Identification of a FUS splicing mutation in a large family with amyotrophic lateral sclerosis

Center of Excellence in Neuromics of Université de Montréal, CHUM Research Center, Montreal, Quebec, Canada.
Journal of Human Genetics (Impact Factor: 2.46). 12/2010; 56(3):247-9. DOI: 10.1038/jhg.2010.162
Source: PubMed


Amyotrophic lateral sclerosis (ALS) is a severe neurodegenerative disease characterized by the degeneration of upper and lower motor neurons. Genetic studies have led, thus far, to the identification of 12 loci and 9 genes for familial ALS (FALS). Although the distribution and impact of superoxide dismutase 1 mutations has been extensively examined for over a decade, the recently identified FALS-associated FUS gene has been less studied. Therefore, we set out to screen our collection of FALS cases for FUS mutations. All 15 exons of FUS were amplified and sequenced in 154 unrelated FALS cases and 475 ethnically matched healthy individuals. One substitution located in the acceptor splice site of intron 14 was identified in all affected members of a large family, causing the skipping of the last 13 amino acids of the protein and the translation of 7 novel amino acids, resulting from the new translation of a part of the 3' untranslated region. Our study identified a new splicing mutation in the highly conserved C-terminal of the FUS protein. Thus far most FUS mutations are missenses, and our findings, combined with those of others, confirm the importance of the C-terminal portion of the protein, adding additional support for FUS mutations having a critical role in ALS.

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Available from: Hussein Daoud, Apr 08, 2014
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    • "None USA [Kwiatkowski et al., 2009] 48 c.1554 1557delACAG p.R518del Exon 15/RGG rich 1 Spinal None United Kingdom [Bäumer et al., 2010] 49 c.1555 C>T p.Q519X Exon 15/RGG rich 1 n.a. None France [Belzil et al., 2011] "
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    ABSTRACT: Mutations in the TAR DNA Binding Protein gene (TARDBP), encoding the protein TDP-43, were identified in amyotrophic lateral sclerosis (ALS) patients. Interestingly, TDP-43 positive inclusion bodies were first discovered in ubiquitin-positive, tau negative ALS and frontotemporal dementia (FTD) inclusion bodies, and subsequently observed in the majority of neurodegenerative disorders. To date, 47 missense and one truncating mutations have been described in a large number of familial (FALS) and sporadic (SALS) patients. Fused in Sarcoma (FUS) was found to be responsible for a previously identified ALS6 locus, being mutated in both FALS and SALS patients. TARDBP and FUS have a structural and functional similarity and most of mutations in both genes are also clustered in the C-terminus of the proteins. The molecular mechanisms through which mutant TDP-43 and FUS may cause motor neuron degeneration are not well understood. Both proteins play an important role in mRNA transport, axonal maintenance and motor neuron development. Functional characterization of these mutations in in vitro and in vivo systems is helping to better understand how motor neuron degeneration occurs. This report summarizes the biological and clinical relevance of TARDBP and FUS mutations in ALS. All the data reviewed here has been submitted to a database based on the Leiden Open (source) Variation Database(LOVD) and is accessible online at,
    Full-text · Article · Jun 2013 · Human Mutation
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    • "These transgenes included: (i) full-length (FL) WT human FUS (WT-FUS); (ii) four different missense mutations associated with varying clinical severity (as defined by age at onset and by disease duration) of human ALS (R514G and R521G = mild; R522G = moderate and P525L = severe) (1–3) (Supplementary Material, Table S1) and (iii) two different C-terminal-truncated FUS constructs (FUS513 and FUS501—lacking the C-terminal 13 and 25 amino acids of FUS, respectively). While the C-terminal-truncated constructs are artificial, they are very similar to several human C-terminal splicing/frame-shifting truncation mutations that are also associated with severe ALS phenotypes (15,16). Each construct was cloned into a vector containing a C. elegans pan-neuronal promoter Prgef-1and an in-frame green fluorescent protein (GFP S65T) or red fluorescent protein (TagRFP) at the N-terminus. "
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    ABSTRACT: It is unclear whether mutations in fused in sarcoma (FUS) cause familial amyotrophic lateral sclerosis via a loss-of-function effect due to titrating FUS from the nucleus or a gain-of-function effect from cytoplasmic overabundance. To investigate this question, we generated a series of independent Caenorhabditis elegans lines expressing mutant or wild-type (WT) human FUS. We show that mutant FUS, but not WT-FUS, causes cytoplasmic mislocalization associated with progressive motor dysfunction and reduced lifespan. The severity of the mutant phenotype in C. elegans was directly correlated with the severity of the illness caused by the same mutation in humans, arguing that this model closely replicates key features of the human illness. Importantly, the mutant phenotype could not be rescued by overexpression of WT-FUS, even though WT-FUS had physiological intracellular localization, and was not recruited to the cytoplasmic mutant FUS aggregates. Our data suggest that FUS mutants cause neuronal dysfunction by a dominant gain-of-function effect related either to neurotoxic aggregates of mutant FUS in the cytoplasm or to dysfunction in its RNA-binding functions.
    Full-text · Article · Sep 2011 · Human Molecular Genetics
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    ABSTRACT: The recent identification of ALS-linked mutations in FUS and TDP-43 has led to a major shift in our thinking in regard to the potential molecular mechanisms of amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD). RNA-mediated proteinopathy is increasingly being recognized as a potential cause of neurodegenerative disorders. FUS and TDP-43 are structurally and functionally similar proteins. FUS is a DNA/RNA binding protein that may regulate aspects of RNA metabolism, including splicing, mRNA processing, and micro RNA biogenesis. It is unclear how ALS-linked mutations perturb the functions of FUS. This review highlights recent advances in understanding the functions of FUS and discusses findings from FUS animal models that provide several key insights into understanding the molecular mechanisms that might contribute to ALS pathogenesis.
    Full-text · Article · Jan 2012 · Brain research
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