PITX2 induction leads to impaired cardiomyocyte function in arrhythmogenic cardiomyopathy

Sebastiaan J van Kampen; Su Ji Han; Willem B van Ham; Eirini Kyriakopoulou; Elizabeth W Stouthart; Birgit Goversen; Jantine Monshouwer-Kloots; Ilaria Perini; Hesther de Ruiter; Petra van der Kraak; Aryan Vink; Linda W van Laake; Judith A Groeneweg; Teun P de Boer; Hoyee Tsui; Cornelis J Boogerd; Toon A B van Veen; Eva van Rooij

doi:10.1016/j.stemcr.2023.01.015

PITX2 induction leads to impaired cardiomyocyte function in arrhythmogenic cardiomyopathy

Sebastiaan J van Kampen, Su Ji Han, Willem B van Ham, Eirini Kyriakopoulou, Elizabeth W Stouthart, Birgit Goversen, Jantine Monshouwer-Kloots, Ilaria Perini, Hesther de Ruiter, Petra van der Kraak, Aryan Vink, Linda W van Laake, Judith A Groeneweg, Teun P de Boer, Hoyee Tsui, Cornelis J Boogerd, Toon A B van Veen, Eva van Rooij

Hubrecht Institute

Onderzoeksoutput: Bijdrage aan wetenschappelijk tijdschrift/periodieke uitgave › Artikel › Wetenschappelijk › peer review

1 Citaat (Scopus)

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Arrhythmogenic cardiomyopathy (ACM) is an inherited progressive disease characterized by electrophysiological and structural remodeling of the ventricles. However, the disease-causing molecular pathways, as a consequence of desmosomal mutations, are poorly understood. Here, we identified a novel missense mutation within desmoplakin in a patient clinically diagnosed with ACM. Using CRISPR-Cas9, we corrected this mutation in patient-derived human induced pluripotent stem cells (hiPSCs) and generated an independent knockin hiPSC line carrying the same mutation. Mutant cardiomyocytes displayed a decline in connexin 43, NaV1.5, and desmosomal proteins, which was accompanied by a prolonged action potential duration. Interestingly, paired-like homeodomain 2 (PITX2), a transcription factor that acts a repressor of connexin 43, NaV1.5, and desmoplakin, was induced in mutant cardiomyocytes. We validated these results in control cardiomyocytes in which PITX2 was either depleted or overexpressed. Importantly, knockdown of PITX2 in patient-derived cardiomyocytes is sufficient to restore the levels of desmoplakin, connexin 43, and NaV1.5.

Originele taal-2	Engels
Pagina's (van-tot)	749-764
Aantal pagina's	16
Tijdschrift	Stem Cell Reports
Volume	18
Nummer van het tijdschrift	3
DOI's	https://doi.org/10.1016/j.stemcr.2023.01.015
Status	Gepubliceerd - 14 mrt. 2023

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10.1016/j.stemcr.2023.01.015

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van Kampen, S. J., Han, S. J., van Ham, W. B., Kyriakopoulou, E., Stouthart, E. W., Goversen, B., Monshouwer-Kloots, J., Perini, I., de Ruiter, H., van der Kraak, P., Vink, A., van Laake, L. W., Groeneweg, J. A., de Boer, T. P., Tsui, H., Boogerd, C. J., van Veen, T. A. B., & van Rooij, E. (2023). PITX2 induction leads to impaired cardiomyocyte function in arrhythmogenic cardiomyopathy. Stem Cell Reports, 18(3), 749-764. https://doi.org/10.1016/j.stemcr.2023.01.015

@article{943d3f51bb9149bda00132ef3ff5c208,

title = "PITX2 induction leads to impaired cardiomyocyte function in arrhythmogenic cardiomyopathy",

abstract = "Arrhythmogenic cardiomyopathy (ACM) is an inherited progressive disease characterized by electrophysiological and structural remodeling of the ventricles. However, the disease-causing molecular pathways, as a consequence of desmosomal mutations, are poorly understood. Here, we identified a novel missense mutation within desmoplakin in a patient clinically diagnosed with ACM. Using CRISPR-Cas9, we corrected this mutation in patient-derived human induced pluripotent stem cells (hiPSCs) and generated an independent knockin hiPSC line carrying the same mutation. Mutant cardiomyocytes displayed a decline in connexin 43, NaV1.5, and desmosomal proteins, which was accompanied by a prolonged action potential duration. Interestingly, paired-like homeodomain 2 (PITX2), a transcription factor that acts a repressor of connexin 43, NaV1.5, and desmoplakin, was induced in mutant cardiomyocytes. We validated these results in control cardiomyocytes in which PITX2 was either depleted or overexpressed. Importantly, knockdown of PITX2 in patient-derived cardiomyocytes is sufficient to restore the levels of desmoplakin, connexin 43, and NaV1.5.",

keywords = "Humans, Myocytes, Cardiac/metabolism, Connexin 43/genetics, Desmoplakins/genetics, Induced Pluripotent Stem Cells/metabolism, Mutation, Cardiomyopathies",

author = "{van Kampen}, {Sebastiaan J} and Han, {Su Ji} and {van Ham}, {Willem B} and Eirini Kyriakopoulou and Stouthart, {Elizabeth W} and Birgit Goversen and Jantine Monshouwer-Kloots and Ilaria Perini and {de Ruiter}, Hesther and {van der Kraak}, Petra and Aryan Vink and {van Laake}, {Linda W} and Groeneweg, {Judith A} and {de Boer}, {Teun P} and Hoyee Tsui and Boogerd, {Cornelis J} and {van Veen}, {Toon A B} and {van Rooij}, Eva",

year = "2023",

month = mar,

day = "14",

doi = "10.1016/j.stemcr.2023.01.015",

language = "English",

volume = "18",

pages = "749--764",

journal = "Stem Cell Reports",

issn = "2213-6711",

publisher = "Cell Press",

number = "3",

}

van Kampen, SJ, Han, SJ, van Ham, WB, Kyriakopoulou, E, Stouthart, EW, Goversen, B, Monshouwer-Kloots, J, Perini, I, de Ruiter, H, van der Kraak, P, Vink, A, van Laake, LW, Groeneweg, JA, de Boer, TP, Tsui, H, Boogerd, CJ, van Veen, TAB & van Rooij, E 2023, 'PITX2 induction leads to impaired cardiomyocyte function in arrhythmogenic cardiomyopathy', Stem Cell Reports, vol. 18, nr. 3, blz. 749-764. https://doi.org/10.1016/j.stemcr.2023.01.015

TY - JOUR

T1 - PITX2 induction leads to impaired cardiomyocyte function in arrhythmogenic cardiomyopathy

AU - van Kampen, Sebastiaan J

AU - Han, Su Ji

AU - van Ham, Willem B

AU - Kyriakopoulou, Eirini

AU - Stouthart, Elizabeth W

AU - Goversen, Birgit

AU - Monshouwer-Kloots, Jantine

AU - Perini, Ilaria

AU - de Ruiter, Hesther

AU - van der Kraak, Petra

AU - Vink, Aryan

AU - van Laake, Linda W

AU - Groeneweg, Judith A

AU - de Boer, Teun P

AU - Tsui, Hoyee

AU - Boogerd, Cornelis J

AU - van Veen, Toon A B

AU - van Rooij, Eva

PY - 2023/3/14

Y1 - 2023/3/14

N2 - Arrhythmogenic cardiomyopathy (ACM) is an inherited progressive disease characterized by electrophysiological and structural remodeling of the ventricles. However, the disease-causing molecular pathways, as a consequence of desmosomal mutations, are poorly understood. Here, we identified a novel missense mutation within desmoplakin in a patient clinically diagnosed with ACM. Using CRISPR-Cas9, we corrected this mutation in patient-derived human induced pluripotent stem cells (hiPSCs) and generated an independent knockin hiPSC line carrying the same mutation. Mutant cardiomyocytes displayed a decline in connexin 43, NaV1.5, and desmosomal proteins, which was accompanied by a prolonged action potential duration. Interestingly, paired-like homeodomain 2 (PITX2), a transcription factor that acts a repressor of connexin 43, NaV1.5, and desmoplakin, was induced in mutant cardiomyocytes. We validated these results in control cardiomyocytes in which PITX2 was either depleted or overexpressed. Importantly, knockdown of PITX2 in patient-derived cardiomyocytes is sufficient to restore the levels of desmoplakin, connexin 43, and NaV1.5.

AB - Arrhythmogenic cardiomyopathy (ACM) is an inherited progressive disease characterized by electrophysiological and structural remodeling of the ventricles. However, the disease-causing molecular pathways, as a consequence of desmosomal mutations, are poorly understood. Here, we identified a novel missense mutation within desmoplakin in a patient clinically diagnosed with ACM. Using CRISPR-Cas9, we corrected this mutation in patient-derived human induced pluripotent stem cells (hiPSCs) and generated an independent knockin hiPSC line carrying the same mutation. Mutant cardiomyocytes displayed a decline in connexin 43, NaV1.5, and desmosomal proteins, which was accompanied by a prolonged action potential duration. Interestingly, paired-like homeodomain 2 (PITX2), a transcription factor that acts a repressor of connexin 43, NaV1.5, and desmoplakin, was induced in mutant cardiomyocytes. We validated these results in control cardiomyocytes in which PITX2 was either depleted or overexpressed. Importantly, knockdown of PITX2 in patient-derived cardiomyocytes is sufficient to restore the levels of desmoplakin, connexin 43, and NaV1.5.

KW - Humans

KW - Myocytes, Cardiac/metabolism

KW - Connexin 43/genetics

KW - Desmoplakins/genetics

KW - Induced Pluripotent Stem Cells/metabolism

KW - Mutation

KW - Cardiomyopathies

U2 - 10.1016/j.stemcr.2023.01.015

DO - 10.1016/j.stemcr.2023.01.015

M3 - Article

C2 - 36868229

SN - 2213-6711

VL - 18

SP - 749

EP - 764

JO - Stem Cell Reports

JF - Stem Cell Reports

IS - 3

ER -

PITX2 induction leads to impaired cardiomyocyte function in arrhythmogenic cardiomyopathy

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