Biallelic variants in the RNA exosome gene EXOSC5 are associated with developmental delays, short stature, cerebellar hypoplasia and motor weakness
Year: 2020
Type: article
Study design: Case Report
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.
Source: Human Molecular Genetics
DOI: 10.1093/hmg/ddaa108
Authors: Anne Slavotinek, Doriana Misceo, Stephanie Htun, Linda Mathisen, Eirik Frengen, Michelle Foreman, Jennifer E Hurtig, Liz Enyenihi, Maria C Sterrett, Sara W Leung, Dina Schneidman-Duhovny, Juvianee Estrada-Veras, Jacque L Duncan, Charlotte A Haaxma, Erik-Jan Kamsteeg, Vivian Xia, Daniah Beleford, Yue Si, Ganka Douglas, Hans Einar Treidene, Ambro van Hoof, Milo B Fasken, Anita H Corbett
Institutions: University of California, San Francisco, Oslo University Hospital, University of Oslo, The University of Texas Health Science Center at Houston, Emory University, Hebrew University of Jerusalem, Uniformed Services University of the Health Sciences, Walter Reed National Military Medical Center, Radboud University Nijmegen, Radboud University Medical Center, Donders Institute for Brain, Cognition and Behaviour
Language: English
Topic: RNA Research and Splicing
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: bronze
Awards: Genomic sequencing to aid diagnosis in pediatric and prenatal practice: Examining clinical utility, ethical implications, payer coverage, and data integration in a diverse population., Insight into the RNA processing and decay pathways critical for proper neuronal development and function through focus on mutations that cause Pontocerebellar Hypoplasia, A Budding Yeast Model for Human Disease-Mutations in the RNA Exosome, TRAINING PROGRAM IN BIOCHEMISTRY, CELL AND DEVELOPMENT BIOLOGY
OpenAlex ID: W3033203285