Mutations in FUS, an RNA Processing Protein, Cause Familial Amyotrophic Lateral Sclerosis Type 6

By C. Vance, B. Rogelj, T. Hortobágyi, K. D. Vos, A. Nishimura, J. Sreedharan, Xun Hu, Bradley N. Smith, D. Ruddy, Paul Wright and 12 more. Science, 2009

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Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease that is familial in 10% of cases. We have identified a missense mutation in the gene encoding fused in sarcoma (FUS) in a British kindred, linked to ALS6. In a survey of 197 familial ALS index cases, we identified two further missense mutations in eight families. Postmortem analysis of three cases with FUS mutations showed FUS-immunoreactive cytoplasmic inclusions and predominantly lower motor neuron degeneration. Cellular expression studies revealed aberrant localization of mutant FUS protein. FUS is involved in the regulation of transcription and RNA splicing and transport, and it has functional homology to another ALS gene, TARDBP, which suggests that a common mechanism may underlie motor neuron degeneration.

Subfields: Genetics, Molecular Biology, Neurology

View Paper: https://www.semanticscholar.org/paper/f34d623e887b9eab138a9c23bc3c837c4733db8a

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Citations in the corpus

A Liquid-to-Solid Phase Transition of the ALS Protein FUS Accelerated by Disease Mutation. (2015, positive): “Mutations in the NLS increase the cytosolic fraction of FUS (Kwiatkowski et al., 2009; Vance et al., 2009).”
Cell-free formation of RNA granules: bound RNAs identify features and components of cellular assemblies. (2012, background): “There is no question that these LCdomains can enter into irreversible fibrous aggregates, just as happens with the LC domains housed within many gene products associated with neurodegenerative disease (Koyano et al., 1999; Kwiatkowski et al., 2009; Neumann et al., 2006; Vance et al., 2009).”
Microglia in neurodegenerative diseases: mechanism and potential therapeutic targets (2023, background): “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 lower frequency (<5%).(307) Postmortem studies and in vivo Microglia in neuro”
Oxidative stress in ALS: key role in motor neuron injury and therapeutic target. (2010, background): “pathogenesis of ALS, with the discovery of mutations in two genes with RNA/DNA-binding functions, TDP-43 [11,12] and FUS/TLS [9,10],”
Long pre-mRNA depletion and RNA missplicing contribute to neuronal vulnerability from loss of TDP-43 (2011, background): “Approximately 70% (11,852) of annotated proteincoding genes in mouse satisfied at least 1 RPKM in either condition.”