EXOSC3 encodes exosome component 3, a subunit of the human RNA exosome complex.
The exosome plays a critical role in regulating gene expression by processing and degrading various RNA molecules. Mutations in EXOSC3most significantly disrupt the processing of precursor rRNAs. However, it remains unclear why dysfunction of the exosome affects the cerebellum, pons, and spinal motor neurons, especially since there is no evidence indicating that EXOSC3is specifically expressed in these regions of the brain.
More severe forms of the condition have been linked to rare genetic changes, including missense mutations, nonsense mutations, as well as deletions and duplications. Patients with these more deleterious variants may exhibit pronounced atrophy of the pons and significantly reduced life expectancy.
One of the most common pathogenic variants identified in the EXOSC3 gene is c.395A>C (p.Asp132Ala). Studies suggest that individuals with homozygosity tend to exhibit a milder form of the condition compared to those with compound heterozygosity. Interestingly, a reported case involving two siblings described a milder presentation of the condition despite having compound heterozygous variants in EXOSC3: c.155delC and c.80T>G.
EXOSC3