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. 2018 Oct 15;471(5):755–768. doi: 10.1007/s00424-018-2214-0

Table 3.

Studies reporting cardiomyocyte phenotypes in hiPSC-CM from patients with genetically determined DCM or syndromes associated with DCM phenotypes or from hiPSC lines in which mutations had been introduced

Mutation Disease Peak force T1 T2 Cell size Disarray Other phenotypes CRISPR/TALEN Ctr. Karyotype Ctr. Reference
TNNT2
Het p.Arg173Trp		 DCM − 80% (AFM) n.d. n.d. +/− Yes Desensitized NE response of rate, RMP − 40 mV, APD +/−, smaller Ca2+ and caffeine transient (~2 s), TTP and TTD caffeine + 100% (WT 0.5/1.2 s), rescue by SERCA OE, metoprolol rescues disorganization No Yes [87]
LMNA
Het p.Arg225X (n = 3), another fs mut		 DCM n.d. n.d. n.d. n.d. n.d. Nuclear abnormalities, apoptosis,MEK-inhibition-sensitive, ERK up No Yes [84]
DES
Het p.Ala285Val, + 43 stop/gain mut		 DCM n.d. n.d. n.d. n.d. n.d. Morphological abnormalities + 700%, aggregates, peak Ca2+ transient +/−, − dF/dt − 40%, abnormal Iso response No No [91]
TAZ
Het c.517delG Het c.328T>C		 Barth − 50–70% n.d. n.d. n.d. Yes Decreased mito ox rate, immature cardiolipin, reduced ATP content, excess ROS, tafazzin-sensitive, MitoTempo-sensitive Yes Yes [99]
TNNT2
p.Arg173Trp		 DCM − 60% (TFM) n.d. n.d. n.d. n.d. ISO response down, TTP/TTD +/− (~1 s), cAMP response to Iso − 50%, rate − 60%, PDE2,3,5 mRNA several folds up, rescue of cAMP and force by FSK + IBMX No No [103]
TTN
p.Ser14450fsX4		 DCM n.d. n.d. n.d. n.d. Yes MYH6, MYH7, ACTC1–50%, rescue by exon skipping No No [29]
DMD
Dp427m		 DMD n.d. n.d. n.d. n.d. n.d. More apoptosis, almost complete lack of MYL2, MYL3 and TPM1 mRNA, ICa − 40%, resting [Ca2+] + 40%, beneficial effects by Poloxamer 188 No [54]
TTN
3 diff. Truncating mut, CRISPR induction		 DCM − 60–80% (EHT) n.d. n.d. n.d. + 400% Stronger phenotype on stiffer posts, rate − 50%, lower SL (1.6 vs. 1,75 μm), lower MYH7/MYH6 ratio, beneficial effect of VEGF No No [35]
PLN
Het p.Arg14del
(R14del)		 DCM − 60–90% n.d. up n.d. n.d. Resting [Ca2+] + 30%, irregular Ca2+ transient + 500%, caffeine transient + 75%, RMP − 49 vs. − 58 mV, NPPA/NPPB + 300–900%, MYH7/MYH6 + 60% Off-target effects Yes [43]
RBM20
p.Arg636Ser
2 clones each WT/mut		 DCM n.d. n.d. n.d. n.d. Yes Increased sarcomere length (WT 1.4 μm), increased Ca2+ peak, AUC, decay time at much lower rate Yes [104]
TNNT2
p.Arg173Trp
2 clones each		 DCM (−) Inconsistent n.d. n.d. n.d. Yes Lower rate of cells beat, myosin ATPase − 20%, beneficial effects of omecamtiv No [9]
RBM20
p.Ser635Ala
2 clones each		 DCM − 40% (EHT) +/− (100 μm2) Yes Actinin periodicity − 80%, lower resting [Ca2+], peak [Ca2+] + 50%, TTP/TTD + 60/150%, duration + 150%, all at 70% lower rate, normal Iso force response, lower length-stress response, TTN + MYH7 exon exclusion No [86]
BAG3
KO induced in WT, 2 lines
MYBPC3 KO		 DCM − 50% (MTF) n.d. n.d. n.d. Yes Stronger disarray increased by bortezomib, normal bortezomib-response in MYBPC3-KO Yes Yes [42]
DMD
3 different mut		 DMD − 30–70% (EHT) n.d. n.d. n.d. n.d. Correction of phenotype by CRISPR Yes No [55]
DMPK
CTG repeats in, 4 × 6 clones analysed		 DM1 Rundown n.d. n.d. n.d. n.d. Nuclear RNA CUG foci, nuclear size + 30%, irregularity, MDP − 52 vs. − 60 mV, APD − 20%, AP amplitude − 20%, upstroke velocity down, force rundown (AFM); altered splicing of MBNL1, MBNL2, TNNT2, SCN5A; fetal SCN5A isoforms, α-MHC and TnT protein down No Yes [85]

ACTC1 α-cardiac actin gene, α-MHC α-myosin heavy chain, AFM atomic force microscopy, ANP/BNP atrial/brain natriuretic peptide, AP action potential, APD action potential duration, AUC area under the curve, BAG3 BCL2-associated athanogene 3, cAMP cyclic adenosine monophosphate, CRISPR clustered regularly interspaced short palindromic repeats/Cas 9 gene correction, DES desmin gene, Disarray abnormal sarcomeric organization, DM1 myotonic dystrophy type 1, DMD Duchenne muscular dystrophy, DMD dystrophin gene, DMPK dystrophia myotonica protein kinase, EHT engineered heart tissue, ERK extracellular signal-regulated kinase, an important MAPK, Fs frameshift, FSK forskolin, IBMX isobutylmethylxanthine, ICa L-type Ca2+ current, Iso isoprenaline, KO knockout, LMNA lamin A/C gene, MBNL muscle blind-like, MDP maximal diastolic potential, MEK mitogen-activated protein (MAPK) kinase kinase, Mut mutation, MYBPC3 cardiac myosin-binding protein C (cMyBPC) gene, MYH6/MYH7 mRNA of α-/β-myosin heavy chain, MYL2 regulatory myosin light chain gene, ventricular isoform (MLC2v), MYL3 essential myosin light chain gene (MLC1v), NPPA atrial natriuretic peptide gene/mRNA, NPPB brain natriuretic peptide gene/mRNA, NE norepinephrine, PDE phosphodiesterase, PLN phospholamban gene, RBM20 RNA binding motif protein 20 gene, RMP resting membrane potential, ROS reactive oxygen species, SCN5A sodium voltage-gated channel alpha subunit 5 (Nav1.5) gene, SERCA OE sarcoplasmic reticulum ATPase overexpression, SL sarcomere length, T1 time to peak force, T2 time from peak to relaxation, TALEN transcription activator-like effector nuclease-mediated gene correction, TAZ tafazzin gene, TFM traction force microscopy, TNNT2 cardiac troponin T gene/mRNA, TnT cardiac troponin T, TPM1 tropomyosin gene, TTD time-to-decay, TTN titin gene, TTP time-to-peak, VEGF vascular endothelial growth factor, WT wild type