{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,16]],"date-time":"2026-07-16T05:47:24Z","timestamp":1784180844443,"version":"3.55.0"},"reference-count":23,"publisher":"Wiley","issue":"10","license":[{"start":{"date-parts":[[2015,8,6]],"date-time":"2015-08-06T00:00:00Z","timestamp":1438819200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"name":"Nemours Foundation Cluster Grant Program"},{"DOI":"10.13039\/100013429","name":"Delaware INBRE","doi-asserted-by":"crossref","award":["5P20GM103446"],"award-info":[{"award-number":["5P20GM103446"]}],"id":[{"id":"10.13039\/100013429","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["American J of Med Genetics Pt A"],"published-print":{"date-parts":[[2015,10]]},"abstract":"<jats:sec><jats:label\/><jats:p>Transient receptor potential cation channel, subfamily V, member 4 (TRPV4) is a polymodal modulated non\u2010selective cation channel required for normal development and maintenance of bone and cartilage. Heterozygous mutations of this channel cause a variety of channelopathies, including metatropic dysplasia (MD). We analyzed the effect of a novel <jats:italic>TRPV4<\/jats:italic> mutation c.2398G&gt;A, p.Gly800Asp on intracellular calcium ([Ca<jats:sup>2+<\/jats:sup>]<jats:sub>i<\/jats:sub>) regulation in chondrocytes and compared this response to chondrocytes with a frequently observed mutation, c.2396C&gt;T, p.Pro799Leu. We observed temperature\u2010dependent [Ca<jats:sup>2+<\/jats:sup>]<jats:sub>i<\/jats:sub> oscillations in both intact and MD chondrocytes however, MD mutations exhibited increased peak magnitudes of [Ca<jats:sup>2+<\/jats:sup>]<jats:sub>i<\/jats:sub> during oscillations. We also found increased baseline [Ca<jats:sup>2+<\/jats:sup>]<jats:sub>i<\/jats:sub> in MD primary cells, as well as increased [Ca<jats:sup>2+<\/jats:sup>]<jats:sub>i<\/jats:sub> response to either hypotonic swelling or the TRVP4\u2010specific agonist, GSK1016790A. Oscillations and stimulation responses were blocked with the TRPV4\u2010specific antagonist, GSK205. Analysis of [Ca<jats:sup>2+<\/jats:sup>]<jats:sub>i<\/jats:sub> response kinetics showed that MD chondrocytes had increased frequency of temperature\u2010sensitive oscillations, and the magnitude and duration of [Ca<jats:sup>2+<\/jats:sup>]<jats:sub>i<\/jats:sub> responses to given stimuli. Duration of the response of the p.Gly800Asp mutation to stimulation was greater than for the p.Pro799Leu mutation. These experiments show that this region of the channel is essential for proper [Ca<jats:sup>2+<\/jats:sup>]<jats:sub>i<\/jats:sub> regulation. These studies of primary cells from patients show how both mutant and WT TRPV4 channels regulate cartilage and bone development. \u00a9 2015 Wiley Periodicals, Inc.<\/jats:p><\/jats:sec>","DOI":"10.1002\/ajmg.a.37182","type":"journal-article","created":{"date-parts":[[2015,8,7]],"date-time":"2015-08-07T05:05:02Z","timestamp":1438923902000},"page":"2286-2293","source":"Crossref","is-referenced-by-count":28,"title":["A mutation in <i>TRPV4<\/i> results in altered chondrocyte calcium signaling in severe metatropic dysplasia"],"prefix":"10.1002","volume":"167","author":[{"given":"Lauren","family":"Hurd","sequence":"first","affiliation":[{"name":"Department of Biological Sciences University of Delaware Newark Delaware"},{"name":"Molecular Diagnostics Laboratory Nemours\/Alfred I. duPont Hospital for Children Wilmington Delaware"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Susan M.","family":"Kirwin","sequence":"additional","affiliation":[{"name":"Molecular Diagnostics 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