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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 .

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: DC03610 NIDCD NIH HHS , HL46401 NHLBI NIH HHS , HL52338 NHLBI NIH HHS , MH66398 NIMH NIH HHS, GP0227Y01 Telethon, TI_GP0227Y01 Telethon

Genes referenced: cacna1c

OMIMs referenced: TIMOTHY SYNDROME; TS [+]

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