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Sustained activation of ER-stress induces the unfolded protein response (UPR) pathways, which in turn activate three major effector proteins. We previously reported a missense homozygous mutation in <jats:italic>FBXO32<\/jats:italic> (<jats:italic>MAFbx, Atrogin-1<\/jats:italic>) causing advanced heart failure by impairing autophagy. In the present study, we performed transcriptional profiling and biochemical assays, which unexpectedly revealed a reduced activation of UPR effectors in patient mutant hearts, while a strong up-regulation of the CHOP transcription factor and of its target genes are observed. Expression of mutant FBXO32 in cells is sufficient to induce CHOP-associated apoptosis, to increase the ATF2 transcription factor and to impair ATF2 ubiquitination. ATF2 protein interacts with FBXO32 in the human heart and its expression is especially high in <jats:italic>FBXO32<\/jats:italic> mutant hearts. These findings provide a new underlying mechanism for <jats:italic>FBXO32<\/jats:italic>-mediated cardiomyopathy, implicating abnormal activation of CHOP. These results suggest alternative non-canonical pathways of CHOP activation that could be considered to develop new therapeutic targets for the treatment of <jats:italic>FBXO32<\/jats:italic>-associated DCM.<\/jats:p>","DOI":"10.1038\/s42003-021-02391-9","type":"journal-article","created":{"date-parts":[[2021,7,16]],"date-time":"2021-07-16T10:03:33Z","timestamp":1626429813000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":29,"title":["Mutation in FBXO32 causes dilated cardiomyopathy through up-regulation of ER-stress mediated apoptosis"],"prefix":"10.1038","volume":"4","author":[{"given":"Nadya","family":"Al-Yacoub","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6485-8768","authenticated-orcid":false,"given":"Dilek","family":"Colak","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Salma Awad","family":"Mahmoud","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3559-4617","authenticated-orcid":false,"given":"Maya","family":"Hammonds","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kunhi","family":"Muhammed","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Olfat","family":"Al-Harazi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Abdullah M.","family":"Assiri","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jehad","family":"Al-Buraiki","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Waleed","family":"Al-Habeeb","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Coralie","family":"Poizat","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2021,7,16]]},"reference":[{"key":"2391_CR1","doi-asserted-by":"publisher","first-page":"7","DOI":"10.15420\/cfr.2016:25:2","volume":"3","author":"G Savarese","year":"2017","unstructured":"Savarese, G. & Lund, L. 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