Characterization of FUS Mutations in Amyotrophic Lateral Sclerosis Using RNA-Seq
Author(s)van Blitterswijk, Marka; Wang, Eric T.; Friedman, Brad Aaron; Keagle, Pamela J.; Lowe, Patrick; Leclerc, Ashley Lyn; van den Berg, Leonard H.; Housman, David E.; Veldink, Jan H.; Landers, John E.; ... Show more Show less
MetadataShow full item record
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.
DepartmentDavid H. Koch Institute for Integrative Cancer Research at MIT; Harvard University--MIT Division of Health Sciences and Technology; Massachusetts Institute of Technology. Department of Biology
Public Library of Science
van Blitterswijk, Marka, Eric T. Wang, Brad A. Friedman, Pamela J. Keagle, Patrick Lowe, Ashley Lyn Leclerc, Leonard H. van den Berg, David E. Housman, Jan H. Veldink, and John E. Landers. Characterization of FUS Mutations in Amyotrophic Lateral Sclerosis Using RNA-Seq. Edited by Huaibin Cai. PLoS ONE 8, no. 4 (April 8, 2013): e60788.
Final published version