UMass Chan Medical School Faculty Publications

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Department of Neurology

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Amyotrophic Lateral Sclerosis; Exons; HEK293 Cells; Humans; Introns; Mutation; RNA, Small Interfering; RNA-Binding Protein FUS; Sequence Analysis, RNA


Genetics | Nervous System Diseases


Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease resulting in severe muscle weakness and eventual death by respiratory failure. Although little is known about its pathogenesis, mutations in fused in sarcoma/translated in liposarcoma (FUS) are causative for familial ALS. FUS is a multifunctional protein that is involved in many aspects of RNA processing. To elucidate the role of FUS in ALS, we overexpressed wild-type and two mutant forms of FUS in HEK-293T cells, as well as knocked-down FUS expression. This was followed by RNA-Seq to identify genes which displayed differential expression or altered splicing patterns. Pathway analysis revealed that overexpression of wild-type FUS regulates ribosomal genes, whereas knock-down of FUS additionally affects expression of spliceosome related genes. Furthermore, cells expressing mutant FUS displayed global transcription patterns more similar to cells overexpressing wild-type FUS than to the knock-down condition. This observation suggests that FUS mutants do not contribute to the pathogenesis of ALS through a loss-of-function. Finally, our results demonstrate that the R521G and R522G mutations display differences in their influence on transcription and splicing. Taken together, these results provide additional insights into the function of FUS and how mutations contribute to the development of ALS.


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Copyright 2013 van Blitterswijk et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

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van Blitterswijk M, Wang ET, Friedman BA, Keagle PJ, Lowe P, et al. (2013) Characterization of FUS Mutations in Amyotrophic Lateral Sclerosis Using RNA-Seq. PLoS ONE 8(4): e60788. doi:10.1371/journal.pone.0060788. Link to article on publisher's site

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