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However, heterozygous knockout of the murine BAG3 gene did not cause a detectable phenotype. To model BAG3 cardiomyopathy in a human system, we generated an isogenic series of human induced pluripotent stem cells (iPSCs) with loss-of-function mutations in BAG3. Heterozygous BAG3 mutations reduced protein expression, disrupted myofibril structure, and compromised contractile function in iPSC-derived cardiomyocytes (iPS-CMs). BAG3-deficient iPS-CMs were particularly sensitive to further myofibril disruption and contractile dysfunction upon exposure to proteasome inhibitors known to cause cardiotoxicity. We performed affinity tagging of the endogenous BAG3 protein and mass spectrometry proteomics to further define the cardioprotective chaperone complex that BAG3 coordinates in the human heart. Our results establish a model for evaluating protein quality control pathways in human cardiomyocytes and their potential as therapeutic targets and susceptibility factors for cardiac drug toxicity.<\/jats:p>","DOI":"10.1172\/jci.insight.94623","type":"journal-article","created":{"date-parts":[[2017,7,19]],"date-time":"2017-07-19T11:22:28Z","timestamp":1500463348000},"source":"Crossref","is-referenced-by-count":95,"title":["A BAG3 chaperone complex maintains cardiomyocyte function during proteotoxic stress"],"prefix":"10.1172","volume":"2","author":[{"given":"Luke M.","family":"Judge","sequence":"first","affiliation":[{"name":"Department of Pediatrics, UCSF, San Francisco, California, USA."},{"name":"Gladstone Institutes, San Francisco, California, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Juan A.","family":"Perez-Bermejo","sequence":"additional","affiliation":[{"name":"Gladstone Institutes, San Francisco, California, USA."},{"name":"Department of Cellular 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