Life science
Medical & healthcare

Identification of a causative gene for dilated
cardiomyopathy and future precision medicine

Life science

Department of Cardiology, Graduate School of Medicine
Assistant Professor Hidetaka Kioka		

https://researchmap.jp/hkioka?lang=en

Specially Appointed Associate Professor Yoshihiro Asano

https://researchmap.jp/osaka-med-yasano?lang=en

Professor Yasushi Sakata				https://researchmap.jp/C4589?lang=en

Abstract
Dilated cardiomyopathy (DCM) is a major cause of heart failure,
characterized by ventricular dilatation and systolic dysfunction. We
identified that homozygous truncating mutations in the gene encoding BAG co-chaperone 5 (BAG5) caused inherited DCM in unrelated multiple patients with complete penetrance. BAG5 acts as anucleotide exchange factor for heat shock cognate 71 kDa protein(HSC70), promoting ADP release and activating HSC70-mediatedprotein folding. Bag5 mutant knock-in mice exhibited ventriculardilatation, arrhythmogenicity, and poor prognosis under catecholamine stimulation, recapitulating the human DCM phenotype, andadministration of an adeno-associated virus 9 vector carrying thewild-type BAG5 gene could fully ameliorate these DCM phenotypes.

ing in cases of DCM, and that gene therapy may potentially be atreatment for this disease. In addition, our study demonstrated thatmaintaining proteostasis is essential for cardiomyocyte. Further
study focusing on proteostasis network in cardiomyocytes would
shed light on the development of novel therapy for cardiomyopathy
and heart failure.

▍ Background & Results
Heart failure is an increasingly serious public health issue, affecting more than 37.7 million individuals worldwide. The prognosis ofpatients with heart failure is still poor, with 5-year survival rates of
45.5%, regardless of advanced medical therapy. DCM, characterized by ventricular dilatation and systolic dysfunction, is one of themajor causes of end-stage heart failure requiring heart transplantation. Inherited DCM can be caused by mutations in genes encoding the sarcomere, cytoskeleton, nuclear membrane, desmosome,and calcium-handling proteins. However, the underlying genetic
causes of approximately 60%–80% of familial DCM cases remain
unknown. Identifying the further genetic causes of DCM could improve the utility of genetic testing and might lead to new insights
into the pathogenesis of heart failure. Molecular chaperones are
essential for maintaining protein homeostasis (proteostasis) underphysiological and stress conditions. Impaired proteostasis has
been implicated in various diseases, including Alzheimer’s disease
and Parkinson’s disease, diabetes mellitus, cancer, myopathy, andcardiovascular diseases. We revealed that the BAG co-chaperone
5 (BAG5) is a causative gene for juvenile-onset DCM with complete
penetrance. Immunocytochemical analysis revealed that BAG5localized 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, andcalcium handling abnormalities. After demonstrating that BAG5mutations led to loss of functional BAG5 protein, we also showedthat administration of an AAV9-BAG5 vector in a murine model
could restore cardiac function.

Fig.1 Loss of function mutations in the cochaperone protein BAG5 can leadto dilated cardiomyopathy and ultimately heart failure through an impaired
quality control of junctional membrane complex (JMC) proteins.
E-C coupling: Excitation-Contraction couplingFig.2 A. Cardiac MRI. B. Survival after phenylephrine administration.

▍ Significance of the research and Future perspective
Our study suggests that BAG5 may be a target for genetic test-

P a t e n t PCT/JP2020/042283
Hakui, Hideyuki et al. Loss-of-function mutations in the co-chaperone protein BAG5 cause dilated cardiomyopathy requiring heart transplantation. SciTransl Med. 2022, 14(628): eabf3274. doi: 10.1126/scitranslmed.abf3274
Tr e a t i s e
Hakui, Hideyuki et al. Refractory ventricular arrhythmias in a patient with dilated cardiomyopathy caused by a nonsense mutation in BAG5. Circ J. 2022,
86(12): 2043. doi: 10.1253/circj.CJ-22-0329
UR
L http://www.cardiology.med.osaka-u.ac.jp/?page_id=34278
K e y w o r d cardiomyopathy, gene therapy, precision medicine, proteostasis