CaV1.2 Calcium Channel Dysfunction Causes a Multisystem Disorder Including Arrhythmia and Autism

@article{Splawski2004CaV12CC,
  title={CaV1.2 Calcium Channel Dysfunction Causes a Multisystem Disorder Including Arrhythmia and Autism},
  author={Igor Splawski and Katherine W. Timothy and Leah M. Sharpe and Niels Decher and Pradeep Kumar and Raffaella Bloise and Carlo Napolitano and Peter J. Schwartz and Robert M. Joseph and Karen Condouris and Helen Tager-Flusberg and Silvia G. Priori and Michael C Sanguinetti and Mark T. Brookline Keating},
  journal={Cell},
  year={2004},
  volume={119},
  pages={19-31}
}
Ca(V)1.2, the cardiac L-type calcium channel, is important for excitation and contraction of the heart. Its role in other tissues is unclear. Here we present Timothy syndrome, a novel disorder characterized by multiorgan dysfunction including lethal arrhythmias, webbing of fingers and toes, congenital heart disease, immune deficiency, intermittent hypoglycemia, cognitive abnormalities, and autism. In every case, Timothy syndrome results from the identical, de novo Ca(V)1.2 missense mutation… Expand
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Computer modeling showed prolongation of cardiomyocyte action potentials and delayed afterdepolarizations, factors that increase risk of arrhythmia, and data indicate that gain-of-function mutations of CaV1.2 exons 8 and 8A cause distinct forms of TS. Expand
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The properties of recently reported typical and atypical TS phenotypes and the effective gating changes exhibited by missense mutations associated with long QTs without extracardiac symptoms, unrelated to TS are presented and discussed. Expand
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This chapter discusses genetic abnormalities that lead to altered intracellular calcium handling and susceptibility to ventricular tachyarrhythmias, and reviews the clinical manifestations and management strategies for each of the conditions. Expand
Inherited calcium channelopathies in the pathophysiology of arrhythmias
TLDR
An overview of the structural organization and the function of calcium-handling proteins and the mechanisms by which mutations determine the clinical phenotype is provided and defects in genes encoding proteins that form the voltage-dependent L-type calcium channel are reviewed. Expand
L-type Ca2+ channel mutations and T-wave alternans: a model study.
  • Zheng I. Zhu, C. Clancy
  • Biology, Medicine
  • American journal of physiology. Heart and circulatory physiology
  • 2007
TLDR
The model simulations suggest that the Timothy Syndrome mutation is sufficient to cause the clinical phenotype and allows for the revelation of the complex interactions of currents underlying it. Expand
Calcium Signaling and Cardiac Arrhythmias.
TLDR
The key role of Ca2+ in normal cardiac function-in particular, excitation-contraction coupling and normal electric rhythms is reviewed, followed by various inherited arrhythmia syndromes caused by mutations in Ca2-handling proteins. Expand
L-type Calcium Channel Disease
TLDR
The structure, physiology, and pathophysiology of the cardiac Cav1.2 encoded by the CACNA1c gene is reviewed, which is involved in the pathogenesis of Timothy syndrome. Expand
Cellular mechanisms of ventricular arrhythmias in a mouse model of Timothy syndrome (long QT syndrome 8).
TLDR
It is proposed that CaV1.2-TS channels increase [Ca(2+)] in the cytosol and the SR, creating a Ca(2+)overloaded state that increases the probability of arrhythmogenic spontaneous SR Ca( 2+) release. Expand
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