Disease modeling of a mutation in α‐actinin 2 guides clinical therapy in hypertrophic cardiomyopathy

Prondzynski, Maksymilian; Lemoine, Marc D.; Zech, Antonia TL; Horváth, András; Mauro, Vittoria Di; Koivumäki, Jussi T.; Kresin, Nico; Busch, Josefine; Krause, Eike; Krämer, Elisabeth; Schlossarek, Saskia; Spohn, Michael; Friedrich, Felix W.; Münch, Julia; Laufer, Sandra D.; Redwood, Charles; Volk, Alexander E; Hansen, Arne; Mearini, Giulia; Catalucci, Daniele; Meyer, Christian; Christ, Torsten; Patten, Monica; Eschenhagen, Thomas; Carrier, Lucie

doi:10.15252/emmm.202216423

Cited by 14 publications

(30 citation statements)

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“…We reproduced previous findings observed in 2D-cultured heterozygous ACTN2 (ACTN2het) hiPSC-CMs [8], such as hypertrophy and myofibrillar disarray in ACTN2mut hiPSC-CMs. Furthermore, diseased cells exhibited dysregulation of pathways involved in sarcomere function and proteostasis, and ACTN2mut EHTs exhibited force impairment, resembling a DCM phenotype [27-30].…”

Section: Discussionsupporting

confidence: 90%

“…Cultivation, CRISPR/Cas9 gene editing, and differentiation of hiPSC lines into CMs were as previously described [8]. A detailed methodology is provided in the Supplement.…”

Section: Generation and Culture Of Hipsc-cms In 2d And Eht Formatsmentioning

confidence: 99%

“…Both ACTN2wt and ACTN2mut lines were derived from the previously described heterozygous ACTN2 HCM hiPSC line (ACTN2het; c.740C>T; [8]) using CRISPR/Cas9 gene editing and homology directed repair. Initially, both hiPSC lines were intended to produce an isogenic control without the mutation.…”

Section: Actn2mut 2d-cultured Hipsc-cms Display Hypertrophy Myofibril...mentioning

confidence: 99%

“…Genetic variants in ACTN2 are associated in the heterozygous state with common inherited cardiac diseases, which are hypertrophic (HCM), dilated (DCM), and restrictive (RCM) cardiomyopathy [5][6][7][8]. Although considered as a rare disease gene [9], recent reports showed the association of homozygous ACTN2 variants with core myopathy [10], or progressive, severe RCM [6].…”

Section: Introductionmentioning

confidence: 99%

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ACTN2mutant causes proteopathy in human iPSC-derived cardiomyocytes

Zech

Prondzynski

Singh

et al. 2021

Preprint

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RationaleGenetic variants in ACTN2, encoding α-actinin 2 (ACTN2), are associated with several forms of (cardio)myopathy in the heterozygous state, and can cause progressive, severe cardiomyopathy in the homozygous state. We previously reported a heterozygous missense (c.740C>T) ACTN2 variant, associated with hypertrophic cardiomyopathy (HCM), which induced an electro-mechanical phenotype in human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs).ObjectiveTo evaluate the impact of heterozygosity and homozygosity of the c.740C>T ACTN2 variant on cardiomyocyte structure and function.Methods and ResultsNext to the previously established hiPSC line carrying the heterozygous ACTN2 variant (ACTN2het), we created a homozygous line (ACTN2hom) with CRISPR/Cas9. Differentiation into cardiomyocytes revealed myofibrillar disarray, increased cell area and volume, multinucleation, and ACTN2 aggregates in mutant hiPSC-CMs. Live cell imaging in hiPSC-CMs showed an inverse correlation between sarcomeric incorporation and aggregation of exogenously expressed mutant ACTN2. RNA-seq and proteomic analyses showed alteration of several canonical pathways involved in metabolism, oxidative and cellular stress, and proteostasis, including the ubiquitin-proteasome system (UPS) and autophagy-lysosomal pathway (ALP) in mutant hiPSC-CMs. Detailed evaluation of the UPS and ALP, including a high-content screening with a mWasabi-mTagRFP-hLC3 tandem construct, revealed a global activation of these systems in mutant hiPSC-CMs. The ACTN2 missense variant caused allele dose-dependent and -independent effects on several cardiomyocyte features. ACTN2hom exhibited markedly lower levels of sarcomere-associated proteins, and hypocontractility in engineered heart tissues, resembling a dilated cardiomyopathy phenotype.ConclusionThis study showed allele dose-independent effects of the ACTN2 variant on multinucleation, ACTN2 aggregation, and UPS activation, and allele dose-dependent effects of the variant on cellular hypertrophy, myofibrillar disarray, and ALP activation. Activation of the proteolytic systems is likely to cope with ACTN2 aggregation. Our data indicates proteopathy as an additional cellular feature caused by the c.740C>T ACTN2 variant, which may contribute to human ACTN2-associated inherited cardiomyopathy.

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Section: Discussionsupporting

confidence: 90%

“…Cultivation, CRISPR/Cas9 gene editing, and differentiation of hiPSC lines into CMs were as previously described [8]. A detailed methodology is provided in the Supplement.…”

Section: Generation and Culture Of Hipsc-cms In 2d And Eht Formatsmentioning

confidence: 99%

Section: Actn2mut 2d-cultured Hipsc-cms Display Hypertrophy Myofibril...mentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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ACTN2mutant causes proteopathy in human iPSC-derived cardiomyocytes

Zech

Prondzynski

Singh

et al. 2021

Preprint

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“…Patient‐derived hiPSC‐CMs were able to recapitulate the different disease phenotypes in the culture‐dish, to provide mechanistic insights into disease processes, and to screen for existing and novel therapeutic measures. Combing the hiPSC‐CM technology with genome‐editing approaches (CRISPR/Cas system, see infra) provided further insights into the genetic causes of various cardiomyopathies by creation of isogenic‐control lines (mutation correction in diseased hiPSCs or mutation creation in wild‐type hiPSCs) 105–107 and by evaluating the potential role of variants of unknown significance and modifier genes 108 …”

Section: Opportunities To Intervene – a New Toolboxmentioning

confidence: 99%

Targeted therapies in genetic dilated and hypertrophic cardiomyopathies: from molecular mechanisms to therapeutic targets. A position paper from the Heart Failure Association (HFA) and the Working Group on Myocardial Function of the European Society of Cardiology (ESC)

Boer

Heymans

Backs

et al. 2022

European J of Heart Fail

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Genetic cardiomyopathies are disorders of the cardiac muscle, most often explained by pathogenic mutations in genes encoding sarcomere, cytoskeleton, or ion channel proteins. Clinical phenotypes such as heart failure and arrhythmia are classically treated with generic drugs, but aetiology-specific and targeted treatments are lacking. As a result, cardiomyopathies still present a major burden to society,

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The emerging role of heart‐on‐a‐chip systems in delineating mechanisms of SARS‐CoV‐2‐induced cardiac dysfunction

Zhao

Radišić

2023

Bioengineering & Transla Med

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Coronavirus disease 2019 (COVID‐19) has been a major global health concern since its emergence in 2019, with over 680 million confirmed cases as of April 2023. While COVID‐19 has been strongly associated with the development of cardiovascular complications, the specific mechanisms by which viral infection induces myocardial dysfunction remain largely controversial as studies have shown that the severe acute respiratory syndrome coronavirus‐2 can lead to heart failure both directly, by causing damage to the heart cells, and indirectly, by triggering an inflammatory response throughout the body. In this review, we summarize the current understanding of potential mechanisms that drive heart failure based on in vitro studies. We also discuss the significance of three‐dimensional heart‐on‐a‐chip technology in the context of the current and future pandemics.

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Disease modeling of a mutation in α‐actinin 2 guides clinical therapy in hypertrophic cardiomyopathy

Cited by 14 publications

References 0 publications

ACTN2mutant causes proteopathy in human iPSC-derived cardiomyocytes

ACTN2mutant causes proteopathy in human iPSC-derived cardiomyocytes

Targeted therapies in genetic dilated and hypertrophic cardiomyopathies: from molecular mechanisms to therapeutic targets. A position paper from the Heart Failure Association (HFA) and the Working Group on Myocardial Function of the European Society of Cardiology (ESC)

The emerging role of heart‐on‐a‐chip systems in delineating mechanisms of SARS‐CoV‐2‐induced cardiac dysfunction

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