Spliceosomal protein eftud2 mutation leads to p53-dependent apoptosis in zebrafish neural progenitors

Nucleic Acids Res. 2017 Apr 7;45(6):3422-3436. doi: 10.1093/nar/gkw1043.


Haploinsufficiency of EFTUD2 (Elongation Factor Tu GTP Binding Domain Containing 2) is linked to human mandibulofacial dysostosis, Guion-Almeida type (MFDGA), but the underlying cellular and molecular mechanisms remain to be addressed. We report here the isolation, cloning and functional analysis of the mutated eftud2 (snu114) in a novel neuronal mutant fn10a in zebrafish. This mutant displayed abnormal brain development with evident neuronal apoptosis while the development of other organs appeared less affected. Positional cloning revealed a nonsense mutation such that the mutant eftud2 mRNA encoded a truncated Eftud2 protein and was subjected to nonsense-mediated decay. Disruption of eftud2 led to increased apoptosis and mitosis of neural progenitors while it had little effect on differentiated neurons. Further RNA-seq and functional analyses revealed a transcriptome-wide RNA splicing deficiency and a large amount of intron-retaining and exon-skipping transcripts, which resulted in inadequate nonsense-mediated RNA decay and activation of the p53 pathway in fn10a mutants. Therefore, our study has established that eftud2 functions in RNA splicing during neural development and provides a suitable zebrafish model for studying the molecular pathology of the neurological disease MFDGA.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis*
  • Brain / abnormalities
  • Cloning, Molecular
  • Exons
  • Introns
  • Mutation
  • Neural Stem Cells / cytology*
  • Neurogenesis / genetics*
  • Neurons / cytology
  • Nonsense Mediated mRNA Decay
  • Peptide Elongation Factors / genetics*
  • RNA Splicing
  • RNA Splicing Factors / genetics*
  • Spinal Cord / abnormalities
  • Transcriptome
  • Tumor Suppressor Protein p53 / metabolism
  • Zebrafish / genetics
  • Zebrafish / growth & development
  • Zebrafish Proteins / genetics*
  • Zebrafish Proteins / metabolism


  • Eftud2 protein, zebrafish
  • Peptide Elongation Factors
  • RNA Splicing Factors
  • Tumor Suppressor Protein p53
  • Zebrafish Proteins
  • tp53 protein, zebrafish