title: Arrhythmogenesis in Timothy Syndrome is associated with defects in Ca(2+)-dependent inactivation.
abstract: Timothy Syndrome (TS) is a multisystem disorder, prominently featuring cardiac action potential prolongation with paroxysms of life-threatening arrhythmias. The underlying defect is a single de novo missense mutation in CaV1.2 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.
authors.affiliation: Calcium Signals Laboratory, Departments of Biomedical Engineering and Neuroscience, The Johns Hopkins University School of Medicine, Ross Building, Room 713, 720 Rutland Avenue, Baltimore, Maryland 21205, USA.
authors.forename: Ivy E
authors.initials: IE
authors.lastname: Dick
authors.affiliation: Calcium Signals Laboratory, Departments of Biomedical Engineering and Neuroscience, The Johns Hopkins University School of Medicine, Ross Building, Room 713, 720 Rutland Avenue, Baltimore, Maryland 21205, USA.
authors.forename: Rosy
authors.initials: R
authors.lastname: Joshi-Mukherjee
authors.affiliation: Calcium Signals Laboratory, Departments of Biomedical Engineering and Neuroscience, The Johns Hopkins University School of Medicine, Ross Building, Room 713, 720 Rutland Avenue, Baltimore, Maryland 21205, USA.
authors.forename: Wanjun
authors.initials: W
authors.lastname: Yang
authors.affiliation: Calcium Signals Laboratory, Departments of Biomedical Engineering and Neuroscience, The Johns Hopkins University School of Medicine, Ross Building, Room 713, 720 Rutland Avenue, Baltimore, Maryland 21205, USA.
authors.forename: David T
authors.initials: DT
authors.lastname: Yue
mesh_terms: D000818:Animals; D001145:Arrhythmias, Cardiac / Q000235:genetics / Q000378:metabolism*; D001321:Autistic Disorder / Q000235:genetics / Q000378:metabolism*; D002118:Calcium / Q000378:metabolism*; D020746:Calcium Channels, L-Type / Q000235:genetics / Q000378:metabolism; D005260:Female; D006168:Guinea Pigs; D006801:Humans; D008133:Long QT Syndrome / Q000235:genetics / Q000378:metabolism*; D008297:Male; D020125:Mutation, Missense; D032383:Myocytes, Cardiac / Q000378:metabolism; D013576:Syndactyly / Q000235:genetics / Q000378:metabolism*
chemical_list: D020746:Calcium Channels, L-Type; C419385:L-type calcium channel alpha(1C); D002118:Calcium
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