Introduction 15 1 2013; Mattijssen et al., 2024). Another POLR3-related disorder, caused by POLR3GL variants, also has splicing alteration (Terhal et al., 2020). While significant progress has been made in characterizing the molecular and cellular effects of Pol III mutations, and many hypotheses on the disease mechanisms have been formed, no treatment targets have been yet identified. Understanding why certain tissues and cell types are more severely affected in 4H will be critical to develop targeted therapeutic strategies. CURRENT 4H DISEASE MODELS To advance knowledge on 4H leukodystrophy, it is essential to develop robust disease models that can capture its complex cellular and molecular phenotypes, enabling the investigation of tissue-specific vulnerability and potential therapeutic targets. The field has made several efforts in this direction. Early attempts using mouse models with known 4Hassociated POLR3A variants such as c.2015G>A (p.Gly672Glu), did however not have neurological abnormalities or Pol III transcript alterations. Additionally, Polr3a−/−null mice were embryonic lethal (Choquet et al., 2017). Similarly, a mouse model for POLR3B variant c.308G>A was embryonic lethal when homozygous. While a double-mutant (Polr3aG672E/null Polr3b+/R103) did not show neurological or transcription abnormalities (Choquet, Pinard, et al., 2019). Recent advancements have overcome these problems, and now mouse models harbouring Polr3a and Polr3b variants are available and reflect leukodystrophy phenotypes (Merheb et al., 2021; Michell-Robinson et al., 2023; Moir et al., 2024) These new disease models are invaluable tools to progress research on 4H leukodystrophy but the absence of phenotypes in the earlier mouse models shows that vulnerability to Pol III mutations likely varies between species, underscoring the need for human-derived models. Considering the many variants causing 4H and the broad clinical spectrum, a patient- and/or mutation-specific approach may be necessary to fully capture the complexity of the disease. Currently, the availability of human tissue samples from individuals with 4H leukodystrophy is limited. Post-mortem tissue is scarce and typically obtained only at the end stage of the disease, providing limited insight into early disease processes and progression—key aspects for therapy development. While patient-derived fibroblasts have been used, these are not the cells that show defects in 4H. MO3.13 oligodendroglial cell models have been used in
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