Mutations in the transient receptor potential vanilloid 4 gene (TRPV4), encoding a widely expressed Ca2+-permeable ion channel, result in autosomal dominant diseases of peripheral nerve (Charcot-Marie-Tooth disease type 2C, congenital distal spinal muscular atrophy, scapuloperoneal spinal muscular atrophy) or the skeletal system (metatropic dysplasia, spondylometaphyseal dysplasia Kozlowski type, spondyloepiphyseal dysplasia Maroteaux type, autosomal dominant brachyolmia, parastremmatic dysplasia, familial digital arthropathy-brachydactyly). TRPV4-mediated nerve and bone disorders are characterised by considerable phenotypic variability, including severe congenital-onset disease to complete nonpenetrance in the case of nerve disease-associated mutations. Most often, individual TRPV4 mutations have been associated with distinct organ system diseases; although overlap syndromes may occur. Heterologous expression studies have identified a number of functional changes in the TRPV4 ion channel resulting from disease-causing mutations, the most prominent being increased constitutive channel activity. As many of these changes are shared by TRPV4 mutants causing different diseases, however, it remains unclear how particular mutations in TRPV4 result in such diverse disease phenotypes. In this chapter, we outline the clinical and pathological features of the known forms of TRPV4-mediated disease, as well as the effects of disease-causing mutations on TRPV4 assembly, expression and channel activity. We also explore current thinking on the pathogenenic mechanisms contributing to different forms of TRPV4 channelopathy. Elucidation of these mechanisms will be an important step in the development of new therapeutic interventions for these diseases.
