Insight into the RNA Exosome Complex Through Modeling Pontocerebellar Hypoplasia Type 1b Disease Mutations in Yeast
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Pontocerebellar hypoplasia type 1b (PCH1b) is an autosomal recessive disorder that causes cerebellar hypoplasia and spinal motor neuron degeneration, leading to mortality in early childhood. PCH1b is caused by mutations in the RNA exosome subunit gene, EXOSC3 The RNA exosome is an evolutionarily conserved complex, consisting of nine different core subunits, and one or two 3'-5' exoribonuclease subunits, that mediates several RNA degradation and processing steps. The goal of this study is to assess the functional consequences of the amino acid substitutions that have been identified in EXOSC3 in PCH1b patients. To analyze these EXOSC3 substitutions, we generated the corresponding amino acid substitutions in the Saccharomyces cerevisiae ortholog of EXOSC3, Rrp40 We find that the rrp40 variants corresponding to EXOSC3-G31A and -D132A do not affect yeast function when expressed as the sole copy of the essential Rrp40 protein. In contrast, the rrp40-W195R variant, corresponding to EXOSC3-W238R in PCH1b patients, impacts cell growth and RNA exosome function when expressed as the sole copy of Rrp40 The rrp40-W195R protein is unstable, and does not associate efficiently with the RNA exosome in cells that also express wild-type Rrp40 Consistent with these findings in yeast, the levels of mouse EXOSC3 variants are reduced compared to wild-type EXOSC3 in a neuronal cell line. These data suggest that cells possess a mechanism for optimal assembly of functional RNA exosome complex that ca…
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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 [21]
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 [21]
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 [21]
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References 76 · Cited by 41
- Authors
- Fasken, M. B., Losh, J. S., Leung, S. W., Brutus, S., Avin, B., Vaught, J. C., Potter-Birriel, J., Craig, T., Conn, G. L., Mills-Lujan, K., Corbett, A. H., & van Hoof, A.
- Affiliations
- Emory University (US)
- Department of Biology , Emory University, Atlanta, Georgia 30322
- The University of Texas Health Science Center at Houston (US)
- Department of Biochemistry
- Department of Microbiology and Molecular Genetics , University of Texas Health Science Center-Houston, Texas 77030
- Corresponding author
- Corbett, Anita H
- Venue
- Genetics
- Publisher
- Oxford University Press (OUP)
- Published
- 2017-01-01
- Volume
- 205
- Issue
- 1
- Pages
- 221-237
- ISSN
- 0016-6731 (ISSN-L)
- 1943-2631
- PMC
- PMC5223504
- OpenAlex
- W2533042037
- Cited by
- 41
- References
- 76
- Citations by year
- 2026: 7 · 2025: 8 · 2024: 1 · 2023: 3 · 2022: 3 · 2021: 2 · 2020: 5 · 2019: 3 · 2018: 4 · 2017: 4 · 2015: 1
- FWCI
- 1.91
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- academic.oup.com/journals/pages/open_access/funder_policies/chorus/standard_publication_model (vor)
- Locations
- Genetics (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Howard Hughes Medical Institute
- National Institute of General Medical Sciences (R01GM099790, R01GM058728, R25GM099644)
- 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
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetics and Neurodevelopmental Disorders
- Keywords
- EXOSC3, RNA exosome, Saccharomyces cerevisiae, pathogenic variants, amino acid substitutions, protein stability, protein complex formation, cerebellar hypoplasia, motor neuron degeneration, yeast model
- MeSH terms
- Cerebellar Diseases, Exoribonucleases, Mutation, Saccharomyces cerevisiae, RNA-Binding Proteins, RNA Stability, Saccharomyces cerevisiae Proteins, Exosome Multienzyme Ribonuclease Complex
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