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We explored the clinical and molecular characteristics of DCM associated with\n                    <jats:italic>BAG5<\/jats:italic>\n                    variants, uncovering the consistently severe manifestations of the disease and its impact on the endoplasmic reticulum (ER) stress response. The analysis involved three siblings affected by DCM and arrhythmia, along with their four unaffected siblings, their unaffected father, and their mother who exhibited arrhythmia. The parents were consanguineous. Exome and Sanger sequencing identified a novel\n                    <jats:italic>BAG5<\/jats:italic>\n                    variant, c.444_445delGA (p.Lys149AsnfsTer6), homozygous in affected siblings and heterozygous in parents and unaffected siblings. We generated heterozygous and homozygous\n                    <jats:italic>Bag5<\/jats:italic>\n                    point mutant knock-in (KI) mice and evaluated cardiac pathophysiology under stress conditions, including tunicamycin (TN) administration.\n                    <jats:italic>Bag5\u2212\/\u2212<\/jats:italic>\n                    mice displayed no abnormalities up to 12\u00a0months old and showed no anomalies during an exercise stress test. However, following TN injection,\n                    <jats:italic>Bag5\u2212\/\u2212<\/jats:italic>\n                    mice exhibited significantly reduced left ventricular fractional shortening (LVFS) and ejection fraction (LVEF). Their cardiac tissues exhibited a notable increase in apoptotic cells, despite non-distinctive changes in CHOP and GRP78 levels. Interestingly, only\n                    <jats:italic>Bag5<\/jats:italic>\n                    KI male mice demonstrated arrhythmia, which was more pronounced in\n                    <jats:italic>Bag5\u2212\/\u2212<\/jats:italic>\n                    than in\n                    <jats:italic>Bag5<\/jats:italic>\n                    +\/\u2212males. Here, our study reveals a novel\n                    <jats:italic>BAG5<\/jats:italic>\n                    mutation causing DCM by impairing the ER stress response, with observed sex-specific arrhythmia differences.\n                  <\/jats:p>","DOI":"10.1038\/s41598-024-62764-y","type":"journal-article","created":{"date-parts":[[2024,5,25]],"date-time":"2024-05-25T05:01:22Z","timestamp":1716613282000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["A novel BAG5 variant impairs the ER stress response pathway, causing dilated cardiomyopathy and arrhythmia"],"prefix":"10.1038","volume":"14","author":[{"given":"Rutairat","family":"Wongong","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anusak","family":"Kijtawornrat","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chalurmpon","family":"Srichomthong","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Siraprapa","family":"Tongkobpeth","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Phichittra","family":"Od-Ek","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Adjima","family":"Assawapitaksakul","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Natarin","family":"Caengprasath","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Apichai","family":"Khongphatthanayothin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thantrira","family":"Porntaveetus","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vorasuk","family":"Shotelersuk","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2024,5,25]]},"reference":[{"key":"62764_CR1","doi-asserted-by":"publisher","first-page":"531","DOI":"10.1038\/nrcardio.2013.105","volume":"10","author":"RE Hershberger","year":"2013","unstructured":"Hershberger, R. 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