Biallelic variants in the RNA exosome gene EXOSC5 are associated with developmental delays, short stature, cerebellar hypoplasia and motor weakness

Abstract

The RNA exosome is an essential ribonuclease complex required for processing and/or degradation of both coding and non-coding RNAs. We identified five patients with biallelic variants in EXOSC5, which encodes a structural subunit of the RNA exosome. The clinical features of these patients include failure to thrive, short stature, feeding difficulties, developmental delays that affect motor skills, hypotonia and esotropia. Brain MRI revealed cerebellar hypoplasia and ventriculomegaly. While we ascertained five patients, three patients with distinct variants of EXOSC5 were studied in detail. 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. The additional two patients ascertained are siblings who had an early frameshift mutation in EXOSC5 and the p.Thr114Ile missense variant that were inherited in trans. We employed three complementary approaches to explore the requirement for EXOSC5 in brain development and assess consequences of pathogenic EXOSC5 variants. Loss of function for exosc5 in zebrafish results in shortened and curved tails/bodies, reduced eye/head size and edema. We modeled pathogenic EXOSC5 variants in both budding yeast and mammalian cells. Some of these variants cause defects in RNA exosome function as well as altered interactions with other RNA exosome subunits. These findings expand the number of genes encoding RNA exosome subunits linked to human disease while also suggesting that disease mechanism varies depending on the specific pathogenic variant.

Short stature, hearing loss, retinitis pigmentosa, and distinctive facies syndrome: A case report

“…EXOSC5 mutations involve patients with cerebellar hypoplasia, short stature, and developmental delay. Loss of function studies in zebrafish of the different pathogenic variants observed in the patients resulted in variable expressivity of phenotype in the zebrafish, suggesting the expressed phenotype depended on specific pathogenic variant present (Slavotinek et al, 2020). However, the exact molecular mechanism connecting RNA exosome dysfunction in disease and remains unclear (Morton et al, 2018).…”

Caught in the act—Visualizing ribonucleases during eukaryotic ribosome assembly

“…The RNA exosome is a multi-subunit RNA degradation machinery evolved from the bacterial degradosome PNPase that is involved in the processing and degradation of a wide variety of RNAs, including pre-rRNAs (Gudipati et al, 2012;Hojka-Osinska et al, 2021;Mitchell et al, 1997;Schneider et al, 2012;Sloan et al, 2012 Beheshtian et al, 2019;Bizzari et al, 2020;Boczonadi et al, 2014;Burns et al, 2018;Calame et al, 2021;Chapman et al, 2011;Di Donato et al, 2016;Ding et al, 2012;Dziembowski et al, 2007;Kobyłecki et al, 2018;Lebreton et al, 2008;Lorentzen et al, 2008;Preti et al, 2013;Sakamoto et al, 2021;Schaeffer et al, 2009;Schneider et al, 2007;Schneider et al, 2009;Slavotinek et al, 2020;Sloan et al, 2013;…”

Nuclear RNA Exosome and Pervasive Transcription: Dual Sculptors of Genome Function

“…EXOSC9 mutations are associated with PCH1d that exhibit spinal motor neuropathy and cerebellar atrophy, while the abnormalities of the pons are modest [88]. A recent study demonstrated that mutations in EXOSC5 are associated with a novel form of exosomepathy, characterized by developmental delays, short stature, cerebellar hypoplasia, and motor weakness [89]. In addition, the bi-allelic missense variant of EXOSC1 was recently linked to the disease condition of PCH [90].…”