Introduction 13 1 These examples illustrate that the Pol III transcriptome is extensive and supports a diverse range of fundamental cellular processes. However, it remains unclear if and how these transcripts and the processes they are involved in are affected by 4H related POLR3 variants. RNA POL III - In 4H leukodystrophy The identification of the causal genes for 4H syndrome significantly improved diagnostic capabilities, yet it raised the question of how mutations in Pol III—a protein that is abundantly expressed and essential for transcription—result in this disease. Despite ongoing research, the precise mechanisms underlying the pathogenesis of 4H leukodystrophy remain unclear. One proposed mechanism is that certain mutations disrupt the structure, complex formation, or cellular localization of Pol III. For example, mutations in POLR1C have been shown to impair the assembly and nuclear import of RNA Pol III (Thiffault et al., 2015). Similarly, mutations in POLR3B that map to conserved protein domains have been hypothesized to interfere with DNA binding, modify the catalytic cleft, or disrupt subunit interactions (Tetreault et al., 2011). Experimental studies have shown that a specific POLR3B variant affected complex assembly, that could be restored by riluzole administration (Pinard et al., 2022). Another POLR3B variant caused aberrant association of individual enzyme subunits rather than affecting overall enzyme assembly (Choquet, Pinard, et al., 2019; Djordjevic et al., 2021). Another potential pathological mechanism in 4H involves alterations in POLR3 gene and/or protein expression. In various samples of patients with POLR3A variants, amongst which fibroblasts, grey and white matter tissue, decreased Pol IIIA subunit expression has been reported (Bernard et al., 2011; Perrier, Gauquelin, et al., 2020). Similarly, a decrease in POLR3 gene expression has been described in patients with POLR3D variants (Macintosh, Perrier, et al., 2023). Additionally, mutant clones harbouring 4H-related POLR3A variants showed reduced Pol IIIA protein and POLR3A mRNA levels, however this was not consistent across all clones (Choquet, Forget, et al., 2019). For POLR3B variants, decreased gene levels have been described as well (Mattijssen et al., 2024). The afore mentioned findings have only been reported in small cohorts, often linked to variants causing severe phenotypes. This leaves uncertainty about whether these findings are universal.
RkJQdWJsaXNoZXIy MTk4NDMw