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Citations to this article

Investigation of a dilated cardiomyopathy–associated variant in BAG3 using genome-edited iPSC-derived cardiomyocytes
Chris McDermott-Roe, … , Aron Geurts, Kiran Musunuru
Chris McDermott-Roe, … , Aron Geurts, Kiran Musunuru
Published November 14, 2019
Citation Information: JCI Insight. 2019;4(22):e128799. https://doi.org/10.1172/jci.insight.128799.
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Research Article Cardiology Genetics

Investigation of a dilated cardiomyopathy–associated variant in BAG3 using genome-edited iPSC-derived cardiomyocytes

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Abstract

Mutations in B cell lymphoma 2–associated athanogene 3 (BAG3) are recurrently associated with dilated cardiomyopathy (DCM) and muscular dystrophy. Using isogenic genome-edited human induced pluripotent stem cell–derived cardiomyocytes (iPSC-CMs), we examined how a DCM-causing BAG3 mutation (R477H), as well as complete loss of BAG3 (KO), impacts myofibrillar organization and chaperone networks. Although unchanged at baseline, fiber length and alignment declined markedly in R477H and KO iPSC-CMs following proteasome inhibition. RNA sequencing revealed extensive baseline changes in chaperone- and stress response protein–encoding genes, and protein levels of key BAG3 binding partners were perturbed. Molecular dynamics simulations of the BAG3-HSC70 complex predicted a partial disengagement by the R477H mutation. In line with this, BAG3-R477H bound less HSC70 than BAG3-WT in coimmunoprecipitation assays. Finally, myofibrillar disarray triggered by proteasome inhibition in R477H cells was mitigated by overexpression of the stress response protein heat shock factor 1 (HSF1). These studies reveal the importance of BAG3 in coordinating protein quality control subsystem usage within the cardiomyocyte and suggest that augmenting HSF1 activity might be beneficial as a means to mitigate proteostatic stress in the context of BAG3-associated DCM.

Authors

Chris McDermott-Roe, Wenjian Lv, Tania Maximova, Shogo Wada, John Bukowy, Maribel Marquez, Shuping Lai, Amarda Shehu, Ivor Benjamin, Aron Geurts, Kiran Musunuru

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Total citations by year

Year: 2025 2024 2023 2022 2021 2020 Total
Citations: 1 2 7 5 11 6 32
Citation information
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Citations to this article in year 2023 (7)

Title and authors Publication Year
Cardiac calcium regulation in human induced pluripotent stem cell cardiomyocytes: Implications for disease modeling and maturation
Ernst P, Bidwell PA, Dora M, Thomas DD, Kamdar F
Frontiers in Cell and Developmental Biology 2023
Functional genomics in stroke: current and future applications of iPSCs and gene editing to dissect the function of risk variants
Granata A
BMC Cardiovascular Disorders 2023
Transcriptome studies of inherited dilated cardiomyopathies.
Koslow M, Mondaca-Ruff D, Xu X
Mammalian genome : official journal of the International Mammalian Genome Society 2023
Bag3 Regulates Mitochondrial Function and the Inflammasome Through Canonical and Noncanonical Pathways in the Heart
Wang J, Tomar D, Martin TG, Dubey S, Dubey PK, Song J, Landesberg G, McCormick MG, Myers VD, Merali S, Merali C, Lemster B, McTiernan CF, Khalili K, Madesh M, Cheung JY, Kirk JA, Feldman AM
JACC: Basic to Translational Science 2023
Dysregulated Autophagy and Sarcomere Dysfunction in Patients With Heart Failure With Co‐Occurrence of P63A and P380S BAG3 Variants
Martin TG, Pak H, Gerhard GS, Merali S, Merali C, Lemster B, Dubey P, McTiernan CF, Bristow MR, Feldman AM, Kirk JA
Journal of the American Heart Association: Cardiovascular and Cerebrovascular Disease 2023
Harnessing human genetics and stem cells for precision cardiovascular medicine
Caudal A, Snyder MP, Wu JC
2023
Two Cases of Myofibrillar Myopathies: Genetic and Quality of Life Study
Angelini C, Ceolin C, Rodriguez AA, Nigro V
Muscles 2023

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