This area investigates the molecular consequences of PHOX2B polyalanine expansions in CCHS. Using patient-derived neuronal models and complementary cellular systems, the work characterises how PHOX2B mutations affect cell-cycle control, oxidative stress responses, autophagy–proteasome function and neuronal differentiation. Transcriptomic and functional analyses highlight consistent dysregulation of stress-response and neurodevelopmental pathways, compatible with the autonomic and neurodevelopmental defects observed in patients. Pathway and network analyses are used to prioritise candidate mechanisms and druggable nodes, supporting the identification of potential therapeutic strategies, including histone deacetylase inhibitors. Overall, this research links PHOX2B genotype to concrete cellular phenotypes and testable therapeutic hypotheses in CCHS.

Nathan Beckouche, Muriel Thoby-Brisson