. 2013 Nov;3(11):a014027. doi: 10.1101/cshperspect.a014027

Table 1.

Cardiac diseases for which induced pluripotent stem cell models have been generated

Disease	Affected gene and gene function	Mutation	Phenotype in hiPSC-derived cardiac cells	Cellular assays	Control iPSC lines	Patient iPSC lines	Rescue and drug testing	References
*Cardiochannelopathies*
LQT1	KCNQ1, pore-forming α subunit of the channel generating the slow component of the delayed rectifier potassium current I_Ks	c.569G > A; p.R190Q	Prolonged APD, impaired AP rate adaptation, EADs upon β-adrenergic stress, decreased I_Ks, aberrant subcellular localization of KCNQ1 owing to trafficking defect of the channel	Whole-cell patch clamp, immunohisto-chemistry	Two iPSC lines: unrelated 32- and 36- yr-old women	Two iPSC lines: 8-yr-old son and 42-yr-old father	Propanolol	Moretti et al. 2010b
		c.1893delC; p.P631fs/33	Prolonged FPD, EADs upon β-adrenergic stress, impaired I_Ks, trafficking defect of KCNQ1 to the membrane	Whole-cell patch clamp, MEA, immunohistochemistry	Two iPSC lines: unrelated individuals	One iPSC line: 13-yr-old boy	Propanolol	Egashira et al. 2012
LQT2	KCNH2, pore-forming α subunit of the channel generating the rapid component of the delayed rectifier potassium current I_Kr	c.1841C > T; p.A614V	Prolonged APD and FPD owing to reduced I_Kr, arrhythmia	Whole-cell patch clamp, MEA	One iPSC line: unrelated individual	One iPSC line: 28-yr-old woman	Nifedipine, Pinacidil, Ranolazine	Itzhaki et al. 2011a
		c.1681G > A; p.A561T	Prolonged APD and FPD, arrhythmia under β-adrenergic stress, reduced I_Kr	Whole-cell patch clamp, MEA	One iPCS line: generated from ESC-derived fibroblasts; one ESC line	Two iPSC lines: daughter and mother	Propranolol, Nicorandil, PD-118057	Matsa et al. 2011
		c.526C > T; p.R176W	Prolonged APD and FPD, reduced I_Kr, arrhythmia under β-adrenergic stress	Whole-cell patch clamp, MEA	Four iPSC lines: unrelated individuals; one ESC line	Two iPSC lines: 61-yr-old man and his sister	Erythromycin, Sotalol, Cisapride	Lahti et al. 2012
LQT3, Brugada syndrome	SCN5A, pore-forming α subunit of the cardiac Na⁺ channel	c.5387_5389insTGA; p.1795insD	Increased APD, decreased I_Na⁺	Whole-cell patch clamp	One iPSC line: unrelated 51-yr-old woman	One iPSC line: 47-yr-old man	N/A	Davis et al. 2012
Timothy syndrome (LQT8)	CACNA1C, pore-forming α subunit of L-type Ca²⁺ channel	c.1216G > A; p.G406R	Irregular contraction, increased Ca²⁺ influx, prolonged APD, irregular electrical activity, reduced voltage-dependent inactivation of L-type current, arrhythmias, abnormal Ca²⁺ transients	Whole-cell patch clamp, Ca²⁺ imaging	Two iPSC lines: unrelated individuals	Two iPCS lines	Roscovitine	Yazawa et al. 2011
CPVT1	RYR2, Ca²⁺ release channel of the SR	c.1217C > T; p.S406 L	Increased diastolic Ca²⁺, reduced SR-Ca²⁺, increased frequency and duration of Ca²⁺ sparks, arrhythmia and DADs	Whole-cell patch clamp, Ca²⁺ imaging, immuno-histochemistry	One iPSC line: unrelated 32-yr-old woman	One iPSC line: 24-yr-old woman	Dantrolene	Jung et al. 2012
		c.7447T > A; p.F2483I	DADs upon catecholaminergic stimulus, higher amplitude and longer duration of Ca²⁺ sparks	Whole-cell patch clamp, MEA, Ca²⁺ imaging	Two iPSC lines: unrelated individuals; three ESC lines	One iPSC line: 46-yr-old woman	N/A	Fatima et al. 2011
		c.12056T > G; p.M4109R	DADs, irregular Ca²⁺ transients, store-overload-induced Ca²⁺ release	Whole-cell patch clamp, MEA, Ca²⁺ imaging	One iPSC line: unrelated individual	One iPSC line: 30-yr-old woman	Flecainide, Thapsigargin	Itzhaki et al. 2012
CPVT2	CASQ2, SR Ca²⁺-binding protein	c.1183G > C; p.D307H	DADs, oscillatory arrhythmic prepotentials, after-contractions, increased diastolic Ca²⁺, less organized myofibrils, enlarged SR cisternae	Whole-cell patch clamp, Ca²⁺ imaging, TEM, immunohisto-chemistry	Three iPSC lines: unrelated 25-yr-old man, 23- and 42-yr-old woman	Two iPSC lines: 12-yr-old boy and 30-yr-old woman	N/A	Novak et al. 2012
*Cardiomyopathies*
DCM	TNTT2, cardiac troponin T, a sarcomeric protein	p.R173W	Abnormal distribution of sarcomeric protein α-actinin, increased sarcomeric disorganization upon ionotropic and mechanical stress, impaired Ca²⁺ handling, decreased contractility	TEM, immuno-histochemistry, whole-cell patch clamp, Ca²⁺ imaging, atomic force microscopy	Three iPSC lines: father, son, and grandson	Four iPSC lines: mother, two sons, and grandson	SERCA2a overexpression, metoprolol, norepinephrine	Sun et al. 2012
HCM	MYH7, β-myosin heavy chain, a sarcomeric protein	c.1988G > A; p.R663H	Hypertrophic cardiomyocytes: cellular enlargement and multinucleation, increased myofibril content and sarcomere disorganization, ANF expression, elevation of β-myosin/α-myosin ratio, calcineurin activation, NFAT nuclear translocation, contractile arrhythmia and DADs, Ca²⁺ cycling dysfunction and elevated [Ca²⁺]_i	Immunohisto-chemistry, whole-cell patch clamp, MEA, Ca²⁺ imaging	Five iPSC lines: 55-yr-old husband and 20-, 16-, 14-, and 13-yr-old children	Five iPSC lines: 53-yr-old mother and 21-, 18-, 14-, and 10-yr-old children	Propranolol, Verapamil, Nifedipin, Diltiazem, Lidocaine, Mexiletine, Ranolazine	Lan et al. 2013
LEOPARD syndrome	PTPN11, a protein tyrosine phosphatase SHP2	c.1403C > T; p.T468M	Hypertrophic cardiomyocytes: increase in size, increased sarcomeric organization, preferential nuclear localization of NFATC4, increase of phosphorylated proteins MEK1, EGFR	Cardiomyocyte cell size determination, immunohisto-chemistry, phosphoproteomics	Two iPSC lines: unrelated individual and unaffected brother of the female patient; one ESC line	Two iPSC lines: 25-yr-old woman and 34-yr-old man	N/A	Carvajal-Vergara et al. 2010
ARVC	PKP2, plakophilin 2, a desmosomal protein	c.1841T > C; p.L614P	Decreased expression of desmosomal proteins PKP2, PG, increased lipid droplets upon adipogenic stimulus	Immunohisto-chemistry, TEM, Oil Red O staining	One iPCS line: unrelated 32-yr-old man	One iPSC line: 30-yr-old man	N/A	Ma et al. 2013
		c.2484C > T; r2483_2489del c.2013delC; p.R672fsX683	Abnormal PG nuclear translocation and decreased β-catenin activity, lipogenesis and apoptosis upon adipogenic stimulus, Ca²⁺-handling defects	Immunohisto-chemistry, Nile Red staining, functional assays of FAO and glycolysis, Ca²⁺ imaging	Two iPCS lines: unrelated female and male fetuses; one ESC line	Two iPSC lines: unrelated female and male individuals	Wild-type PKP2 overexpression	Kim et al. 2013
*Vascular diseases*
Pompe’s disease	GAA, acid α glucosidase, a lysosomal glycogen-degrading enzyme	c.1935C > A/1935C > A; 1935C > A/2040 + 1G > T	Increased glycogen levels, deteriorating mitochondria, autophagosome-like structures, reduced cellular respiration	Immunohistoche-mistry, electron microscopy, O₂ consumption rate measurement	One iPSC line: unrelated individual, autologous patient’s iPSC lines with inducible GAA transgene; two hESC lines	One iPSC line per mutation	GAA transgene, rhGAA; 3-methyladenin L-carnitine	Huang et al. 2011
Hutchinson-Gilford progeria syndrome	LMNA, lamin A	c.1824C > T; p.G608G	Premature senescence of SMC associated with vascular aging: reduced telomere length, compromised cell proliferation owing to accumulation of progerin (slice variant of lamin A)	Immunohistochemistry, cell proliferation assay, telomere length analysis	Two iPSC lines: parents of the patients	Two iPSC lines	shRNA targeting progerin	Zhang et al. 2011a
SVAS/WBS	ELN, elastin, monomeric protein tropoelastin, which is secreted, cross-linked, and organized into ELN polymer	SVAS: GTAT insertion in exon 9; WBS: 1.4 MB microdeletion at 7q11.23 including ELN gene	SMCs: Decreased organization of SM α-actin filament bundles, increased proliferation, increased migration to PDGF	Immunohisto-chemistry, migration and proliferation assays	Two iPCS lines: unrelated 12- and 1-yr-old boys	Two iPSC lines: 39-yr-old man with SVAS and 1-yr-old boy with WBS	Recombinant elastin, overexpression of constitutive RhoA	Ge et al. 2012

ANF, atrial natriuretic factor; APD, action potential duration; CPVT, catecholaminergic polymorphic ventricular tachycardia; DADs, delayed after-depolarizations; DCM, dilated cardiomyopathy; EADs, early after-depolarizations; EGFR, epidermal growth factor receptor; FAO, fatty acid oxidation; FPD, field potential duration; HCM, hypertrophic cardiomyopathy; LQT, long-QT syndrome; MEA, multielectrode array; MEK1, mitogen-activated protein kinase kinase 1; NFATC4, T-cell transcription factor NFAT3; PG, plakoglobin; SERCA2a, sarco/endoplasmic reticulum Ca²⁺-ATPase; SMC, smooth muscle cell; SR, sarcoplasmic reticulum; SVAS/WBS, supraventricular arrhythmias/Williams syndrome; TEM, transmission electron microscopy.