Table 1.
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 IKs | c.569G > A; p.R190Q | Prolonged APD, impaired AP rate adaptation, EADs upon β-adrenergic stress, decreased IKs, 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 IKs, 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 IKr | c.1841C > T; p.A614V | Prolonged APD and FPD owing to reduced IKr, 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 IKr | 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 IKr, 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 INa+ | 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.