Biallelic variants in the RNA exosome gene EXOSC5 are associated with developmental delays, short stature, cerebellar hypoplasia and motor weakness
| Autor: | Juvianee I. Estrada-Veras, Eirik Frengen, Linda Mathisen, Liz Enyenihi, Hans Einar Treidene, Daniah Beleford, Yue Si, Ganka Douglas, Michelle Foreman, Jacque L. Duncan, Jennifer E. Hurtig, Anne Slavotinek, Erik-Jan Kamsteeg, Charlotte A. Haaxma, Sara W. Leung, Milo B. Fasken, Ambro van Hoof, Anita H. Corbett, Dina Schneidman-Duhovny, Stephanie Htun, Doriana Misceo, Maria C. Sterrett, Vivian Xia |
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| Rok vydání: | 2020 |
| Předmět: |
Exosome complex
Developmental Disabilities Medical and Health Sciences Sensory disorders Donders Center for Medical Neuroscience [Radboudumc 12] Exon 0302 clinical medicine Cerebellum 2.1 Biological and endogenous factors Missense mutation Aetiology Frameshift Mutation Zebrafish Genetics (clinical) Genetics & Heredity Genetics 0303 health sciences Exosome Multienzyme Ribonuclease Complex Homozygote RNA-Binding Proteins General Medicine Biological Sciences Disorders of movement Donders Center for Medical Neuroscience [Radboudumc 3] Hypotonia Pedigree General Article medicine.symptom Mutation Missense Dwarfism Biology Nervous System Malformations Frameshift mutation 03 medical and health sciences Rare Diseases Clinical Research Antigens Neoplasm medicine Animals Humans Antigens Molecular Biology Gene Loss function 030304 developmental biology Neurosciences Mutation Neoplasm Missense 030217 neurology & neurosurgery |
| Zdroj: | Human Molecular Genetics, 29, 13, pp. 2218-2239 Hum Mol Genet Human molecular genetics, vol 29, iss 13 Human Molecular Genetics, 29, 2218-2239 |
| ISSN: | 1460-2083 0964-6906 |
| DOI: | 10.1093/hmg/ddaa108 |
| Popis: | Contains fulltext : 225143.pdf (Publisher’s version ) (Closed access) 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. |
| Databáze: | OpenAIRE |
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