ArticlePloS one2011
Increased basal activity is a key determinant in the severity of human skeletal dysplasia caused by TRPV4 mutations.
Article in PloS one, 2011. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 41 papers.
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Who cites it
41 citing papers in PubMed, 72 citations in OpenAlex.
- Small molecule inhibition rescues the skeletal dysplasia phenotype of Trpv4 mutant mice.JCI insight · 2026Article
- Moderately severe osteogenesis imperfecta-like osteochondrodysplasia associated with heterozygous variants in bothJBMR plus · 2025Article
- Skeletal dysplasia-causing mutations in TRPV4 alter the chondrocyte transcriptomic response to mechanical loading.American journal of physiology. Cell physiology · 2025Article
- Comparison of the natural course of clinical and radiologic features in 13 patients with TRPV4-related skeletal dysplasias.Pediatric radiology · 2025Article
- TRPV4 Channel in Neurological Disease: from Molecular Mechanisms to Therapeutic Potential.Molecular neurobiology · 2025Review
- Combined clinical, structural and cellular studies discriminate pathogenic and benign TRPV4 variants.Brain : a journal of neurology · 2025Article
- Tuning the Response of Synthetic Mechanogenetic Gene Circuits Using Mutations in TRPV4.Tissue engineering. Part A · 2025Article
- The role of transient receptor potential channels in chronic kidney disease-mineral and bone disorder.Frontiers in pharmacology · 2025Review
- Implications of mechanosensitive ion channels in the pathogenesis of osteoarthritis: a comprehensive review.Frontiers in cell and developmental biology · 2025Review
- Recent advances on the structure and the function relationships of the TRPV4 ion channel.Channels (Austin, Tex.) · 2024Review
- Identification and Properties of TRPV4 Mutant Channels Present in Polycystic Kidney Disease Patients.Function (Oxford, England) · 2024Article
- TRPV4-dependent CaBiophysical journal · 2024Article
- TRPV4-mediated CaFASEB bioAdvances · 2023Article
- Article
- Targeted Activation of G-Protein Coupled Receptor-Mediated CaTissue engineering. Part A · 2022Article
- Neuropathy-causing TRPV4 mutations disrupt TRPV4-RhoA interactions and impair neurite extension.Nature communications · 2021Article
- TRPing to the Point of Clarity: Understanding the Function of the Complex TRPV4 Ion Channel.Cells · 2021Review
- Mutations in calmodulin-binding domains of TRPV4/6 channels confer invasive properties to colon adenocarcinoma cells.Channels (Austin, Tex.) · 2020Article
- Transient receptor potential vanilloid 1 and 4 double knockout leads to increased bone mass in mice.Bone reports · 2020Article
- Volume sensing in the transient receptor potential vanilloid 4 ion channel is cell type-specific and mediated by an N-terminal volume-sensing domain.The Journal of biological chemistry · 2019Article
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Authors and funding
3 authors at 1 institution in 1 country.
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Abstract
TRPV4 is a mechanically activated Ca(2+)-passing channel implicated in the sensing of forces, including those acting on bones. To date, 33 mutations are known to affect human bone development to different extents. The spectrum of these skeletal dysplasias (SD) ranges from dominantly inherited mild brachylomia (BO) to neonatal lethal forms of metatropic dysplasia (MD). Complexities of the results from fluorescence and electrophysiological studies have led to questions on whether channel activity is a good predictor of disease severity. Here we report on a systematic examination of 14 TRPV4 mutant alleles covering the entire SD spectrum. Expressed in Xenopus oocyte and without any stimulation, the wild-type channel had a ~1% open probability (Po) while those of most of the lethal MD channels approached 100%. All mutant channels had higher basal open probabilities, which limited their further increase by agonist or hypotonicity. The magnitude of this limitation revealed a clear correlation between the degree of over-activity (the molecular phenotype) and the severity of the disease over the entire spectrum (the biological phenotype). Thus, while other factors are at play, our results are consistent with the increased TRPV4 basal activity being a critical determinant of the severity of skeletal dysplasia. We discuss how the channel over-activity may lead to the "gain-of-function" phenotype and speculate that the function of wild-type TRPV4 may be secondary in normal bone development but crucial in an acute process such as fracture repair in the adult.
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Registered trials
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