Taken together, our results demonstrate how failure of TRPV4–RhoA interactions due to neuropathy mutations serves to both directly and indirectly activate RhoA and exacerbate increased TRPV4 channel activity, thus creating a multi-hit scenario resulting in dysregulation of TRPV4-mediated calcium influx and RhoA-mediated cytoskeletal changes. This evidence concerns the gene TRPV4 and neuropathy.