UMMS Affiliation

Department of Microbiology and Physiological Systems

Publication Date


Document Type



Amino Acids, Peptides, and Proteins | Biochemistry, Biophysics, and Structural Biology | Congenital, Hereditary, and Neonatal Diseases and Abnormalities | Nucleic Acids, Nucleotides, and Nucleosides


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.


EXOSC2, RNA decay/processing, RNA exosome, Rrp4, exosomopathy

Rights and Permissions

© 2021 Sterrett et al.; Published by Cold Spring Harbor Laboratory Press for the RNA Society. This article, published in RNA, is available under a Creative Commons License (Attribution 4.0 International), as described at

DOI of Published Version



Sterrett MC, Enyenihi L, Leung SW, Hess L, Strassler SE, Farchi D, Lee RS, Withers ES, Kremsky I, Baker RE, Basrai MA, van Hoof A, Fasken MB, Corbett AH. 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. PMID: 34162742; PMCID: PMC8370739. Link to article on publisher's site

Journal/Book/Conference Title

RNA (New York, N.Y.)

Related Resources

Link to Article in PubMed

PubMed ID


Creative Commons License

Creative Commons Attribution 4.0 License
This work is licensed under a Creative Commons Attribution 4.0 License.