Genome wide array analysis indicates that an amyotrophic lateral sclerosis mutation of FUS causes an early increase of CAMK2N2 in vitro

Paolo Convertini, Jiayu Zhang, Pierre de la Grange, Lawrence J. Hayward, Haining Zhu, Stefan Stamm

Research output: Contribution to journalArticlepeer-review

6 Scopus citations

Abstract

Mutations in the RNA binding protein FUS (fused in sarcoma) have been linked to a subset of familial amyotrophic lateral sclerosis (ALS) cases. The mutations are clustered in the C-terminal nuclear localization sequence (NLS). Various FUS mutants accumulate in the cytoplasm whereas wild-type (WT) FUS is mainly nuclear. Here we investigate the effect of one ALS causing mutant (FUS-δNLS, also known as R495X) on pre-mRNA splicing and RNA expression using genome wide exon-junction arrays. Using a non-neuronal stable cell line with inducible FUS expression, we detected early changes in RNA composition. In particular, mutant FUS-δNLS increased calcium/calmodulin-dependent protein kinase II inhibitor 2 (CAMK2N2) at both mRNA and protein levels, whereas WT-FUS had no effect. Chromatin immunoprecipitation experiments showed that FUS-δNLS accumulated at the CAMK2N2 promoter region, whereas promoter occupation by WT-FUS remained constant. Given the loss of FUS-δNLS in the nucleus through the mutation-induced translocation, this increase of promoter occupancy is surprising. It indicates that, despite the obvious cytoplasmic accumulation, FUS-δNLS can act through a nuclear gain of function mechanism.

Original languageEnglish (US)
Pages (from-to)1129-1135
Number of pages7
JournalBiochimica et Biophysica Acta - Molecular Basis of Disease
Volume1832
Issue number8
DOIs
StatePublished - 2013
Externally publishedYes

Keywords

  • ALS
  • Amyotrophic lateral sclerosis
  • Array analysis
  • FUS
  • Fused in sarcoma

ASJC Scopus subject areas

  • Molecular Medicine
  • Molecular Biology

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