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Minor intron splicing is regulated by FUS and affected by ALS‐associated FUS mutants

Type of publication Peer-reviewed
Publikationsform Original article (peer-reviewed)
Author Reber Stefan, Stettler Jolanda, Filosa Giuseppe, Colombo Martino, Jutzi Daniel, Lenzken Silvia C, Schweingruber Christoph, Bruggmann Rémy, Bachi Angela, Barabino Silvia ML, Mühlemann Oliver, Ruepp Marc‐David,
Project Quality control of gene expression: towards understanding mechanism and physiological role of nonsense-mediated mRNA decay (NMD)
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Original article (peer-reviewed)

Journal The EMBO Journal
Volume (Issue) 35(14)
Page(s) 1504 - 1521
Title of proceedings The EMBO Journal
DOI 10.15252/embj.201593791

Open Access

Type of Open Access Publisher (Gold Open Access)


Fused in sarcoma (FUS) is a ubiquitously expressed RNA‐binding protein proposed to function in various RNA metabolic pathways, including transcription regulation, pre‐mRNA splicing, RNA transport and microRNA processing. Mutations in the FUS gene were identified in patients with amyotrophic lateral sclerosis (ALS), but the pathomechanisms by which these mutations cause ALS are not known. Here, we show that FUS interacts with the minor spliceosome constituent U11 snRNP, binds preferentially to minor introns and directly regulates their removal. Furthermore, a FUS knockout in neuroblastoma cells strongly disturbs the splicing of minor intron‐containing mRNAs, among them mRNAs required for action potential transmission and for functional spinal motor units. Moreover, an ALS‐associated FUS mutant that forms cytoplasmic aggregates inhibits splicing of minor introns by trapping U11 and U12 snRNAs in these aggregates. Collectively, our findings suggest a possible pathomechanism for ALS in which mutated FUS inhibits correct splicing of minor introns in mRNAs encoding proteins required for motor neuron survival.