The Mutation of Transient Receptor Potential Vanilloid 4 (TRPV4) Cation Channel in Human Diseases

Kang, Sang Sun

doi:10.5772/50520

Cited by 3 publications

(8 citation statements)

References 38 publications

(78 reference statements)

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“…For example, we saw an increase in SOX9 expression in V620I, while no change in T89I. Gain-offunction mutation L619F also increased SOX9 expression (Nonaka et al, 2019), while I604M, which has been reported to not alter conductivity like T89I (Sun, 2012), decreased SOX9 (Saitta (which was not certified by peer review) is the author/funder. All rights reserved.…”

Section: Discussionmentioning

confidence: 78%

“…No reuse allowed without permission. (Sun, 2012). The conflicting basal current results could be due to the species of the TRPV4, but this was not the case regarding channel activation.…”

Section: Discussionmentioning

confidence: 99%

“…In the specific cases of moderate autosomal-dominant brachyolmia and severe metatropic dysplasia, among other dysplasias, arthropathies, and neuropathies, the disease is caused by mutations in transient receptor potential vanilloid 4 (TRPV4), a non-selective cation channel (Andreucci et al, 2011;Sun, 2012). For example, a V620I substitution (exon 12, G858A) in TRPV4 is responsible for moderate brachyolmia, which exhibits short stature, scoliosis, and delayed development of deformed bones (Kang, Shin, Auh, & Chun, 2012;Rock et al, 2008;Sun, 2012). These features, albeit more severe, are also present in metatropic dysplasia.…”

Section: Introductionmentioning

confidence: 99%

“…Skeletal dysplasias comprise a heterogeneous group of over 450 bone and cartilage diseases with an overall birth incidence of 1 in 5000 (Krakow & Rimoin, 2010;Nemec et al, 2012;Ngo, Thapa, Otjen, & Kamps, 2018;Orioli, Castilla, & Barbosa-Neto, 1986;Superti-Furga & Unger, 2007). In the specific cases of moderate autosomal-dominant brachyolmia and severe metatropic dysplasia, among other dysplasias, arthropathies, and neuropathies, the disease is caused by mutations in transient receptor potential vanilloid 4 (TRPV4), a non-selective cation channel (Andreucci et al, 2011;Sun, 2012). For example, a V620I substitution (exon 12, G858A) in TRPV4 is responsible for moderate brachyolmia, which exhibits short stature, scoliosis, and delayed development of deformed bones (Kang, Shin, Auh, & Chun, 2012;Rock et al, 2008;Sun, 2012).…”

Section: Introductionmentioning

confidence: 99%

“…Metatropic dysplasia can be caused by a TRPV4 T89I substitution (exon 2, C366T) and leads to joint contractures, disproportionate measurements, and, in severe cases, death due to small chest size and cardiopulmonary compromise (Camacho et al, 2010;Kang et al, 2012;Sun, 2012).…”

Section: Introductionmentioning

confidence: 99%

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Skeletal dysplasia-causing TRPV4 mutations suppress the hypertrophic differentiation of human iPSC-derived chondrocytes

Dicks

Maksaev²,

Harissa

et al. 2021

Preprint

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Mutations in the TRPV4 ion channel can lead to a range of skeletal dysplasias. However, the mechanisms by which TRPV4 mutations lead to distinct disease severity remain unknown. Here, we use CRISPR-Cas9-edited human induced pluripotent stem cells (hiPSCs) harboring either the mild V620I or lethal T89I mutations to elucidate the differential effects on channel function and chondrogenic differentiation. We found that hiPSC-derived chondrocytes with the V620I mutation exhibited increased basal currents through TRPV4. However, both mutations showed more rapid calcium signaling with a reduced overall magnitude in response to TRPV4 agonist GSK1016790A compared to wildtype. There were no differences in overall cartilaginous matrix production, but the V620I mutation resulted in reduced mechanical properties of cartilage matrix later in chondrogenesis. mRNA sequencing revealed that both mutations upregulated several anterior HOX genes and downregulated antioxidant genes CAT and GSTA1 throughout chondrogenesis. BMP4 treatment upregulated several essential hypertrophic genes in WT chondrocytes; however, this hypertrophic maturation response was inhibited in mutant chondrocytes. These results indicate that the TRPV4 mutations alter BMP signaling in chondrocytes and prevent proper chondrocyte hypertrophy, as a potential mechanism for dysfunctional skeletal development. Our findings provide potential therapeutic targets for developing treatments for TRPV4-mediated skeletal dysplasias.

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Section: Discussionmentioning

confidence: 78%

“…No reuse allowed without permission. (Sun, 2012). The conflicting basal current results could be due to the species of the TRPV4, but this was not the case regarding channel activation.…”

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

Skeletal dysplasia-causing TRPV4 mutations suppress the hypertrophic differentiation of human iPSC-derived chondrocytes

Dicks

Maksaev²,

Harissa

et al. 2021

Preprint

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The Effect of Mutations in the TPR and Ankyrin Families of Alpha Solenoid Repeat Proteins

et al. 2021

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Protein repeats are short, highly similar peptide motifs that occur several times within a single protein, for example the TPR and Ankyrin repeats. Understanding the role of mutation in these proteins is complicated by the competing facts that 1) the repeats are much more restricted to a set sequence than non-repeat proteins, so mutations should be harmful much more often because there are more residues that are heavily restricted due to the need of the sequence to repeat and 2) the symmetry of the repeats in allows the distribution of functional contributions over a number of residues so that sometimes no specific site is singularly responsible for function (unlike enzymatic active site catalytic residues). To address this issue, we review the effects of mutations in a number of natural repeat proteins from the tetratricopeptide and Ankyrin repeat families. We find that mutations are context dependent. Some mutations are indeed highly disruptive to the function of the protein repeats while mutations in identical positions in other repeats in the same protein have little to no effect on structure or function.

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Skeletal dysplasia-causing TRPV4 mutations suppress the hypertrophic differentiation of human iPSC-derived chondrocytes

Dicks

Maksaev

Harissa

et al. 2023

eLife

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The Mutation of Transient Receptor Potential Vanilloid 4 (TRPV4) Cation Channel in Human Diseases

Cited by 3 publications

References 38 publications

Skeletal dysplasia-causing TRPV4 mutations suppress the hypertrophic differentiation of human iPSC-derived chondrocytes

Skeletal dysplasia-causing TRPV4 mutations suppress the hypertrophic differentiation of human iPSC-derived chondrocytes

The Effect of Mutations in the TPR and Ankyrin Families of Alpha Solenoid Repeat Proteins

Skeletal dysplasia-causing TRPV4 mutations suppress the hypertrophic differentiation of human iPSC-derived chondrocytes

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