title: Modeling Timothy syndrome with iPS cells.
abstract: Genetic mutations in ion channel genes that are associated with cardiac arrhythmias have been identified over the past several decades. However, little is known about the pathophysiological processes. An important limitation has been the difficulty of using human cardiomyocytes to study arrhythmias and identify drugs. To circumvent this issue, we have developed a method using human-induced pluripotent stem cells to generate cardiomyocytes from individuals with Timothy syndrome (TS), a genetic disorder characterized by QT prolongation, ventricular tachycardia, and autism. The TS ventricular-like cardiomyocytes exhibit deficits in contraction, electrical signaling, and calcium handling, as revealed by live cell imaging and electrophysiological studies. We tested candidate drugs in TS cardiomyocytes and found that roscovitine could successfully rescue these cellular phenotypes. The use of a human cellular model of cardiac arrhythmias provides a useful new platform not only to study disease mechanisms but also to develop new therapies to treat cardiac arrhythmias.
authors.affiliation: Department of Neurobiology, Stanford University School of Medicine, Stanford, CA, USA.
authors.forename: Masayuki
authors.initials: M
authors.lastname: Yazawa
authors.forename: Ricardo E
authors.initials: RE
authors.lastname: Dolmetsch
mesh_terms: D000200:Action Potentials; D000889:Anti-Arrhythmia Agents / Q000494:pharmacology; D001321:Autistic Disorder; D020746:Calcium Channels, L-Type / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D020013:Calcium Signaling; D002460:Cell Line; D020022:Genetic Predisposition to Disease; D006801:Humans; D057026:Induced Pluripotent Stem Cells / Q000187:drug effects / Q000378:metabolism*; D007700:Kinetics; D008133:Long QT Syndrome / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology; D009154:Mutation; D009200:Myocardial Contraction; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000378:metabolism*; D010641:Phenotype; D011687:Purines / Q000494:pharmacology; D000077546:Roscovitine; D013576:Syndactyly / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology
chemical_list: D000889:Anti-Arrhythmia Agents; C079146:CACNA1C protein, human; D020746:Calcium Channels, L-Type; D011687:Purines; D000077546:Roscovitine