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Using induced pluripotent stem cells to investigate cardiac phenotypes in Timothy syndrome

2011; Nature Portfolio; Volume: 471; Issue: 7337 Linguagem: Inglês

10.1038/nature09855

1476-4687

Masayuki Yazawa, Brian Hsueh, Xiaolin Jia, Anca M. Pașca, Jonathan A. Bernstein, Joachim Hallmayer, Ricardo E. Dolmetsch,

Pluripotent Stem Cells Research

It is difficult to model cardiac arrhythmias in mice and other genetically tractable animals because the mechanisms of cardiomyocyte contraction in these animals are unlike those in humans. A new model for studying these conditions is reported, in the form of cardiomyocytes produced from induced pluripotent stem cells derived by reprogramming fibroblasts from two patients with Timothy syndrome, a disorder characterized by autism, immune deficiency and cardiac arrhythmias. The abnormal electrical and calcium-signalling properties of these patients' cells were restored by a drug, roscovitine, known to increase voltage-dependent inactivation of CaV1.2, a calcium channel that is defective in patients with Timothy syndrome. A mutation in the gene CACNA1C, encoding the L-type calcium channel CaV1.2 in humans, causes Timothy syndrome, a disorder characterized by autism, syndactyly, immune deficiency and cardiac arrhythmias. This study generated induced pluripotent stem cells from the fibroblasts of two patients with Timothy syndrome and converted them into cardiac cells. The patient cells displayed abnormal electrical and calcium signalling properties, which were restored by a drug, roscovitine, known to increase the voltage-dependent inactivation of CaV1.2. Individuals with congenital or acquired prolongation of the QT interval, or long QT syndrome (LQTS), are at risk of life-threatening ventricular arrhythmia1,2. LQTS is commonly genetic in origin but can also be caused or exacerbated by environmental factors1,3. A missense mutation in the L-type calcium channel CaV1.2 leads to LQTS in patients with Timothy syndrome4,5. To explore the effect of the Timothy syndrome mutation on the electrical activity and contraction of human cardiomyocytes, we reprogrammed human skin cells from Timothy syndrome patients to generate induced pluripotent stem cells, and differentiated these cells into cardiomyocytes. Electrophysiological recording and calcium (Ca2+) imaging studies of these cells revealed irregular contraction, excess Ca2+ influx, prolonged action potentials, irregular electrical activity and abnormal calcium transients in ventricular-like cells. We found that roscovitine, a compound that increases the voltage-dependent inactivation of CaV1.2 (refs 6–8), restored the electrical and Ca2+ signalling properties of cardiomyocytes from Timothy syndrome patients. This study provides new opportunities for studying the molecular and cellular mechanisms of cardiac arrhythmias in humans, and provides a robust assay for developing new drugs to treat these diseases.