​What is Bag 3 Myofibrillar Myopathy 6 ?

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Mutations in the Bag3 protein are broadly characterized as Myofibrillar Myopathy (Myofibriller=muscle fiber; Myopathy=muscle disease).

 

Myofibrillar myopathy is an emerging classification of diseases affecting the heart and skeletal muscle. Previously these were known as “desmin-related myopathies".

 

Myofibrillar myopathies are rare complex diseases caused by mutations in  BAG3, CRYAB, DES, FLNC, FHL1, MYOT, ZASP/LDB3, HMERF. They are related symptomatically to Muscular Dystrophies and other cardiac diseases that are more common (dilated cardiomyopathies). However, the mechanisms of different mutations are not clearly predictable, and descriptions are based primarily on a limited number of published case studies.

 

Hallmark Features:

 

At the cellular level, myofibrillar myopathies share some common characteristics under the microscope. This includes an accumulation of intracellular aggregates or proteins and degeneration of cellular structures. The accumulation of aggregated proteins may be a common occurrence, designating these diseases as “Protein Aggregation Myopathies”, paralleling the disease processes in neurodegenerative diseases (Alzheimer’s Disease, Parkinson’s Disease, Huntington’s Disease).

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The members of the BAG (BCL2-ASSOCIATED ATHANOGENE 3) family of proteins are protective proteins found in many cells of the body. BAG1, BAG2, and BAG3 bind to heat shock protein 70 (HSC70) to assist with its chaperone functions (preventing protein misfolding).

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Beyond their function in protecting cells from stress throughout the body, BAG3 co-chaperones have a role in maintaining protein folding. BAG3 mutations lead primarily to skeletal muscle and heart defects. The resulting disease is characterized broadly as a Myofibrillar Myopathy.

 

The link between the Bag3 P209L mutation and disease was first identified in 2009. Three (3) unrelated patients with childhood-onset of rapidly progressive myofibrillar myopathy were found to have the Bag3 P209L mutation. The clinical features of Bag3 P209L disease include childhood onset proximal and distal muscle weakness, respiratory insufficiency, hypertrophy cardiomyopathy, and peripheral neuropathy.

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