Chapter 1 22 Figure 4: Overview of 4H mutations within this cohort and their evolutionary conservation. Schematic representation of mutations in 4H patient cohort in A) POLR3A gene and B) POLRB gene. Open triangles intron mutations, filled triangles exon mutations. Overview of genetic conservation for C) POLR3A and D) POLR3B intron variants. E) Reconstruction of protein Pol III A and B subunit with DNA (black) and RNA (gray), and exon mutations (red circles) according to PDB ID: 7DN3 Human RNA Polymerase III elongation complex, images created using Mol* (Li et al., 2021; Sehnal et al., 2021). Conservation of amino acid sequences per mutation in F) Pol III A and G) B subunit. Conservation according to MultiZ alignment of the UCSC Genome Browser on Human GRCh38/hg38 (Nassar et al. 2023). Species: Homo sapiens (human), Mus musculus (mouse), Danio rerio (zebrafish), Drosophila melanogaster (fruit fly), Caenorhabditis elegans (roundworm) and Saccharomyces cerevisiae (yeast). “=” means aligning species has one or more unalignable bases in the gap region, “-“ no bases in the aligned species. Chapter 3: To further explore neuronal phenotypes in 4H leukodystrophy and whether changes are disease-specific or more generally affected in leukodystrophies, we studied key phenotypic and transcriptomic differences between Ctrl, 4H and GLD neurons. By comparing neuronal changes in 4H and GLD, this chapter highlights the heterogeneity of leukodystrophies and the necessity of refining disease models. The findings underscore a
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