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Cited by 257Fetal and Pediatric Neurological DisordersGenetics and Neurodevelopmental DisordersGenomics and Rare Diseases

Mutations in the RNA exosome component gene EXOSC3 cause pontocerebellar hypoplasia and spinal motor neuron degeneration

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Wan, Jijun, Yourshaw, Michael, Mamsa, Hafsa, Rudnik-Schöneborn, Sabine, Menezes, Manoj P, Hong, Ji Eun, Leong, Derek W, Senderek, Jan +18 more·2012·Nature Genetics
DOI 10.1038/ng.2254PMC PMC3366034
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Abstract

RNA exosomes are multi-subunit complexes conserved throughout evolution and are emerging as the major cellular machinery for processing, surveillance and turnover of a diverse spectrum of coding and noncoding RNA substrates essential for viability. By exome sequencing, we discovered recessive mutations in EXOSC3 (encoding exosome component 3) in four siblings with infantile spinal motor neuron disease, cerebellar atrophy, progressive microcephaly and profound global developmental delay, consistent with pontocerebellar hypoplasia type 1 (PCH1; MIM 607596). We identified mutations in EXOSC3 in an additional 8 of 12 families with PCH1. Morpholino knockdown of exosc3 in zebrafish embryos caused embryonic maldevelopment, resulting in small brain size and poor motility, reminiscent of human clinical features, and these defects were largely rescued by co-injection with wild-type but not mutant exosc3 mRNA. These findings represent the first example of an RNA exosome core component gene that is responsible for a human disease and further implicate dysregulation of RNA processing in cerebellar and spinal motor neuron maldevelopment and degeneration.

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  • PCH1B is characterized by marked hypotonia, progressive cerebellar atrophy, and motor neuron dysfunction.

    “PCH1B is a subtype characterized by marked hypotonia, progressive cerebellar atrophy, and motor neuron dysfunction and caused by variants in the EXOSC3 gene15,18,21–23,25.”

    From EXOSC3 G191 Variants Trigger System-Wide Recalibration of RNA Processing Machinery (2026) · cites this paper as [25]

    The Methods’ Clinical characterization section (page unavailable) reports hypotonia from birth, prominent cerebellar atrophy, and confirmed spinal motor neuron disease; the Abstract links EXOSC3 mutations to PCH1. The paper describes progressive microcephaly and suggests a cerebellar degenerative process, but these passages do not establish that the cerebellar atrophy itself was progressive. (LLM, conf=0.84)

    Experimental — accuracy not yet measured

  • Patients harboring EXOSC3 p.G31A present with absent tendon reflexes, significant neurogenic muscle atrophy, and survival typically limited to the first six months of life.

    “patients harboring the EXOSC3 p.Gly31Ala (p.G31A) variant present with absent tendon reflexes, significant neurogenic muscle atrophy, and survival typically limited to the first six months of life25,36.”

    From EXOSC3 G191 Variants Trigger System-Wide Recalibration of RNA Processing Machinery (2026) · cites this paper as [25]

    The mutation-description passage (section labeled Abstract; page unavailable) identifies Gly31Ala in affected Families 4 and 9, and Methods > Clinical characterization reports neurogenic muscle atrophy in the PCH1 cohort. Our copy does not establish absent tendon reflexes or survival typically limited to six months for Gly31Ala carriers; the atrophy finding is not stated specifically for those carriers. (LLM, conf=0.85)

    Experimental — accuracy not yet measured

  • Pathogenic variants in EXOSC3 cause pontocerebellar hypoplasia type 1B (PCH1B).

    “Pathogenic variants in EXOSC3, a noncatalytic subunit of the RNA exosome, cause pontocerebellar hypoplasia type 1B (PCH1B)”

    From EXOSC3 G191 Variants Trigger System-Wide Recalibration of RNA Processing Machinery (2026) · cites this paper as [25]

    The paper reports that disease-causing EXOSC3 mutations lead to pontocerebellar hypoplasia type 1 (PCH1), including mutations identified in eight additional PCH1 families (Abstract; page not provided). Our copy does not use the more specific designation PCH1B, so it supports the EXOSC3–PCH1 link but not that subtype label. (LLM, conf=0.83)

    Experimental — accuracy not yet measured

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References 50 · Cited by 257

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Authors
Wan, J., Yourshaw, M., Mamsa, H., Rudnik-Schöneborn, S., Menezes, M. P., Hong, J. E., Leong, D. W., Senderek, J., Salman, M. S., Chitayat, D., Seeman, P., von Moers, A., Graul-Neumann, L., Kornberg, A. J., Castro-Gago, M., Sobrido, M.-J., Sanefuji, M., Shieh, P. B., Salamon, N., Kim, R. C., Vinters, H. V., Chen, Z., Zerres, K., Ryan, M. M., Nelson, S. F., & Jen, J. C.
Affiliations
  • University of California, Los Angeles (US)
  • Children's Hospital at Westmead (AU)
  • Universitätsklinikum Aachen (DE)
  • Children's Hospital of Winnipeg (CA)
  • Mount Sinai Hospital (CA)
  • Charles University (CZ)
  • Charité – Universitätsmedizin Berlin (DE)
  • Royal Children's Hospital (AU)
  • Instituto de Salud Carlos III (ES)
  • Kyushu University (JP)
  • University of California, Irvine (US)
Corresponding author
Jen, Joanna C
ORCID
Venue
Nature Genetics
Publisher
Springer Science and Business Media LLC
Published
2012-04-29
Volume
44
Issue
6
Pages
704-708
ISSN
  • 1061-4036 (ISSN-L)
  • 1546-1718
DOI
10.1038/ng.2254
PMC
PMC3366034
OpenAlex
W1987279431
Cited by
257
References
50
Citations by year
2026: 13 · 2025: 18 · 2024: 14 · 2023: 19 · 2022: 13 · 2021: 16 · 2020: 22 · 2019: 16 · 2018: 25 · 2017: 25 · 2016: 17 · 2015: 9 · 2014: 24 · 2013: 21 · 2012: 5
FWCI
16.59
Type
journal article
Language
en
Open access
Licence
www.springer.com/tdm (tdm)
Locations
  • Nature Genetics (publishedVersion)
  • PubMed (publishedVersion)
  • Europe PMC (PubMed Central) (acceptedVersion)
  • PubMed Central (acceptedVersion)
  • eScholarship (California Digital Library) (submittedVersion)
  • Minerva Access (University of Melbourne) (submittedVersion)
  • RWTH Publications (RWTH Aachen) (submittedVersion)
  • RUNA. Repositorio Institucional del Sergas (Servicio Gallego de Salud (SERGAS)) (submittedVersion, other-oa)
Funders
  • National Eye Institute (R01EY015311)
  • National Institute of Neurological Disorders and Stroke (R01NS064183)
  • National Institute of Arthritis and Musculoskeletal and Skin Diseases (P30AR057230)
Topics
  • Health Sciences › Medicine › Pediatrics, Perinatology and Child Health › Fetal and Pediatric Neurological Disorders
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetics and Neurodevelopmental Disorders
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genomics and Rare Diseases
Keywords
EXOSC3, RNA exosome, recessive mutations, RNA metabolism, cerebellar atrophy, microcephaly, global developmental delay, zebrafish morpholino knockdown, RNA processing, brain development
MeSH terms
Animals, Cerebellum, Humans, Motor Neurons, Nerve Degeneration, Olivopontocerebellar Atrophies, Pons, RNA, Spinal Nerves, Zebrafish, RNA-Binding Proteins, Exosomes, Gene Knockdown Techniques, Exosome Multienzyme Ribonuclease Complex

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