Characterization of FUS Mutations in Amyotrophic Lateral Sclerosis Using RNA-Seq

Marka Van Blitterswijk, 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, John E. Landers

Research output: Contribution to journalArticle

9 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
Article numbere60788
JournalPLoS One
Volume8
Issue number4
DOIs
StatePublished - Apr 8 2013
Externally publishedYes

Fingerprint

Amyotrophic Lateral Sclerosis
Genes
RNA
Transcription
mutation
Mutation
Neurodegenerative diseases
mutants
Spliceosomes
Gene Knockdown Techniques
Liposarcoma
pathogenesis
transcription (genetics)
Muscle
spliceosomes
HEK293 Cells
Muscle Weakness
Cells
Respiratory Insufficiency
Sarcoma

ASJC Scopus subject areas

  • Agricultural and Biological Sciences(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine(all)

Cite this

Van Blitterswijk, M., Wang, E. T., Friedman, B. A., Keagle, P. J., Lowe, P., Leclerc, A. L., ... Landers, J. E. (2013). Characterization of FUS Mutations in Amyotrophic Lateral Sclerosis Using RNA-Seq. PLoS One, 8(4), [e60788]. https://doi.org/10.1371/journal.pone.0060788

Characterization of FUS Mutations in Amyotrophic Lateral Sclerosis Using RNA-Seq. / Van Blitterswijk, Marka; Wang, Eric T.; Friedman, Brad A.; Keagle, Pamela J.; Lowe, Patrick; Leclerc, Ashley Lyn; van den Berg, Leonard H.; Housman, David E.; Veldink, Jan H.; Landers, John E.

In: PLoS One, Vol. 8, No. 4, e60788, 08.04.2013.

Research output: Contribution to journalArticle

Van Blitterswijk, M, Wang, ET, Friedman, BA, Keagle, PJ, Lowe, P, Leclerc, AL, van den Berg, LH, Housman, DE, Veldink, JH & Landers, JE 2013, 'Characterization of FUS Mutations in Amyotrophic Lateral Sclerosis Using RNA-Seq', PLoS One, vol. 8, no. 4, e60788. https://doi.org/10.1371/journal.pone.0060788
Van Blitterswijk, Marka ; Wang, Eric T. ; Friedman, Brad A. ; Keagle, Pamela J. ; Lowe, Patrick ; Leclerc, Ashley Lyn ; van den Berg, Leonard H. ; Housman, David E. ; Veldink, Jan H. ; Landers, John E. / Characterization of FUS Mutations in Amyotrophic Lateral Sclerosis Using RNA-Seq. In: PLoS One. 2013 ; Vol. 8, No. 4.
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