{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,8]],"date-time":"2026-10-08T19:12:00Z","timestamp":1791486720148,"version":"4.3.4"},"reference-count":53,"publisher":"American Association for the Advancement of Science (AAAS)","issue":"628","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Sci. Transl. Med."],"published-print":{"date-parts":[[2022,1,19]]},"abstract":"<jats:p>\n            Dilated cardiomyopathy (DCM) is a major cause of heart failure, characterized by ventricular dilatation and systolic dysfunction. Familial DCM is reportedly caused by mutations in more than 50 genes, requiring precise disease stratification based on genetic information. However, the underlying genetic causes of 60 to 80% of familial DCM cases remain unknown. Here, we identified that homozygous truncating mutations in the gene encoding Bcl-2\u2013associated athanogene (BAG) co-chaperone 5 (\n            <jats:italic>BAG5<\/jats:italic>\n            ) caused inherited DCM in five patients among four unrelated families with complete penetrance. BAG5 acts as a nucleotide exchange factor for heat shock cognate 71 kDa protein (HSC70), promoting adenosine diphosphate release and activating HSC70-mediated protein folding.\n            <jats:italic>Bag5<\/jats:italic>\n            mutant knock-in mice exhibited ventricular dilatation, arrhythmogenicity, and poor prognosis under catecholamine stimulation, recapitulating the human DCM phenotype, and administration of an adeno-associated virus 9 vector carrying the wild-type\n            <jats:italic>BAG5<\/jats:italic>\n            gene could fully ameliorate these DCM phenotypes. Immunocytochemical analysis revealed that BAG5 localized to junctional membrane complexes (JMCs), critical microdomains for calcium handling.\n            <jats:italic>Bag5<\/jats:italic>\n            -mutant mouse cardiomyocytes exhibited decreased abundance of functional JMC proteins under catecholamine stimulation, disrupted JMC structure, and calcium handling abnormalities. We also identified heterozygous truncating mutations in three patients with tachycardia-induced cardiomyopathy, a reversible DCM subtype associated with abnormal calcium homeostasis. Our study suggests that loss-of-function mutations in\n            <jats:italic>BAG5<\/jats:italic>\n            can cause DCM, that\n            <jats:italic>BAG5<\/jats:italic>\n            may be a target for genetic testing in cases of DCM, and that gene therapy may potentially be a treatment for this disease.\n          <\/jats:p>","DOI":"10.1126\/scitranslmed.abf3274","type":"journal-article","created":{"date-parts":[[2022,1,19]],"date-time":"2022-01-19T18:59:50Z","timestamp":1642618790000},"source":"Crossref","is-referenced-by-count":21,"title":["Loss-of-function mutations in the co-chaperone protein BAG5 cause dilated cardiomyopathy requiring heart transplantation"],"prefix":"10.1126","volume":"14","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-0335-3149","authenticated-orcid":true,"given":"Hideyuki","family":"Hakui","sequence":"first","affiliation":[{"name":"Department of Cardiovascular Medicine, Osaka University Graduate School of Medicine, Suita, Osaka 565-0871, Japan."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5534-9272","authenticated-orcid":true,"given":"Hidetaka","family":"Kioka","sequence":"additional","affiliation":[{"name":"Department of Cardiovascular Medicine, Osaka University Graduate School of Medicine, Suita, Osaka 565-0871, Japan."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1739-4734","authenticated-orcid":true,"given":"Yohei","family":"Miyashita","sequence":"additional","affiliation":[{"name":"Department of Cardiovascular Medicine, Osaka University Graduate School of Medicine, Suita, Osaka 565-0871, Japan."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shunsuke","family":"Nishimura","sequence":"additional","affiliation":[{"name":"Department of Cardiovascular Medicine, Osaka University Graduate School of Medicine, Suita, Osaka 565-0871, Japan."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ken","family":"Matsuoka","sequence":"additional","affiliation":[{"name":"Department of Medical Biochemistry, Osaka University Graduate School of Frontier Biosciences, Suita, Osaka 565-0871, Japan."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4619-3680","authenticated-orcid":true,"given":"Hisakazu","family":"Kato","sequence":"additional","affiliation":[{"name":"Department of Medical Biochemistry, Osaka University Graduate School of Frontier Biosciences, Suita, Osaka 565-0871, Japan."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Osamu","family":"Tsukamoto","sequence":"additional","affiliation":[{"name":"Department of Medical Biochemistry, Osaka University Graduate School of Frontier Biosciences, Suita, Osaka 565-0871, Japan."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuki","family":"Kuramoto","sequence":"additional","affiliation":[{"name":"Department of Cardiovascular Medicine, Osaka University Graduate School of Medicine, Suita, Osaka 565-0871, Japan."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ayako","family":"Takuwa","sequence":"additional","affiliation":[{"name":"Department of Cardiovascular Medicine, Osaka University Graduate School of Medicine, Suita, Osaka 565-0871, Japan."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yusuke","family":"Takahashi","sequence":"additional","affiliation":[{"name":"Department of Molecular Pharmacology, National Cerebral and Cardiovascular Center, Suita, Osaka 564-8565, Japan."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5100-9561","authenticated-orcid":true,"given":"Shigeyoshi","family":"Saito","sequence":"additional","affiliation":[{"name":"Department of Medical Physics and Engineering, Division of Health Sciences, Osaka University Graduate School of Medicine, Suita, Osaka 565-0871, Japan."},{"name":"Department of Biomedical Imaging, National Cerebral and Cardiovascular Center, Suita, Osaka 564-8565, Japan."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kunio","family":"Ohta","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, School of Medicine, Institute of Medical, Pharmaceutical and Health Sciences, Kanazawa University, Kanazawa, Ishikawa 920-8640, Japan."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hiroshi","family":"Asanuma","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, Meiji University of Integrative Medicine, Nantan, Kyoto 629-0392, Japan."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hai Ying","family":"Fu","sequence":"additional","affiliation":[{"name":"Department of Clinical Medicine and Development, National 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Japan."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yoshiki","family":"Sawa","sequence":"additional","affiliation":[{"name":"Department of Cardiovascular Surgery, Osaka University Graduate School of Medicine, Suita, Osaka 565-0871, Japan."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Masafumi","family":"Kitakaze","sequence":"additional","affiliation":[{"name":"Department of Clinical Medicine and Development, National Cerebral and Cardiovascular Center, Suita, Osaka 564-8565, Japan."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Seiji","family":"Takashima","sequence":"additional","affiliation":[{"name":"Department of Medical Biochemistry, Osaka University Graduate School of Frontier Biosciences, Suita, Osaka 565-0871, Japan."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yasushi","family":"Sakata","sequence":"additional","affiliation":[{"name":"Department of Cardiovascular Medicine, Osaka University Graduate 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