A budding yeast model for human disease mutations in the EXOSC2 cap subunit of the RNA exosome complex

RNA. 2021 Sep;27(9):1046-1067. doi: 10.1261/rna.078618.120. Epub 2021 Jun 23.


RNA exosomopathies, a growing family of diseases, are linked to missense mutations in genes encoding structural subunits of the evolutionarily conserved, 10-subunit exoribonuclease complex, the RNA exosome. This complex consists of a three-subunit cap, a six-subunit, barrel-shaped core, and a catalytic base subunit. While a number of mutations in RNA exosome genes cause pontocerebellar hypoplasia, mutations in the cap subunit gene EXOSC2 cause an apparently distinct clinical presentation that has been defined as a novel syndrome SHRF (short stature, hearing loss, retinitis pigmentosa, and distinctive facies). We generated the first in vivo model of the SHRF pathogenic amino acid substitutions using budding yeast by modeling pathogenic EXOSC2 missense mutations (p.Gly30Val and p.Gly198Asp) in the orthologous S. cerevisiae gene RRP4 The resulting rrp4 mutant cells show defects in cell growth and RNA exosome function. Consistent with altered RNA exosome function, we detect significant transcriptomic changes in both coding and noncoding RNAs in rrp4-G226D cells that model EXOSC2 p.Gly198Asp, suggesting defects in nuclear surveillance. Biochemical and genetic analyses suggest that the Rrp4 G226D variant subunit shows impaired interactions with key RNA exosome cofactors that modulate the function of the complex. These results provide the first in vivo evidence that pathogenic missense mutations present in EXOSC2 impair the function of the RNA exosome. This study also sets the stage to compare exosomopathy models to understand how defects in RNA exosome function underlie distinct pathologies.

Keywords: EXOSC2; RNA decay/processing; RNA exosome; Rrp4; exosomopathy.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, N.I.H., Intramural
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Amino Acid Sequence
  • Amino Acid Substitution
  • Aspartic Acid / chemistry
  • Aspartic Acid / metabolism
  • Dwarfism / enzymology
  • Dwarfism / genetics
  • Dwarfism / pathology
  • Exoribonucleases / chemistry
  • Exoribonucleases / genetics*
  • Exoribonucleases / metabolism
  • Exosome Multienzyme Ribonuclease Complex / chemistry
  • Exosome Multienzyme Ribonuclease Complex / genetics*
  • Exosome Multienzyme Ribonuclease Complex / metabolism
  • Facies
  • Gene Expression
  • Glycine / chemistry
  • Glycine / metabolism
  • Hearing Loss / enzymology
  • Hearing Loss / genetics
  • Hearing Loss / pathology
  • Humans
  • Models, Biological
  • Models, Molecular
  • Mutation, Missense*
  • Protein Conformation
  • RNA, Fungal / chemistry
  • RNA, Fungal / genetics*
  • RNA, Fungal / metabolism
  • RNA-Binding Proteins / chemistry
  • RNA-Binding Proteins / genetics*
  • RNA-Binding Proteins / metabolism
  • Retinitis Pigmentosa / enzymology
  • Retinitis Pigmentosa / genetics
  • Retinitis Pigmentosa / pathology
  • Saccharomyces cerevisiae / enzymology
  • Saccharomyces cerevisiae / genetics*
  • Saccharomyces cerevisiae Proteins / chemistry
  • Saccharomyces cerevisiae Proteins / genetics*
  • Saccharomyces cerevisiae Proteins / metabolism
  • Sequence Homology, Amino Acid
  • Syndrome


  • EXOSC2 protein, human
  • RNA, Fungal
  • RNA-Binding Proteins
  • RRP4 protein, S cerevisiae
  • Saccharomyces cerevisiae Proteins
  • Aspartic Acid
  • Exoribonucleases
  • Exosome Multienzyme Ribonuclease Complex
  • Glycine