BAG3 – BAG3-related Myofibrillar Myopathy

Myofibrillar myopathy (MFM) associated with heterozygous mutations in BAG3 manifests as a severe, early-onset dominant muscle disorder. Affected individuals typically present in childhood with rapidly progressive proximal weakness, rigid spine, respiratory insufficiency, and frequently cardiomyopathy (PMID:19085932; PMID:21361913). Phenotypic variability includes cases with predominant cardiomyopathy preceding weakness (PMID:25728519) or absence of cardiac involvement (PMID:30061062). Peripheral neuropathy and polyneuropathy are reported in a subset, broadening the clinical spectrum (PMID:22734908).

Genetic analysis reveals a recurrent de novo c.626C>T (p.Pro209Leu) alteration in exon 3 of BAG3 in multiple unrelated families, as well as additional missense variants such as c.625C>T (p.Pro209Ser) and c.1408C>T (p.Pro470Ser) (PMID:19085932; PMID:31853710). The disorder follows an autosomal dominant inheritance pattern with at least one reported segregation in a parent–offspring pair (PMID:21361913).

Extensive experimental work supports both haploinsufficiency and toxic gain-of-function mechanisms. Expression of BAG3^P209L in zebrafish and mouse models recapitulates myofibrillar disintegration and aggregate formation, while knock-down of Bag3 induces similar pathology, rescued by wild-type but not mutant BAG3 (PMID:25273835; PMID:31953038). Cellular assays demonstrate aberrant aggregation of BAG3 mutants with co-chaperones Hsp70 and HspB8, impaired autophagic flux, and apoptosis of muscle nuclei (PMID:30559338; PMID:26545904).

Some reports note atypical or mild phenotypes lacking cardiomyopathy or respiratory failure, indicating variable expressivity but no clear refuting evidence (PMID:30145633; PMID:30061062). No alternative gene–disease associations have been proposed for these cases.

Integrated evidence from over 10 unrelated probands, familial segregation, reproducible functional concordance across models, and therapeutic rescue experiments establish a definitive gene–disease relationship. This supports the clinical utility of BAG3 genetic testing for early diagnosis and management of MFM, and guides genotype-driven therapeutic strategies.

Key Take-home: Heterozygous BAG3 mutations cause a definitive autosomal dominant myofibrillar myopathy marked by early onset weakness, rigid spine, respiratory insufficiency, and cardiomyopathy, underpinned by toxic protein aggregation and autophagy impairment.

References

• Annals of neurology • 2009 • Mutation in BAG3 causes severe dominant childhood muscular dystrophy PMID:19085932
• Clinical genetics • 2012 • BAG3-related myofibrillar myopathy in a Chinese family. PMID:21361913
• Neuromuscular disorders : NMD • 2015 • BAG3 myofibrillar myopathy presenting with cardiomyopathy. PMID:25728519
• Paediatric anaesthesia • 2015 • Anesthetic considerations in myofibrillar myopathy. PMID:25216331
• Journal of the peripheral nervous system : JPNS • 2012 • BAG3 mutations: another cause of giant axonal neuropathy. PMID:22734908
• Acta neuropathologica • 2014 • Zebrafish models of BAG3 myofibrillar myopathy suggest a toxic gain of function leading to BAG3 insufficiency. PMID:25273835
• The American journal of pathology • 2020 • BAG3P215L/KO Mice as a Model of BAG3P209L Myofibrillar Myopathy. PMID:31953038
• Nature communications • 2018 • Myopathy associated BAG3 mutations lead to protein aggregation by stalling Hsp70 networks. PMID:30559338
• Journal of muscle research and cell motility • 2015 • BAG3-related myopathy, polyneuropathy and cardiomyopathy with long QT syndrome. PMID:26545904
• Genes & genomics • 2018 • BAG3 mutation in a patient with atypical phenotypes of myofibrillar myopathy and Charcot-Marie-Tooth disease. PMID:30145633

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