Myofibrillar Myopathy Type 6 (BAG3)

Myofibrillar Myopathy Type 6 (BAG3) is a severe childhood-onset neuromuscular disorder with rapidly progressive proximal and generalized weakness, rigid spine, contractures, polyneuropathy and respiratory failure. Restrictive cardiomyopathy and arrhythmia are frequent and can require early cardiac transplantation.
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Genetics

Classically caused by the de novo heterozygous BAG3 c.626C>T, p.Pro209Leu variant and inherited as an autosomal dominant trait. Other BAG3 variants cause partially overlapping myopathy, neuropathy and cardiomyopathy phenotypes.

Molecular Mechanism

BAG3 is a central co-chaperone in chaperone-assisted selective autophagy at the muscle Z-disc. p.Pro209Leu sequesters BAG3 and partner chaperones into aggregates, blocking autophagy and mitophagy and causing sarcomere disintegration, proteotoxic stress and muscle-cell failure.

Therapy

Treatment is supportive, with intensive neuromuscular, respiratory and cardiac surveillance and timely ventilatory or transplant support. Metformin, autophagy modulation and BAG3-directed gene or silencing strategies have shown preclinical activity but are not established therapies.

CCP Activity

CCP characterizes humanized BAG3-associated MFM6 models for further preclinical development.

Mouse Models Mouse Models & Gene Cards

Mouse ModelsGene Cards
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