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XB-ART-2951
Cell October 1, 2004; 119 (1): 19-31.

Ca(V)1.2 calcium channel dysfunction causes a multisystem disorder including arrhythmia and autism.

Splawski I , Timothy KW , Sharpe LM , Decher N , Kumar P , Bloise R , Napolitano C , Schwartz PJ , Joseph RM , Condouris K , Tager-Flusberg H , Priori SG , Sanguinetti MC , Keating MT .


Abstract
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 G406R. Ca(V)1.2 is expressed in all affected tissues. Functional expression reveals that G406R produces maintained inward Ca(2+) currents by causing nearly complete loss of voltage-dependent channel inactivation. This likely induces intracellular Ca(2+) overload in multiple cell types. In the heart, prolonged Ca(2+) current delays cardiomyocyte repolarization and increases risk of arrhythmia, the ultimate cause of death in this disorder. These discoveries establish the importance of Ca(V)1.2 in human physiology and development and implicate Ca(2+) signaling in autism.

PubMed ID: 15454078
Article link: Cell
Grant support: [+]
Genes referenced: cacna1c
GO keywords: L-type voltage-gated calcium channel complex

Disease Ontology terms: Timothy syndrome
OMIMs: TIMOTHY SYNDROME; TS [+]


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