Loss-of-function mutations in the co-chaperone protein BAG5 cause dilated cardiomyopathy requiring heart...

Area of Science:

• Cardiovascular Genetics
• Molecular Cardiology
• Genetic Medicine

Background:

• Dilated cardiomyopathy (DCM) is a primary cause of heart failure, marked by ventricular enlargement and impaired contraction.
• While over 50 genes are linked to familial DCM, the genetic basis for 60-80% of cases remains unidentified.
• Understanding the genetic underpinnings of DCM is crucial for accurate patient stratification and therapeutic development.

Purpose of the Study:

• To identify novel genetic causes of familial dilated cardiomyopathy (DCM).
• To investigate the functional role of the Bcl-2–associated athanogene 5 (BAG5) gene in cardiac function and DCM pathogenesis.
• To explore the therapeutic potential of BAG5 gene augmentation for DCM.

Main Methods:

• Genetic sequencing to identify mutations in familial DCM patients.
• Generation and analysis of Bag5 mutant knock-in mouse models.
• Adeno-associated virus 9 (AAV9) vector-mediated gene delivery for wild-type BAG5 expression.
• Immunocytochemistry and calcium handling studies in cardiomyocytes.

Main Results:

• Homozygous truncating mutations in BAG5 were identified as a cause of inherited DCM in four unrelated families.
• Bag5 mutant mice recapitulated DCM phenotypes, including ventricular dilatation and arrhythmogenicity, which were fully ameliorated by AAV9-BAG5 gene therapy.
• BAG5 deficiency disrupted junctional membrane complex (JMC) structure and calcium handling in cardiomyocytes, particularly under catecholamine stimulation.

Conclusions:

• Loss-of-function mutations in BAG5 are a novel cause of inherited dilated cardiomyopathy.
• BAG5 plays a critical role in maintaining cardiac structure and function, particularly calcium handling at JMCs.
• BAG5 represents a potential target for genetic testing in DCM and a candidate for gene therapy interventions.