The puzzle of TRPV4 channelopathies

Abstract

Hereditary channelopathies, that is, mutations in channel genes that alter channel function and are causal for the pathogenesis of the disease, have been described for several members of the transient receptor potential channel family. Mutations in the TRPV4 gene, encoding a polymodal Ca(2+) permeable channel, are causative for several human diseases, which affect the skeletal system and the peripheral nervous system, with highly variable phenotypes. In this review, we describe the phenotypes of TRPV4 channelopathies and overlapping symptoms. Putative mechanisms to explain the puzzle, and how mutations in the same region of the channel cause different diseases, are discussed and experimental approaches to tackle this surprising problem are suggested.

Figure 1

Domain structure and disease-causing mutations in TRPV4. A schematic view of the TRPV4 channel indicating several domains and mutants that cause skeletal dysplasias, neuropathies and the arthropathy FDAB. (A) Secondary structure of TRPV4, with putative functional domains. (B) Mutation frequency along the amino acid sequence of TRPV4 for all TRPV4-dependent diseases, as well as for skeletal dysplasias, FDAB and neuropathies. FDAB, familial digital arthropathy brachydactyly.

Figure 2

Spectrum of TRPV4-pathies. Qualitative description of the occurrence of skeletal, motor and sensory system dysfunctions in clinically distinct TRPV4-dependent diseases. Top: Bartholomeo Eustachi, Tabulae anatomicae, Rome, P. Junchus, 1783. Bottom: René Descartes, De homine figuris, Leiden, P. Leffen and F. Moyard, 1662. Illustrations are from the public domain of the US National Library of Medicine.

Figure 3

Five potential mechanisms coupling mutations in TRPV4 to disease pathology. See text for more details. AIP4, E3 ubiquitin ligase; NGF, nerve growth factor; TrkA, tropomyosin receptor kinase A.