Exosomopathies are a collection of rare diseases caused by mutations in genes that encode structural subunits of the RNA exosome complex. The RNA exosome is critical for both processing and degrading many RNA targets. Mutations in individual RNA exosome subunit genes (termed EXOSC genes) are linked to a variety of distinct diseases. These exosomopathies do not arise from homozygous loss-of-function or large deletions in the EXOSC genes likely because some level of RNA exosome activity is essential for viability. Thus, all patients described so far have at least one allele with a missense mutation encoding an RNA exosome subunit with a single pathogenic amino acid change linked to disease. Understanding how these changes lead to the disparate clinical presentations that have been reported for this class of diseases necessitates investigation of how individual pathogenic missense variants alter RNA exosome function. Such studies will require access to patient samples, a challenge for these very rare diseases, coupled with modeling the patient variants. Here, we highlight five recent studies that model pathogenic variants in EXOSC3, EXOSC2, and EXOSC5.

© 2020 by Julia de Amorim, et al. This work is licensed under a Creative Commons Attribution 4.0 International License. Received June 02, 2020. We thank our collaborators including Ambro van Hoof and the researchers who have performed the studies highlighted here. Members of the Corbett laboratory provided invaluable feedback. This work was supported by both a National Institutes of Health F32 grant (GM125350) and a Postdoctoral Enrichment Award from the Burroughs Wellcome Fund to D.J.M., a National Institutes of Health R01 grant (MH107305) to A.H.C., a National Institutes of Health R01 grant (GM130147) to A.v.H. and A.H.C, and a National Institutes of Health grant (U01HG009599) to A.S. J.L.A. was supported by a diversity supplement to National Institutes of Health R01 grant (GM130147). D.J.M. was also supported by the Emory University National Institutes of Health Institutional Research and Academic Career Development Award (IRACDA) (GM000680) Fellowships in Research and Science Teaching (FIRST) Postdoctoral Fellowship. The authors have declared that no conflict of interest exists.

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