(A) Human WT MeCP2 protein and the effect of the three possible reading frames remaining after deletions in the C-terminal deletion-prone region (CT-DPR). The reason why mutations in the disordered C-terminal domain of MeCP2 should cause RTT has been the subject of speculation (Cheng et al., 2014; Li et al., 2020). Our previous work with mouse models of CTD mutations made clear that the truncations themselves do not interfere significantly with MeCP2 function. The effect of multiple prolines on translational termination is less well understood, although there is evidence from bacteria and eukaryotic cells that they may hinder efficient termination (Hayes et al., 2002; Janzen et al., 2002; Matheisl et al., 2015). Figure 9 Download asset Open asset Flow chart for predicting the likely clinical prognosis of deletions in the C-terminal deletion-prone region (CT-DPR) of human MECP2 based on the findings in this study.