The fetal hydrops-associated single-residue mutation L322P abolishes mechanical but not chemical activation of the PIEZO1 ion channel

Abstract

The mechanically activated PIEZO1 ion channel is genetically linked to numerous physiological and pathophysiological processes. For example, deleting PIEZO1 in mice leads to defective lymphatic vessel development, while nonsense mutations in humans are associated with autosomal recessive generalized lymphatic dysplasia (GLD) and non-immune hydrops fetalis. However, it remains unclear whether PIEZO1-dependent biological processes are directly mediated by its intrinsic mechanosensitivity. Here we identified a human fetal hydrops-associated single-residue mutation, L322P (corresponding to L329P in mouse PIEZO1), which completely abolishes PIEZO1s response to mechanical stimuli while maintaining normal plasma membrane expression and responsiveness to its chemical activators, Yoda1 and Jedi1. Remarkably, the mechanical response of the mutant can be restored by Yoda1. These findings demonstrate a direct link between the loss of PIEZO1s mechanosensitivity and the pathophysiological phenotype of fetal hydrops, and raise the therapeutic potential of using PIEZO1 chemical activators to restore the mechanosensitivity of PIEZO1 missense mutants that are associated with genetic diseases such as GLD and hydrops fetalis. Significance StatementGenetic deletion studies have revealed the diverse cellular, physiological, and pathophysiological roles of the mechanically activated PIEZO1 ion channel. However, whether these functions are directly mediated by its mechanosensitivity has remained experimentally unaddressed. In this study, we identified a novel fetal hydrops-associated single-residue mutation, hPIEZO1-L322P, which specifically abolishes PIEZO1s mechanical response while retaining its chemical activation. Remarkably, the mechanical response of the mutant can be fully restored by the PIEZO1 chemical activator Yoda1. These findings address the long-standing question of whether PIEZO1 relies on its mechanosensitivity to mediate in vivo functions, provide critical insights into the mechanosensing mechanism of PIEZO1, and highlight the therapeutic potential of using PIEZO1 chemical activators to rescue the loss of mechanosensitivity caused by missense mutations.