Cav1.2 calcium channel dysfunction causes a multisystem disorder including arrhythmia and autism

被引:1116
作者
Splawski, I [1 ]
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
机构
[1] Harvard Univ, Sch Med, Childrens Hosp,Dept Cardiol, Dept Pediat, Boston, MA 02115 USA
[2] Harvard Univ, Sch Med, Childrens Hosp,Dept Cardiol, Dept Cell Biol, Boston, MA 02115 USA
[3] Univ Utah, Dept Human Genet, Salt Lake City, UT 84112 USA
[4] Univ Utah, Dept Physiol, Salt Lake City, UT 84112 USA
[5] Univ Utah, Nora Eccles Harrison Cardiovasc Res & Training In, Salt Lake City, UT 84112 USA
[6] IRCCS, Fdn Salvatore Maugeri, Dept Mol Cardiol, I-27100 Pavia, Italy
[7] Univ Pavia, Dept Cardiol, I-27100 Pavia, Italy
[8] IRCCS, Policlin San Matteo, I-27100 Pavia, Italy
[9] Boston Univ, Sch Med, Dept Anat & Neurobiol, Boston, MA 02118 USA
关键词
D O I
10.1016/j.cell.2004.09.011
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
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 Ca2+ currents by causing nearly complete loss of voltage-dependent channel inactivation. This likely induces intracellular Ca2+ overload in multiple cell types. In the heart, prolonged Ca2+ 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 Ca2+ signaling in autism.
引用
收藏
页码:19 / 31
页数:13
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