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Cited by 149Genetics and Neurodevelopmental DisordersRNA Research and SplicingHereditary Neurological Disorders

EXOSC8 mutations alter mRNA metabolism and cause hypomyelination with spinal muscular atrophy and cerebellar hypoplasia

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Boczonadi, Veronika, Müller, Juliane S., Pyle, Angela, Munkley, Jennifer, Dor, Talya, Quartararo, Jade, Ferrero, Ileana, Karcagi, Veronika +19 more·2014·Nature Communications
DOI 10.1038/ncomms5287PMC PMC4102769
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Abstract

The exosome is a multi-protein complex, required for the degradation of AU-rich element (ARE) containing messenger RNAs (mRNAs). EXOSC8 is an essential protein of the exosome core, as its depletion causes a severe growth defect in yeast. Here we show that homozygous missense mutations in EXOSC8 cause progressive and lethal neurological disease in 22 infants from three independent pedigrees. Affected individuals have cerebellar and corpus callosum hypoplasia, abnormal myelination of the central nervous system or spinal motor neuron disease. Experimental downregulation of EXOSC8 in human oligodendroglia cells and in zebrafish induce a specific increase in ARE mRNAs encoding myelin proteins, showing that the imbalanced supply of myelin proteins causes the disruption of myelin, and explaining the clinical presentation. These findings show the central role of the exosomal pathway in neurodegenerative disease.

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  • Variants in genes encoding several subunits of the RNA exosome complex have been linked to PCH, including EXOSC3 (PCH1B), EXOSC8 (PCH1C), EXOSC9 (PCH1D), and provisionally EXOSC1 (PCH1F).

    “variants in genes encoding several subunits of the RNA exosome complex have been linked to PCH, including EXOSC3 (PCH1B), EXOSC8 (PCH1C), EXOSC9 (PCH1D), and provisionally EXOSC1 (PCH1F)15–25.”

    From EXOSC3 G191 Variants Trigger System-Wide Recalibration of RNA Processing Machinery (2026) · cites this paper as [24]

    The Discussion links EXOSC3 mutations to PCH1 and reports pathogenic EXOSC8 mutations in patients with cerebellar hypoplasia and spinal muscular atrophy. Our copy identifies EXOSC9 as an exosome subunit, but does not link EXOSC9 or EXOSC1 variants to PCH; it also does not give the listed PCH subtype labels. No page numbers are available in our copy. (LLM, conf=0.88)

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Authors
Boczonadi, V., Müller, J. S., Pyle, A., Munkley, J., Dor, T., Quartararo, J., Ferrero, I., Karcagi, V., Giunta, M., Polvikoski, T., Birchall, D., Princzinger, A., Cinnamon, Y., Lützkendorf, S., Piko, H., Reza, M., Florez, L., Santibanez-Koref, M., Griffin, H., Schuelke, M., Elpeleg, O., Kalaydjieva, L., Lochmüller, H., Elliott, D. J., Chinnery, P. F., Edvardson, S., & Horvath, R.
Affiliations
  • Wellcome Centre for Mitochondrial Research (GB)
  • Hebrew University of Jerusalem (IL)
  • University of Parma (IT)
  • Orszagos Kornyezetegeszsegugyi Intezet (HU)
  • Newcastle University (GB)
  • Stiftung Charité (DE)
  • The University of Western Australia (AU)
ORCID
Venue
Nature Communications
Publisher
Springer Science and Business Media LLC
Published
2014-07-03
Volume
5
Issue
1
Pages
4287-4287
ISSN
2041-1723 (ISSN-L)
DOI
10.1038/ncomms5287
PMC
PMC4102769
OpenAlex
W2026502985
Cited by
149
References
53
Citations by year
2026: 9 · 2025: 14 · 2024: 10 · 2023: 14 · 2022: 13 · 2021: 13 · 2020: 20 · 2019: 14 · 2018: 19 · 2017: 9 · 2016: 7 · 2015: 3 · 2014: 3
FWCI
4.82
Type
journal article
Language
en
Open access
Licence
Locations
  • Nature Communications (publishedVersion, cc-by)
  • Europe PMC (PubMed Central) (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • UWA Profiles and Research Repository (UWA) (submittedVersion, other-oa)
  • RePEc: Research Papers in Economics (submittedVersion)
  • Apollo (University of Cambridge) (submittedVersion, cc-by)
  • Apollo (cc-by)
Funders
  • Wellcome Trust (FP7/2007–2013, 096919, 101876/B/13/Z, 10187 6/Z/13/Z, 101876)
  • National Institute for Health and Care Research (FP7/2007–2013)
  • Parkinson's UK
  • Prostate Cancer UK (PG12-34)
  • European Commission (317433, 305444, 2007–2013, FP7 2007-2013, FP7/2007, 305121)
  • Fondazione Telethon (GGP11011)
  • Einstein Stiftung Berlin (A-2011-63)
  • Medical Research Council (G1000848, FP7/20072013, 98482, MR/K000608/1, G1002274)
  • FP7 Ideas: European Research Council (309548)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetics and Neurodevelopmental Disorders
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA Research and Splicing
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Hereditary Neurological Disorders
Keywords
exosomes, AU-rich elements, mRNA degradation, hypomyelination, spinal muscular atrophy, cerebellar hypoplasia, corpus callosum hypoplasia, myelin proteins, oligodendrocytes, neurodegeneration, missense mutations, zebrafish model
MeSH terms
Amino Acid Sequence, Animals, Cerebellum, Cerebral Cortex, Developmental Disabilities, Female, Fungal Proteins, Homozygote, Humans, Infant, Male, Molecular Sequence Data, Nervous System Malformations, Syndrome, Spinal Muscular Atrophies of Childhood, Zebrafish, Gene Expression, RNA-Binding Proteins, Sequence Analysis, DNA, Hereditary Central Nervous System Demyelinating Diseases, Gene Knockdown Techniques, Agenesis of Corpus Callosum, Exosome Multienzyme Ribonuclease Complex

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