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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 ( s hort stature,  h earing loss,  r etinitis pigmentosa, and distinctive  f acies). 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.

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