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EXOSC3 G191 Variants Trigger System-Wide Recalibration of RNA Processing Machinery.

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Pathogenic EXOSC3 variants cause pontocerebellar hypoplasia type 1B (PCH1B). This study reveals how EXOSC3 G191 variants destabilize the RNA exosome, impacting gene expression and contributing to disease variability.

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Area of Science:

  • Molecular Biology
  • Genetics
  • Biochemistry

Background:

  • Pathogenic variants in EXOSC3, a noncatalytic RNA exosome subunit, cause pontocerebellar hypoplasia type 1B (PCH1B).
  • Significant variability in PCH1B disease severity exists among individuals with different EXOSC3 alleles.
  • The molecular mechanisms underlying RNA exosome dysfunction in individuals with EXOSC3 p.G191 variants are not fully understood.

Purpose of the Study:

  • To investigate the molecular mechanisms of RNA exosome dysfunction caused by EXOSC3 p.G191 variants.
  • To elucidate the relationship between EXOSC3 variants, RNA exosome stability, and phenotypic variability in PCH1B.

Main Methods:

  • CRISPR/Cas9-engineered human cell models harboring EXOSC3 p.G191 variants.
  • Integrated transcriptomic, proteomic, and computational structural analyses.
  • Molecular dynamics and λ-dynamics simulations, protein abundance and thermal stability assays (PISA).

Main Results:

  • EXOSC3 p.G191 variants induced allele- and dosage-dependent alterations in gene expression and splicing, including increased exon 3 skipping.
  • Simulations predicted, and experiments confirmed, thermodynamic destabilization of EXOSC3 variant proteoforms, leading to reduced protein abundance and thermal stability.
  • RNA exosome core subunits and EXOSC10 levels decreased, while catalytic exonuclease DIS3 and other RNA processing pathways were upregulated, indicating compensatory responses.

Conclusions:

  • EXOSC3 p.G191 variants destabilize the RNA exosome complex through altered splicing and protein instability.
  • Compensatory upregulation of specific RNA processing pathways suggests adaptive network responses to maintain cellular function.
  • These findings link molecular mechanisms of RNA exosome dysfunction to the observed phenotypic variability in EXOSC3-associated PCH1B.