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The underlying defect is a single\n                    <jats:italic>de novo<\/jats:italic>\n                    missense mutation in Ca\n                    <jats:sub>V<\/jats:sub>\n                    1.2 channels, either G406R or G402S. Notably, these mutations are often viewed as equivalent, as they produce comparable defects in voltage-dependent inactivation and cause similar manifestations in patients. Yet, their effects on calcium-dependent inactivation (CDI) have remained uncertain. Here, we find a significant defect in CDI in TS channels, and uncover a remarkable divergence in the underlying mechanism for G406R versus G402S variants. Moreover, expression of these TS channels in cultured adult guinea pig myocytes, combined with a quantitative ventricular myocyte model, reveals a threshold behaviour in the induction of arrhythmias due to TS channel expression, suggesting an important therapeutic principle: a small shift in the complement of mutant versus wild-type channels may confer significant clinical improvement.\n                  <\/jats:p>","DOI":"10.1038\/ncomms10370","type":"journal-article","created":{"date-parts":[[2016,1,29]],"date-time":"2016-01-29T05:39:53Z","timestamp":1454045993000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":96,"title":["Arrhythmogenesis in Timothy Syndrome is associated with defects in Ca2+-dependent inactivation"],"prefix":"10.1038","volume":"7","author":[{"given":"Ivy E.","family":"Dick","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rosy","family":"Joshi-Mukherjee","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wanjun","family":"Yang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David T.","family":"Yue","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2016,1,29]]},"reference":[{"key":"BFncomms10370_CR1","doi-asserted-by":"publisher","first-page":"8089","DOI":"10.1073\/pnas.0502506102","volume":"102","author":"I Splawski","year":"2005","unstructured":"Splawski, I. et al. 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