Executive Summary : | The RNA exosome is a crucial machinery in RNA metabolism, facilitating the post-transcriptional surveillance, processing, and degradation of various cellular RNAs. It plays a crucial role in transcription, DNA repair, antiviral defense, and lineage-specific differentiation. Pathogenic variants in several genes encoding for RNA exosome components cause neurodegenerative diseases. Mutations in EXOSC3, EXOSC8, and EXOSC9 are linked to various subgroups of pontocerebellar hypoplasia type 1 (PCH1), cerebellar ataxia, brain abnormalities, and cardiac conduction defect. Recent work at the center identified a biallelic missense pathogenic variant, p.(Ser35Leu), in EXOSC1 associated with a novel PCH phenotype, PCH1F. However, the molecular mechanism underlying PCH1F remains unclear. Studies in yeast, Drosophila, and zebrafish have revealed that RNA exosome dysfunction causes impaired brain and neuronal development. However, how the RNA exosome modulates cell proliferation, patterning, and differentiation in human neurodevelopment remains elusive. This study aims to dissect how the reported EXOSC1 mutation impacts stemness of induced pluripotent stem cells derived from EXOSC1 patient fibroblasts, their subsequent neuronal differentiation, and RNA metabolism during these processes. Using Drosophila, a widely used model for neurodevelopmental disorders, the physiological consequences of EXOSC1 impairment in vivo will be evaluated. Functionally characterizing novel putative pathogenic variants in genes encoding for RNA exosome components will expand our knowledge of genotype-phenotype correlation in this group of disorders. |