Submission Details

TRPV4 was first reported concurrently in relation to autosomal dominant neuromuscular disease in 2010 (Auer-Grumbach et al., PMID: 20037588; Landoure et al., PMID: 20037586). Variants in this gene, which encodes a cell surface calcium-permeable cation channel, have been associated with several disorders including skeletal dysplasias (Brachyolmia, Metatropic dysplasia, etc.), motor-neuropathies (congenital/scapuloperoneal spinal muscle atrophy), and a motor-sensory neuropathy (Charcot-Marie-Tooth disease). As the latter two groups are generally considered a spectrum of disease with variable severity (Toft-Bertelsen and MacAulay, PMID: 33467654), these entities have been evaluated together for the purposes of this curation. The skeletal dysplasias will be evaluated separately. At least fifteen unique variants, usually missense, have been reported in humans. Evidence supporting this gene-disease relationship includes case-level data, segregation data, and experimental data. Variants in this gene have been reported in at least eighteen probands in five publications (PMIDs: 20037586, 20037588, 27066566, 20460441, 25900305). Variants in this gene also segregated with the disorder in over twenty-five additional family members, the majority of which were confirmed via whole exome sequencing. More evidence is available in the literature, but the maximum score for genetic evidence (12 pts.) has been reached. The mechanism for disease is gain-of-function, typically with the mutant incorporating with the wild-type into tetrameric channels and causing variable trafficking modifications. TRPV4 variants do not show any significant genotype-phenotype correlation, with the harboring domain bearing little relation to the resulting phenotypic entity (Toft-Bertelsen and MacAulay). This gene-disease association is additionally supported by a limited amount of experimental evidence. Functional evidence demonstrates that neuropathy mutants disrupt TRPV4's interaction with the GTPase RhoA, as there is a striking reduction of wildtype TRPV4-RhoA interaction when in a tetramer with the neuropathy mutants and no effect with dysplasia mutants (McCray et al., PMID: 33664271). The mild phenotype of TRPV4-null mice and undesirable side effects of TRPV4 inhibitors limit the usefulness of traditional animal models, however there have been several that elucidate some amount of evidence towards the gene's pathogenicity (Everaerts et al., PMID: 20956320). Both a roundworm and drosophila model have been characterized, with the drosophila model utilizing a common neuropathy variant p.Arg269Cys that resulted in variable neuronal and muscular defects. Notably, these effects could be suppressed via TRPV4 inhibitors or ion-channel disruption, indicating a dose-dependent toxic gain-of-function that matched the human probands (Woolums et al., PMID: 32471994). In summary, TRPV4 is definitively associated with autosomal dominant neuromuscular disease. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time.