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Table 3 Studies reporting phenotypes of human iPSC-CM lines with HCM mutations

From: Modeling hypertrophic cardiomyopathy with human cardiomyocytes derived from induced pluripotent stem cells

Mutation

Cell line

Peak force

T1

T2

Cell size

Disarray

Multinucleation

Other phenotypes

Reference

MYH7

Het p.Arg663His

Patient

NA

NA

NA

 + 60%

 + 250%

50% vs. 20%

Increased normalized contractile motion, elevated [Ca2+]i, decreased Ca2+ release, increased DAD

[79]

MYBPC3

Het Gly999-Gln1004del

Patient

NA

NA

NA

 + 20%

 + 50%

NA

cMyBPC–20%

[153]

MYBPC3

Het Exon 25

Patient

NA

NA

NA

 + 50 − 100%

NA

NA

NA

[154]

MYH7

Het p.Arg442Gly

Patient

NA

NA

NA

 + 15%

 + 150%

NA

Resting [Ca2+]i + 20%, decreased Ca2+ store, APD prolongation + 60%, arrhythmias + 300%, ICa and INa up

[155]

MYBPC3

Het c.2373dupG

Patient

 − 50%

NA

NA

±

NA

NA

cMyBPC haploinsufficiency

[156]

TPM1

Het p.Asp175Asn

MYBPC3

Het p.Gln1061X

Patient

NA

NA

NA

± (T);

 + 100% (M)

NA

40% vs. 20% (T); 45% vs. 20% (M)

Prolonged APD, increased arrhythmias (T, not M), increased DAD (M, not T), TPM1 up in T, MYBPC3 up in M

[157]

MYH7

Het p.Glu848Gly

Patient

 − 50%

NA

NA

 + 40%

Yes, but not quantified

NA

Increased Ca2+ sensitivity, KAct + 60%

[158]

MYH7

Het p.Val698Al

Patient

NA

NA

NA

NA

NA

NA

NA

[159]

MYBPC3

Het c.1358-1359insC

Patient

NA

NA

NA

 + 65%

NA

NA

cMyBPC haploinsufficiency

[160]

TNNT2

Het c.236 T > A

Isogenic

NA

NA

NA

NA

NA

NA

Increased Ca2+ sensitivity, decreased peak Ca2+ transients, APD50 prolongation + 70%

[161]

MYBPC3

Het Δ25/ p.Asp389Val

Patient

NA

NA

NA

 + 100%

NA

NA

Ca2+ transient irregularities + 500%

[162]

MT-RNR2

Het m.2336 T > C

Patient

NA

NA

NA

 + 27%

No

NA

[Ca2+]i + 60%, increased SR store, ICa − 43%, APD prolongation + 14%, increased DAD, mitochondrial 16S rRNA − 55%, MMP − 25%, ATP/ADP ratio − 53%;

[163]

MYL3

Het c.170C > G

MYBPC3

Het p.Val321Met

Patient and isogenic

NA

NA

NA

±

No

NA

Increased diastolic [Ca2+]i, DAD, contraction and relaxation (in MYL3, not MYBPC3) velocity slightly up

[164]

TNNT2

Het p.Ile79Asn

Patient

NA

 + 75%

 + 30%

±

 + 60%

NA

Decreased sarcomere length, increased Ca2+ sensitivity, higher Ca2 + buffering, decreased peak Ca2+ transients, shortened early repolarization

[165]

MYH7

Het/Hom c.C9123T

Isogenic

 − 20% (Het); − 70% (Hom)

 + 20%

±

 + 50%

Yes

2% vs. 1%

Increased DAD, basal and maximal respiration up, increased ATP production, MYH7/MYH6 ratio up

[166]

TPM1

Het p.Asp175Asn MYBPC3

Het p.Gln1061X

Patient

NA

NA

NA

NA

NA

NA

Decreased ICa, increased Ito and IK1, increased DAD and EAD

[167]

MYH7

Het p.Arg723Cys;

MYH7

Het p.Arg403Gln;

MYH7

Het p.Arg663His;

MYBPC3

Het p.Arg943x;

TNNI3

Het p.Arg186Gln

Patient

NA

NA

NA

NA

NA

NA

NA

[168]

MYH7

Het p.Glu848Gly

Patient

 − 75%

 − 30%

 − 10%

±

Yes

NA

Impaired fractional shortening, maximal contraction velocity + 15%

[169]

ACTC1

Het p.Glu99Lys

Patient

 + 300% (K1); − 50% (K2)

±(K1); + 50% (K2)

NA

NA

NA

NA

Contraction velocity (K1 up, K2 down), TTP + 115% (K1), CTD90 + 31.4% (K1), increased arrhythmias (K2), increased DAD (K1)

[170]

MYH7

Het p.Arg403Gln;

MYBPC3

Het p.Trp792ValfsX41; MYBPC3

Het p.Arg502Trp

Patient

 + 50 − 100%

±

 + 20 − 65%

 + 30%

 + 60%

NA

Maximal contraction velocity + 79%–121%, highly activated p53 and p21 pathways, elevated mitochondrial content, increased ROS, and elevated ratio of ADP/ATP

[171]

MYBPC3

Het p.Arg943x;

MYBPC3

Het p.Arg1073Pro

Patient and isogenic

±(Het); − 60% (Hom)

NA

NA

±

±

NA

Increased diastolic [Ca2+]i, slower Ca2+ decay, decreased contraction and relaxation velocity (Hom), downregulated expression of ATP2A2

[172]

ACTN2

Het p.Thr247Met

Patient

 + 19%

±

 + 17%

 + 80%

 + 38%

NA

Increased Ca2 + sensitivity, elevated action potential amplitude, APD prolongation + 50%, increased ICa, transcript levels of ACTN2 + 200%

[173]

MYL2

Het p.Arg58Gln

Patient

NA

NA

 + 90%

 + 29%

 + 100%

NA

Diastolic [Ca2+]i − 23%, peak Ca2+ transients − 45%, Ca2+ decay tau + 38%, ICa − 45%, increased arrhythmias

[174]

MYH7

Het p.Arg663His;

MYBPC3

Het p.Val321Met;

MYBPC3

Het p.Val219Leu;

TNNT2

Het p.Arg92Trp

Patient and isogenic

NA

NA

NA

NA

NA

NA

Increased diastolic [Ca2+]i and Ca2 + sensitivity, slower Ca2+ decay, reduced NCX function, decreased sarcomere length, increased maximal contraction velocity, decreased maximal relaxation velocity

[88]

MYH7

Het/Hom c. 9123C > T;

ACTC1

Het/Hom c. 301 G > A

Patient and isogenic

 − 32 − 53% (M); + 41% (A)

 + 10% (M);

 + 47% (A)

 + 20% (M); + 38% (A)

Increased

Yes

NA

Increased diastolic [Ca2+]i (M, not A), elevated systolic [Ca2+]i, increased spontaneous beat rate (M, not A), increased arrhythmias, basal and maximal respirations up

[175]

MYH7

Het p.Arg403Gln

Patient

 + 100%

NA

NA

 + 33%

NA

NA

Increased maximal contraction and relaxation velocity

[176]

MYBPC3

Het c.1377delC

Patient

NA

NA

NA

NA

NA

NA

NA

[177]

MYBPC3

Het Δ25/ p.Asp389Val;    MYH7  Het p.Arg243Cys

Patient

NA

±

 + 24% (MYBPC3); + 39% (MYH7)

 + 76% (MYBPC3); + 180% (MYH7)

NA

23% vs. 6% (MYBPC3); 54% vs. 6% (MYH7)

Increased Ca2+ decay tau, increased arrhythmias, relaxation velocity down

[178]

  1. ACTC1 Cardiac α-actin gene; AP Action potential; APD Action potential duration; ATP2A2 ATPase sarcoplasmic/endoplasmic reticulum Ca2+ transporting 2 gene; [Ca2+]i Intracellular calcium concentration; cMyBPC Cardiac myosin-binding protein C; CTD90 Time from peak Ca2+ to 90% return to baseline; DAD Delayed after depolarization; Del Deletion; Disarray Abnormal sarcomeric organization; EAD Early after depolarization; Het Heterozygous; Hom Homozygous; ICa L-type Ca2+ current; IK1 Inward rectifier potassium; INa Na + current; Ito Transient outward potassium; KAct rate constant reflecting crossbridge turnover rate; MMP Mitochondrial membrane potential; MYBPC3 Cardiac myosin-binding protein C gene; MYH6/MYH7 α-/β-myosin heavy chain gene; MYL2 Myosin light chain 2 gene; MYL3 Myosin light chain 3 gene; MT-RNR2 Mitochondrially encoded 16S RNA gene; NCX Sodium–calcium exchanger; ROS Reactive oxygen species; SR Sarcoplasmic reticulum; T1 time to peak force; T2 Time from peak to relaxation; TNNI3 Cardiac troponin I gene; TNNT2 Cardiac troponin T gene; TPM α-tropomyosin; TPM1 α-tropomyosin gene; TTP Time to peak Ca.2+; Δ25 Δ25 bp intronic deletion in the MYBPC3; ±No difference; NA Not assayed