Overall, in this study we for the first time provide evidence that XLID-causing HUWE1 mutation leads to changed catalytic activity and results in alterations of essential cellular processes, such as maintenance of genome stability and response to oxidative stress, which could be relevant in cortical progenitor zones of human brain, as suggested by HUWE1 localization. The gene discussed is HUWE1; the disease is cask-related x-linked intellectual disability.