Abstract
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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Acknowledgements
VVB, HD and GAR are supported by the Canadian Institutes of Health Research. We would like to thank the patients involved in this study; Mélanie Benard, Isabelle Thibault and Pierre Provencher for sample collection and organization; Anne Noreau, Cynthia Bourassa, Sophie Massart and Bertrand Boutié for technical support; and to acknowledge support from the Association pour la Recherche sur la Sclérose Latérale Amyotrophique (ARS), the Association Française contre les Myopathies (AFM) and the French Group on MND.
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Belzil, V., St-Onge, J., Daoud, H. et al. Identification of a FUS splicing mutation in a large family with amyotrophic lateral sclerosis. J Hum Genet 56, 247–249 (2011). https://doi.org/10.1038/jhg.2010.162
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DOI: https://doi.org/10.1038/jhg.2010.162
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