Authors
Branco, L., Mayer, S.
Abstract
Pontocerebellar hypoplasia (PCH) is a group of ultrarare, neurodegenerative disorders characterized by cerebellar and pontine hypoplasia. Genetic analysis over the last two decades has revealed an increasing number of pathogenic variants in a wide range of broadly expressed genes functioning in RNA processing, tRNA metabolism, and translation. However, the mechanisms linking these ubiquitous processes to brain region-specific vulnerability are unknown. Here, we established a multi-level variant-to-function in silico framework to predict the molecular consequences of PCH-associated variants in TSEN complex genes. These variants were predicted to have heterogeneous effects on diverse protein properties, including stability, subcellular localization, and degradation, supporting variant-specific rather than uniform disease mechanisms. Complementary transcriptomic analyses showed that PCH-associated genes were not globally enriched in the prenatal cerebellum. Instead, their expression was coordinated in a stage- and cell type-specific manner during cerebellar development. We therefore hypothesize that multiple PCH-associated genes are regulated by a common set of transcription factors, providing an explanation of the selective vulnerability of the cerebellum and to the phenotypic convergence of genetically diverse PCH subtypes. In summary, this study prioritizes candidate variants for biochemical, cellular, and in vivo validation, and identifies regulatory programs, cell lineages, and developmental windows for targeted, mechanistically informed disease modelling.
Preprint server:
bioRxiv
The authors list and abstract were imported from bioRxiv on 30 Sep 2026.
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