TRPV4-pathy, a novel channelopathy affecting diverse systems

Abstract

Transient receptor potential cation channel, subfamily V, member 4 (TRPV4) is a calcium-permeable nonselective cation channel of unknown biological function. TRPV4 mutation was first identified in brachyolmia, and then in a spectrum of autosomaldominant skeletal dysplasias, which includes Kozlowski type of spondylometaphyseal dysplasia, metatropic dysplasia, Maroteaux type of spondyloepiphyseal dysplasia and parastremmatic dysplasia. Recently, TRPV4 mutation has also been identified in a spectrum of neuromuscular diseases that includes congenital distal spinal muscular atrophy (SMA), scapuloperoneal SMA, and hereditary motor and sensory neuropathy type IIC. These diverse spectrums of diseases compose a novel channelopathy, TRPV4-pathy, which could further include polygenic traits such as serum sodium concentration and a chronic obstructive pulmonary disease. In this review, we clarified the TRPV4 mutation spectrum, and discussed the phenotypic complexity of TRPV4-pathy and its pathogenic mechanisms. TRPV4-pathy may extend further to other monogenic and polygenic diseases.

Reduced penetrance in hereditary motor neuropathy caused by TRPV4 Arg269Cys mutation

“…TRPV4 mutations cause complex phenotypes with both inter-and intra-familial phenotypic variability, the unifying feature of all identified mutations being, as illustrated here, axonal neuropathy [2,10,22,31]. TRP A absence of response, ADM abductor digiti minimi, AH abductor hallucis, APB abductor pollicis brevis, CMAP compound muscle action potential, DML distal motor latency, EDB extensor digitorum brevis, ND not done, SCV sensory conduction velocity, SNAP sensory nerve action potential, TA tibialis anterior cation channels are polymodal cellular sensors that integrate diverse chemical and physical stimuli in many physiological processes [7,19,25]. Under the umbrella of TRPV4-related channelopathies there is an increasing spectrum of autosomal dominant disorders, including skeletal dysplasias, peripheral neuropathies, or both [5,31].…”

“…The mechanism of both marked phenotypic variability and reduced penetrance in TRPV4-related channelopathies remains unclear. All the mutations so far identified affect residues located in the ankyrin region of the gene [7,25,31]. At the current state of knowledge, it appears that the phenotypic diversity of TRPV4 mutations cannot be explained by simple gain/loss-of-function mechanism, but most likely involve additional molecular partners and affect different signalling networks [7].…”

Fruit Flies in Biomedical Research

“…Fly geneticists also discovered the founding member of the transient receptor potential (TRP) channels (Montell et al 1985;Montell and Rubin 1989). These channels have been shown to play critical roles in vision, pain, heat, and cold perception and the trp founding member promoted the discovery of the vertebrate homologs that are associated with numerous Mendelian diseases (Dai et al 2010;Nilius and Owsianik 2011).…”

Combined Phenotypes of Spondylometaphyseal Dysplasia-Kozlowski Type and Charcot-Marie-Tooth Disease Type 2C Secondary to a TRPV4 Pathogenic Variant

“…However, arginine substitutions in ARD are also commonly observed in TRPV4 pathogenic variants resulting in skeletal dysplasia without neurological findings [Sullivan et al, 2015]. Thus, arginine substitutions are not specific to the spectrum of TRPV4 neuromuscular disorders [Dai et al, 2010]. Based on this report in addition to previous reports, the domain location of TRPV4 pathogenic variants does not appear to exclusively predict the phenotype.…”

“…It has been proposed that the spectrum of neuromuscular disorders is caused specifically by arginine substitutions in the ankyrin repeat domains (ARD) of TRPV4 [Deng et al, 2010;Landouré et al, 2010;Sullivan et al, 2015]. However, arginine substitutions in ARD are also commonly observed in TRPV4 pathogenic variants associated with skeletal dysplasia without neurological findings [Dai et al, 2010].…”