Haematological Characterisation of Mice with Piezo1 Gain-Of-Function Mutation

Abstract

Piezo1 proteins assemble as trimers to form mechanically-activated non-selective cationic channels. In physiology, their role as mechanosensors is critical to vascular development and red blood cell volume regulation. Mutations in Piezo1 are associated with two diseases which share overlapping features, despite opposing effects on the protein. Loss of function mutations are linked to lymphatic dysplasia; whilst gain of function mutations are connected to dehydrated stomatocytosis (DHS), a form of anaemia. Gain-of-function mutations occurring in the extracellular cap domain of the protein have been linked to DHS. To test whether such mutations are sufficient to cause DHS, we generated the equivalent of a human DHS mutation in mice using CRISPR/Cas-9 technology, mirroring the genotype observed in DHS patients. Mice homozygous for the mutation were viable with normal Mendelian inheritance and body weight. Haematological analysis revealed that the mice had characteristics of DHS, with an anaemia phenotype and the presence of stomatocytes in blood smears. The data suggest that point mutation in the Piezo1 cap is sufficient to cause anaemia and that the mutation affects murine Piezo1 similarly to human Piezo1. Further studies will investigate if the mutation has wider implications for other non-haematological systems because of the suggested broad importance of Piezo1 in mammalian physiology. Support by the Wellcome Trust and a British Heart Foundation PhD Studentship to EE.