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- Title
Loss-of-function mutations in the co-chaperone protein BAG5 cause dilated cardiomyopathy requiring heart transplantation.
- Authors
Hakui, Hideyuki; Kioka, Hidetaka; Miyashita, Yohei; Nishimura, Shunsuke; Matsuoka, Ken; Kato, Hisakazu; Tsukamoto, Osamu; Kuramoto, Yuki; Takuwa, Ayako; Takahashi, Yusuke; Saito, Shigeyoshi; Ohta, Kunio; Asanuma, Hiroshi; Fu, Hai Ying; Shinomiya, Haruki; Yamada, Noriaki; Ohtani, Tomohito; Sawa, Yoshiki; Kitakaze, Masafumi; Takashima, Seiji
- Abstract
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–associated athanogene (BAG) co-chaperone 5 (BAG5) 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. Bag5 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 BAG5 gene could fully ameliorate these DCM phenotypes. Immunocytochemical analysis revealed that BAG5 localized to junctional membrane complexes (JMCs), critical microdomains for calcium handling. Bag5-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 BAG5 can cause DCM, that BAG5 may be a target for genetic testing in cases of DCM, and that gene therapy may potentially be a treatment for this disease. DCM is in the BAG5: Most cases of inherited dilated cardiomyopathy (DCM) have no identified genetic cause. Here, Hakui and colleagues identified homozygous truncating mutations in the BAG5 gene, encoding the BAG co-chaperone 5 protein in five patients with inherited DCM. Heterozygous truncating mutations were also found in three patients with tachycardia-induced cardiomyopathy. Correction of a Bag5 mutant knock-in mouse model through gene therapy could ameliorate the DCM phenotype. BAG5 localized to junctional membrane complexes (JMCs), and mutant mouse cardiomyocytes under catecholamine stimulation demonstrated disrupted JMC architecture and calcium handling abnormalities. These findings suggest that BAG5 mutations can cause DCM, which, if diagnosed by genetic testing early enough, may be amenable to gene therapy.
- Subjects
CONNECTIN; NUCLEOTIDE exchange factors; DILATED cardiomyopathy; HEART transplantation; HEAT shock factors; GENETIC testing; HOMEOSTASIS
- Publication
Science Translational Medicine, 2022, Vol 14, Issue 628, p1
- ISSN
1946-6234
- Publication type
Article
- DOI
10.1126/scitranslmed.abf3274