Neurology

View Paper: https://www.semanticscholar.org/paper/e4f72be38aa9c763aaf9fa1a5f524557f4b45d35

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Citations in the corpus

Evaluating drug targets through human loss-of-function genetic variation (2019, positive): “1 in 360,000 SOD1 SOD1 mutations are believed to account for ~12% to 24% of familial ALS 68,69 and 1% of sporadic ALS 68,70 .”
Microglia in neurodegenerative diseases: mechanism and potential therapeutic targets (2023, background): “Mutation in C9orf72 accounts for 40% of familial ALS and FTD cases.(303,304) Mutations in the SOD1 gene (encoding superoxide dismutase 1) occur in ~20% of cases,(305) while mutations in TARDBP (encoding TAR DNA- binding protein 43 [TDP43])(306) and FUS (encoding the fused in sarcoma protein) have a ”
Exome sequencing in amyotrophic lateral sclerosis identifies risk genes and pathways (2015, positive): “Approximately 10% of ALS cases are familial and inherited in an autosomal dominant, autosomal recessive, or Xlinked mode, while the remaining cases are apparently sporadic (2, 3).”
13 reasons why the brain is susceptible to oxidative stress (2018, background): “CuZnSOD causes neurodegeneration is incompletely understood [234,235] but may relate to a toxic gain of function involving protein aggregates,”
Guidelines for the use and interpretation of assays for monitoring autophagy (3rd edition) (2012, positive): “Further evidence comes from the observations that the crucial mitophagy regulators PINK1 and PARK2 show loss-of-function mutations in autosomal recessive juvenile parkinsonism,(1010) and that the putative ribophagy regulator VCP/p97 (an ortholog of yeast Cdc48) as well as the autophagy receptor OPTN”
Molecular Mechanisms of TDP-43 Misfolding and Pathology in Amyotrophic Lateral Sclerosis (2019, background): “While the majority of the ALS cases (∼90–95%) are considered as sporadic (sALS) with unknown cause, ∼5–10% cases involve Mendelian pattern of inheritance of familial gene mutations and are known as familial ALS (fALS) (Renton et al., 2014; Taylor et al., 2016).”