The RNA exosome is an essential ribonuclease complex involved in the processing and degradation of both coding and noncoding RNAs. We present three patients with biallelic variants in EXOSC5, which encodes a structural subunit of the RNA exosome. The common clinical features of these patients comprise failure to thrive, short stature, feeding difficulties, developmental delays that affect motor skills, hypotonia and esotropia. Brain MRI revealed cerebellar hypoplasia and ventriculomegaly. The first patient had a deletion involving exons 5-6 of EXOSC5 and a missense variant, p.Thr114Ile, that were inherited in trans, the second patient was homozygous for p.Leu206His, and the third patient had paternal isodisomy for chromosome 19 and was homozygous for p.Met148Thr. We employed three complementary approaches to explore the requirement for EXOSC5 in brain development and assess the functional consequences of pathogenic variants in EXOSC5. Loss of function for the zebrafish ortholog results in shortened and curved tails and bodies, reduced eye and head size and edema. We modeled pathogenic EXOSC5 variants in both budding yeast and mammalian cells. Some of these variants show defects in RNA exosome function as well as altered interactions with other RNA exosome subunits. Overall, these findings expand the number of genes encoding RNA exosome components that have been implicated in human disease, while also suggesting that disease mechanism varies depending on the specific pathogenic variant.
IntroductionThe RNA exosome is a ribonuclease complex composed of ten, evolutionarily conserved subunits that form a ring-like structure with 3'-5' exonuclease activity that is critical for the processing and degradation of a variety of RNAs both in the nucleus and cytoplasm (1-3). The exosome subunits are designated as exosome component (EXOSC) proteins in humans, mice (M. musculus) and other mammals and ribosomal RNA processing (Rrp) proteins in zebrafish (D. rerio), fruit flies (D. melanogaster) and budding yeast (S. cerevisiae), where the complex was first identified and studied (4, 5). The EXOSC4-9 subunits and their orthologs form a central, six-subunit ring that is covered by a three-subunit cap composed of EXOSC1-3. The ring-like complex creates a central channel through which RNA substrates are threaded to the catalytic subunit, DIS3 or DIS3L, at the base (6-10). In addition to DIS3 or DIS3L, the 9-subunit exosome complex also associates with another catalytic subunit, EXOSC10 at the cap. Notably, DIS3 and EXOSC10 are predominantly nuclear (7,(9)(10)(11), whereas DIS3L is mostly cytoplasmic (12).Although all six structural core ring subunits contain an RNase PH-like domain, they are all catalytically inactive due to amino acid substitutions that replace key catalytic residues (13). Thus, RNA substrates of the RNA exosome access the DIS3 catalytic subunit primarily via interactions with the non-catalytic core channel (14-16). Consistent with the critical function of the RNA exosome in the processing and decay of numerous ce...