Disease modeling of a mutation in α‐actinin 2 guides clinical therapy in hypertrophic cardiomyopathy
Abstract Hypertrophic cardiomyopathy (HCM) is a cardiac genetic disease accompanied by structural and contractile alterations. We identified a rare c.740C>T (p.T247M) mutation in ACTN2, encoding α‐actinin 2 in a HCM patient, who presented with left ventricular hypertrophy, outflow tract obstructi...
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Springer Nature
2019-11-01
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| Series: | EMBO Molecular Medicine |
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| Online Access: | https://doi.org/10.15252/emmm.201911115 |
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| author | Maksymilian Prondzynski Marc D Lemoine Antonia TL Zech András Horváth Vittoria Di Mauro Jussi T Koivumäki Nico Kresin Josefine Busch Tobias Krause Elisabeth Krämer Saskia Schlossarek Michael Spohn Felix W Friedrich Julia Münch Sandra D Laufer Charles Redwood Alexander E Volk Arne Hansen Giulia Mearini Daniele Catalucci Christian Meyer Torsten Christ Monica Patten Thomas Eschenhagen Lucie Carrier |
| author_facet | Maksymilian Prondzynski Marc D Lemoine Antonia TL Zech András Horváth Vittoria Di Mauro Jussi T Koivumäki Nico Kresin Josefine Busch Tobias Krause Elisabeth Krämer Saskia Schlossarek Michael Spohn Felix W Friedrich Julia Münch Sandra D Laufer Charles Redwood Alexander E Volk Arne Hansen Giulia Mearini Daniele Catalucci Christian Meyer Torsten Christ Monica Patten Thomas Eschenhagen Lucie Carrier |
| author_sort | Maksymilian Prondzynski |
| collection | DOAJ |
| description | Abstract Hypertrophic cardiomyopathy (HCM) is a cardiac genetic disease accompanied by structural and contractile alterations. We identified a rare c.740C>T (p.T247M) mutation in ACTN2, encoding α‐actinin 2 in a HCM patient, who presented with left ventricular hypertrophy, outflow tract obstruction, and atrial fibrillation. We generated patient‐derived human‐induced pluripotent stem cells (hiPSCs) and show that hiPSC‐derived cardiomyocytes and engineered heart tissues recapitulated several hallmarks of HCM, such as hypertrophy, myofibrillar disarray, hypercontractility, impaired relaxation, and higher myofilament Ca2+ sensitivity, and also prolonged action potential duration and enhanced L‐type Ca2+ current. The L‐type Ca2+ channel blocker diltiazem reduced force amplitude, relaxation, and action potential duration to a greater extent in HCM than in isogenic control. We translated our findings to patient care and showed that diltiazem application ameliorated the prolonged QTc interval in HCM‐affected son and sister of the index patient. These data provide evidence for this ACTN2 mutation to be disease‐causing in cardiomyocytes, guiding clinical therapy in this HCM family. This study may serve as a proof‐of‐principle for the use of hiPSC for personalized treatment of cardiomyopathies. |
| format | Article |
| id | doaj-art-3dc134090e7a4e27beee5c5b257be092 |
| institution | DOAJ |
| issn | 1757-4676 1757-4684 |
| language | English |
| publishDate | 2019-11-01 |
| publisher | Springer Nature |
| record_format | Article |
| series | EMBO Molecular Medicine |
| spelling | doaj-art-3dc134090e7a4e27beee5c5b257be0922025-08-20T03:06:01ZengSpringer NatureEMBO Molecular Medicine1757-46761757-46842019-11-01111211810.15252/emmm.201911115Disease modeling of a mutation in α‐actinin 2 guides clinical therapy in hypertrophic cardiomyopathyMaksymilian Prondzynski0Marc D Lemoine1Antonia TL Zech2András Horváth3Vittoria Di Mauro4Jussi T Koivumäki5Nico Kresin6Josefine Busch7Tobias Krause8Elisabeth Krämer9Saskia Schlossarek10Michael Spohn11Felix W Friedrich12Julia Münch13Sandra D Laufer14Charles Redwood15Alexander E Volk16Arne Hansen17Giulia Mearini18Daniele Catalucci19Christian Meyer20Torsten Christ21Monica Patten22Thomas Eschenhagen23Lucie Carrier24Institute of Experimental Pharmacology and Toxicology, University Medical Center Hamburg‐EppendorfInstitute of Experimental Pharmacology and Toxicology, University Medical Center Hamburg‐EppendorfInstitute of Experimental Pharmacology and Toxicology, University Medical Center Hamburg‐EppendorfInstitute of Experimental Pharmacology and Toxicology, University Medical Center Hamburg‐EppendorfInstitute of Genetics and Biomedical Research, Milan Unit, National Research CouncilFaculty of Medicine and Health Technology, Tampere UniversityInstitute of Experimental Pharmacology and Toxicology, University Medical Center Hamburg‐EppendorfInstitute of Experimental Pharmacology and Toxicology, University Medical Center Hamburg‐EppendorfInstitute of Experimental Pharmacology and Toxicology, University Medical Center Hamburg‐EppendorfInstitute of Experimental Pharmacology and Toxicology, University Medical Center Hamburg‐EppendorfInstitute of Experimental Pharmacology and Toxicology, University Medical Center Hamburg‐EppendorfBioinformatics Core, University Medical Center Hamburg‐EppendorfInstitute of Experimental Pharmacology and Toxicology, University Medical Center Hamburg‐EppendorfDepartment of Cardiology‐Electrophysiology, University Heart and Vascular CenterInstitute of Experimental Pharmacology and Toxicology, University Medical Center Hamburg‐EppendorfRadcliffe Department of Medicine, University of OxfordInstitute of Human Genetics, University Medical Center Hamburg‐EppendorfInstitute of Experimental Pharmacology and Toxicology, University Medical Center Hamburg‐EppendorfInstitute of Experimental Pharmacology and Toxicology, University Medical Center Hamburg‐EppendorfInstitute of Genetics and Biomedical Research, Milan Unit, National Research CouncilDZHK (German Centre for Cardiovascular Research), partner site Hamburg/Kiel/LübeckInstitute of Experimental Pharmacology and Toxicology, University Medical Center Hamburg‐EppendorfDZHK (German Centre for Cardiovascular Research), partner site Hamburg/Kiel/LübeckInstitute of Experimental Pharmacology and Toxicology, University Medical Center Hamburg‐EppendorfInstitute of Experimental Pharmacology and Toxicology, University Medical Center Hamburg‐EppendorfAbstract Hypertrophic cardiomyopathy (HCM) is a cardiac genetic disease accompanied by structural and contractile alterations. We identified a rare c.740C>T (p.T247M) mutation in ACTN2, encoding α‐actinin 2 in a HCM patient, who presented with left ventricular hypertrophy, outflow tract obstruction, and atrial fibrillation. We generated patient‐derived human‐induced pluripotent stem cells (hiPSCs) and show that hiPSC‐derived cardiomyocytes and engineered heart tissues recapitulated several hallmarks of HCM, such as hypertrophy, myofibrillar disarray, hypercontractility, impaired relaxation, and higher myofilament Ca2+ sensitivity, and also prolonged action potential duration and enhanced L‐type Ca2+ current. The L‐type Ca2+ channel blocker diltiazem reduced force amplitude, relaxation, and action potential duration to a greater extent in HCM than in isogenic control. We translated our findings to patient care and showed that diltiazem application ameliorated the prolonged QTc interval in HCM‐affected son and sister of the index patient. These data provide evidence for this ACTN2 mutation to be disease‐causing in cardiomyocytes, guiding clinical therapy in this HCM family. This study may serve as a proof‐of‐principle for the use of hiPSC for personalized treatment of cardiomyopathies.https://doi.org/10.15252/emmm.201911115disease modelinghuman‐induced pluripotent stem cellshypertrophic cardiomyopathylong QT syndromeprecision medicine |
| spellingShingle | Maksymilian Prondzynski Marc D Lemoine Antonia TL Zech András Horváth Vittoria Di Mauro Jussi T Koivumäki Nico Kresin Josefine Busch Tobias Krause Elisabeth Krämer Saskia Schlossarek Michael Spohn Felix W Friedrich Julia Münch Sandra D Laufer Charles Redwood Alexander E Volk Arne Hansen Giulia Mearini Daniele Catalucci Christian Meyer Torsten Christ Monica Patten Thomas Eschenhagen Lucie Carrier Disease modeling of a mutation in α‐actinin 2 guides clinical therapy in hypertrophic cardiomyopathy EMBO Molecular Medicine disease modeling human‐induced pluripotent stem cells hypertrophic cardiomyopathy long QT syndrome precision medicine |
| title | Disease modeling of a mutation in α‐actinin 2 guides clinical therapy in hypertrophic cardiomyopathy |
| title_full | Disease modeling of a mutation in α‐actinin 2 guides clinical therapy in hypertrophic cardiomyopathy |
| title_fullStr | Disease modeling of a mutation in α‐actinin 2 guides clinical therapy in hypertrophic cardiomyopathy |
| title_full_unstemmed | Disease modeling of a mutation in α‐actinin 2 guides clinical therapy in hypertrophic cardiomyopathy |
| title_short | Disease modeling of a mutation in α‐actinin 2 guides clinical therapy in hypertrophic cardiomyopathy |
| title_sort | disease modeling of a mutation in α actinin 2 guides clinical therapy in hypertrophic cardiomyopathy |
| topic | disease modeling human‐induced pluripotent stem cells hypertrophic cardiomyopathy long QT syndrome precision medicine |
| url | https://doi.org/10.15252/emmm.201911115 |
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