EXOSC8 – Pontocerebellar hypoplasia type 1

Autosomal recessive variants in EXOSC8 cause pontocerebellar hypoplasia type 1 (MONDO:0016396). To date, three unrelated probands have been reported: one Spanish patient with compound heterozygous EXOSC8 variants (splice-site c.390+1delG and missense c.628C>T (p.Pro210Ser)) and two individuals homozygous for distinct missense substitutions ((PMID:34210538), (PMID:29656927)). Affected infants typically present antenatal disease onset, severe hypotonia, global developmental delay, spasticity, nystagmus, microcephaly, optic atrophy, dystonia and ataxia ((PMID:29656927)). Segregation data are limited and no affected relatives beyond probands have been described.

Functional studies support a loss-of-function mechanism. Patient fibroblast assays showed that c.390+1delG induces exon 7 skipping (p.Ser116LysfsTer27), reducing mRNA by 30% and protein by 65% (PMID:34210538). In yeast, mutations in the Rrp43p ortholog impair exosome core stability and alter subunit interactions, consistent with reduced complex integrity (PMID:24237138). No conflicting evidence has been reported.

Key Take-home: EXOSC8 should be included in gene panels for pontocerebellar hypoplasia, particularly in patients with early-onset cerebellar and spinal motor neuron involvement, given its loss-of-function mechanism and consistent functional impact.

References

• European journal of paediatric neurology • 2018 • Pontocerebellar hypoplasia type 1 for the neuropediatrician: Genotype-phenotype correlations and diagnostic guidelines based on new cases and overview of the literature. PMID:29656927
• Neuromuscular disorders • 2021 • New subtype of PCH1C caused by novel EXOSC8 variants in a 16-year-old Spanish patient. PMID:34210538
• Journal of proteome research • 2013 • Proteomic analysis of yeast mutant RNA exosome complexes. PMID:24237138

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