Mutation in BAG3 causes severe dominant childhood muscular dystrophy

Area of Science:

• Genetics
• Neurology
• Cell Biology

Background:

• Myofibrillar myopathies (MFMs) are a group of muscular dystrophies characterized by Z-disk disintegration and accumulation of proteins.
• Genetic heterogeneity is common in MFMs, with mutations in genes like alphaB-crystallin, desmin, myotilin, Zasp, and filamin-C identified previously.
• The BAG3 gene, encoding a Z-disk-associated protein with antiapoptotic functions, was investigated due to its role in muscle integrity.

Purpose of the Study:

• To investigate the role of BAG3 mutations in patients with myofibrillar myopathies.
• To characterize the clinical and pathological features associated with BAG3 mutations in MFMs.

Main Methods:

• Direct sequencing of the BAG3 gene in 53 unrelated MFM patients.
• Histochemistry, immunocytochemistry, and electron microscopy to analyze muscle structural changes.
• Nondenaturing electrophoresis and cell-based assays to examine mutant Bag3 protein behavior and aggregation.

Main Results:

• A heterozygous p.Pro209Leu mutation in BAG3 was identified in three patients.
• Patients presented with childhood-onset progressive muscle weakness, limb and axial involvement, cardiomyopathy, and respiratory insufficiency.
• Muscle pathology included Z-disk disintegration, protein aggregation, and nuclear apoptosis; mutant Bag3 showed altered migration and aggregation in cells.

Conclusions:

• BAG3 mutations define a new, severe form of autosomal dominant childhood muscular dystrophy.
• This discovery expands the genetic landscape of myofibrillar myopathies.
• BAG3-associated myopathy presents with significant cardiac and respiratory complications, highlighting the systemic impact of Z-disk integrity.