title: Using induced pluripotent stem cells to investigate cardiac phenotypes in Timothy syndrome.
abstract: Individuals with congenital or acquired prolongation of the QT interval, or long QT syndrome (LQTS), are at risk of life-threatening ventricular arrhythmia. LQTS is commonly genetic in origin but can also be caused or exacerbated by environmental factors. A missense mutation in the L-type calcium channel Ca(V)1.2 leads to LQTS in patients with Timothy syndrome. 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 (Ca(2+)) imaging studies of these cells revealed irregular contraction, excess Ca(2+) 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 Ca(V)1.2 (refs 6-8), restored the electrical and Ca(2+) 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.
authors.affiliation: Department of Neurobiology, Stanford University School of Medicine, Stanford, California 94305, USA.
authors.forename: Masayuki
authors.initials: M
authors.lastname: Yazawa
authors.forename: Brian
authors.initials: B
authors.lastname: Hsueh
authors.forename: Xiaolin
authors.initials: X
authors.lastname: Jia
authors.forename: Anca M
authors.initials: AM
authors.lastname: Pasca
authors.forename: Jonathan A
authors.initials: JA
authors.lastname: Bernstein
authors.forename: Joachim
authors.initials: J
authors.lastname: Hallmayer
authors.forename: Ricardo E
authors.initials: RE
authors.lastname: Dolmetsch
mesh_terms: D000200:Action Potentials / Q000187:drug effects; D001321:Autistic Disorder; D020746:Calcium Channels, L-Type / Q000235:genetics / Q000378:metabolism; D020013:Calcium Signaling / Q000187:drug effects; D054338:Cell Transdifferentiation; D065150:Cellular Reprogramming / Q000235:genetics; D004353:Drug Evaluation, Preclinical / Q000379:methods*; D005347:Fibroblasts / Q000166:cytology; D057809:HEK293 Cells; D006801:Humans; D057026:Induced Pluripotent Stem Cells / Q000473:pathology*; D008133:Long QT Syndrome / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D020125:Mutation, Missense / Q000235:genetics; D032383:Myocytes, Cardiac / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology*; D018408:Patch-Clamp Techniques; D010641:Phenotype; D011687:Purines / Q000494:pharmacology; D000077546:Roscovitine; D059010:Single-Cell Analysis; D013576:Syndactyly / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism / Q000473:pathology
chemical_list: D020746:Calcium Channels, L-Type; C419385:L-type calcium channel alpha(1C); D011687:Purines; D000077546:Roscovitine