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Variants in EXOSC9 Disrupt the RNA Exosome and Result in Cerebellar Atrophy with Spinal Motor Neuronopathy

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Burns, David T., Donkervoort, Sandra, Müller, Juliane S., Knierim, Ellen, Bharucha-Goebel, Diana, Faqeih, Eissa Ali, Bell, Stephanie K., AlFaifi, Abdullah Y. +22 more·2018·The American Journal of Human Genetics
DOI 10.1016/j.ajhg.2018.03.011PMC PMC5986733
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Abstract

The exosome is a conserved multi-protein complex that is essential for correct RNA processing. Recessive variants in exosome components EXOSC3 , EXOSC8 , and RBM7 cause various constellations of pontocerebellar hypoplasia (PCH), spinal muscular atrophy (SMA), and central nervous system demyelination. Here, we report on four unrelated affected individuals with recessive variants in EXOSC9 and the effect of the variants on the function of the RNA exosome in vitro in affected individuals' fibroblasts and skeletal muscle and in vivo in zebrafish. The clinical presentation was severe, early-onset, progressive SMA-like motor neuronopathy, cerebellar atrophy, and in one affected individual, congenital fractures of the long bones. Three affected individuals of different ethnicity carried the homozygous c.41T>C (p.Leu14Pro) variant, whereas one affected individual was compound heterozygous for c.41T>C (p.Leu14Pro) and c.481C>T (p.Arg161 ∗ ). We detected reduced EXOSC9 in fibroblasts and skeletal muscle and observed a reduction of the whole multi-subunit exosome complex on blue-native polyacrylamide gel electrophoresis. RNA sequencing of fibroblasts and skeletal muscle detected significant >2-fold changes in genes involved in neuronal development and cerebellar and motor neuron degeneration, demonstrating the widespread effect of the variants. Morpholino oligonucleotide knockdown and CRISPR/Cas9-mediated mutagenesis of exosc9 in zebrafish recapitulated aspects of the human phenotype, as they have in other zebrafish models of exosomal disease. Specifically, portions of the cerebellum and hindbrain were absent, and motor neurons failed to develop and migrate properly. In summary, we show that variants in EXOSC9 result in a neurological syndrome combining cerebellar atrophy and spinal motoneuronopathy, thus expanding the list of human exosomopathies.

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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 [20]

    The Discussion identifies EXOSC3 variants as PCH1B and EXOSC8 variants as PCH1C, and proposes EXOSC9-associated disease as PCH1D (page unavailable). Our copy does not link EXOSC1 to PCH1F, even provisionally; the Introduction describes EXOSC1 only as a subunit of the exosome. (LLM, conf=0.88)

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Authors
Burns, D. T., Donkervoort, S., Müller, J. S., Knierim, E., Bharucha-Goebel, D., Faqeih, E. A., Bell, S. K., AlFaifi, A. Y., Monies, D., Millan, F., Retterer, K., Dyack, S., MacKay, S., Morales-Gonzalez, S., Giunta, M., Munro, B., Hudson, G., Scavina, M., Baker, L., Massini, T. C., Lek, M., Hu, Y., Ezzo, D., AlKuraya, F. S., Kang, P. B., Griffin, H., Foley, A. R., Schuelke, M., Horvath, R., & Bönnemann, C. G.
Affiliations
  • Wellcome Centre for Mitochondrial Research (GB)
  • National Institutes of Health (US)
  • Stiftung Charité (DE)
  • King Fahd Medical City (SA)
  • University of Florida Health (US)
  • King Faisal Specialist Hospital & Research Centre (SA)
  • Dalhousie University (CA)
  • Izaak Walton Killam Health Centre (CA)
  • Alfred I. duPont Hospital for Children (US)
  • Broad Institute (US)
ORCID
Venue
The American Journal of Human Genetics
Publisher
Elsevier BV
Published
2018-05
Volume
102
Issue
5
Pages
858-873
ISSN
0002-9297 (ISSN-L)
DOI
10.1016/j.ajhg.2018.03.011
PMC
PMC5986733
OpenAlex
W2800864733
Cited by
88
References
2
Citations by year
2026: 10 · 2025: 10 · 2024: 5 · 2023: 13 · 2022: 10 · 2021: 11 · 2020: 18 · 2019: 8 · 2018: 3
FWCI
3.56
Type
journal article
Language
en
Open access
Licence
Locations
  • The American Journal of Human Genetics (publishedVersion, cc-by)
  • Europe PMC (PubMed Central) (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • Apollo (University of Cambridge) (submittedVersion, cc-by)
  • Apollo (cc-by)
Funders
  • National Human Genome Research Institute
  • National Eye Institute
  • National Institute of Neurological Disorders and Stroke
  • NIH Clinical Center
  • European Research Council (309548)
  • National Heart, Lung, and Blood Institute (UM1 HG008900)
  • Deutsche Forschungsgemeinschaft (SFB 665 TP C4)
  • Wellcome Trust (201064/Z/16/Z)
  • Newton Fund
  • Medical Research Council (MR/N025431/1)
  • National Institutes of Health
  • Massachusetts General Hospital
  • Massachusetts Institute of Technology
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA Research and Splicing
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genomics and Rare Diseases
  • Health Sciences › Medicine › Neurology › Amyotrophic Lateral Sclerosis Research
Keywords
RNA exosome, cerebellar atrophy, spinal muscular atrophy, pontocerebellar hypoplasia, recessive mutations, zebrafish model, RNA processing
MeSH terms
Amino Acid Sequence, Animals, Atrophy, Base Sequence, Cerebellum, Child, Preschool, Female, Fibroblasts, Haplotypes, Humans, Infant, Male, Motor Neurons, Pedigree, Spinal Cord, Genetic Variation, Zebrafish, RNA-Binding Proteins, Muscle, Skeletal, Exosomes, Gene Knockdown Techniques, Exosome Multienzyme Ribonuclease Complex

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