BAG3 P209L Mutation

Currently there are about 20 children in the world with the ultra-rare heterozygous BAG3 P209L c.626C>T mutation. It causes an uncommon form of severe neuromuscular disorder - myofibrillar myopathy 6 (MFM6). The course of the disease is characterized by onset in the first decade of rapidly progressive muscle weakness associated with cardiomyopathy, polyneuropathy, respiratory insufficiency during adolescence, skeletal deformities related to muscle weakness and a rigid spine in some patients. Such children get tired quickly and begin to have trouble walking due to contracture of the achilles tendons resulting in walking on tiptoes.

Most patients are severely affected by the second decade and need cardiac transplant, ventilation, and/or a wheelchair because of rapidly progressing motor and respiratory failure.

Description of the disease

In the first decade children usually develop normally, but motor coordination and muscle strength are lower than in their peers. Doctors state that everything is on the verge of norm and do not suggest anything particular.

Children, in addition to low strength and endurance, usually have a contracted back muscle (which is manifested by the stiffness of the spine), poor jumping skills, and at some point contractures of the Achilles tendons and walking on toes appear.

Around the age of 10, we can observe a reduced lung capacity, hardening of the calf muscles, damage to the peripheral nerves (peripheral polyneuropathy), and in most cases restrictive cardiomyopathy - a disease that manifests itself by diastolic dysfunction resulting from progressing stiffness of the heart's muscles.

In the following years, all muscles weaken rapidly, causing problems with moving, eating, and finally breathing.

Currently, there are no effective procedures and medicines available to stop the disease. From experience and knowledge exchange, we know that:

• strenuous physical exertion should be strictly avoided

• light physiotherapy is indicated to stretch all muscles

• in the case of strong Achilles tendon contractures, stretching by serial plastering is a very effective method - unlike intense stretching exercises that have the opposite effect. In order to avoid recurrence of contractures, it is necessary to wear orthoses supporting the achieved stretch, every day at least overnight

• one scientific study showed that metformin (a long-known drug for diabetes) restores muscle function in sick zebrafish, but it is difficult to determine whether it also has such effects in humans

• other scientific studies show that inhibition of the preteasome increases disease symptoms, therefore the following should be avoided: capsaicin (chili pepper), turmeric and ibuprofen

• you should also avoid cinnamon, which increases the level of BAG3 protein expression by inducing the HSF1 transcription factor (heat shock factor 1)

A simplified scientific view

Currently, the main problematic site is the formation of protein aggregates during the selective autophagy process performed by the CASA complex (a combination of BAG3, HSP70 and HSPB8 proteins). As a result, mutated BAG3 is trapped in the aggregates and wild BAG3 also sticks to the same aggregates, ultimately drastically reducing the amount of available BAG3 protein. This deficiency disrupts many biological processes, most notably the maintenance of the structure of the Z-Discs, the basic muscle scaffold.

The details of how the mutated protein works are described in the fourth and fifth paragraphs of Article 15 listed below. [link]

Research on the BAG3 P209L mutation and MFM6

The mutation was first linked to a muscle disease in 2009. Since then, over a dozen case reports have been published, collectively describing about twenty patients. Animal models, zebrafish and mouse, have been created. A lot of scientific research has been carried out, both on patient-derived cells and the animal models, and elucidated the mechanism of the disease. There have also been several attempts at treatment, including drug repurposing and gene silencing. So far, none of them has resulted in finding an effective medicine that stops or reverses the disease.

Case reports

1. Duygu Selcen MD et al., 2009: Mutation in BAG3 causes severe dominant childhood muscular dystrophy 

2. Zagaa Odgerel et al., 2010: Inheritance patterns and phenotypic features of myofibrillar myopathy associated with a BAG3 mutation 

3. Fatima Jaffer et al., 2012: BAG3 mutations: another cause of giant axonal neuropathy 

4. HC Lee et al., 2012: BAG3‐related myofibrillar myopathy in a Chinese family 

5. Chamindra G. Konersman et al., 2015: BAG3 myofibrillar myopathy presenting with cardiomyopathy 

6. Anna Kostera-Pruszczyk et al., 2015: BAG3-related myopathy, polyneuropathy and cardiomyopathy with long QT syndrome

7. Gregory J. Latham & Grace Lopez, 2015: Anesthetic considerations in myofibrillar myopathy

8. Francesca D’Avila et al., 2016: Exome sequencing identifies variants in two genes encoding the LIM-proteins NRAP and FHL1 in an Italian patient with BAG3 myofibrillar myopathy

9. Seung Ju Kim et al., 2018: BAG3 mutation in a patient with atypical phenotypes of myofibrillar myopathy and Charcot–Marie–Tooth disease 

10. Jean‐Baptiste Noury et al., 2018: Rigid spine syndrome associated with sensory‐motor axonal neuropathy resembling Charcot–Marie‐Tooth disease is characteristic of Bcl‐2‐associated athanogene‐3 gene mutations even without cardiac involvement 

11. A. Schänzer et al., 2018: Dysregulated autophagy in restrictive cardiomyopathy due to Pro209Leu mutation in BAG3

12. A. Schänzer et al., 2018: Clinicopathological features associated with the BAG3-Pro209Leu mutation 

13. Lindsay Malatesta et al., 2020: BAG3 Myopathy Presenting With Prominent Neuropathic Phenotype and No Cardiac or Respiratory Involvement - A Case Report and Literature Review 

14. Yan Xu et al., 2021: BAG3-Related Myofibrillar Myopathy Presenting as Hypercapnia: A Case Report and Literature Review 

Other articles

15. Michael Hesse, Bernd K. Fleischmann et al., 2021: Overexpression of human BAG3P209L in mice causes restrictive cardiomyopathy

16. Meister-Broekema M, Freilich R, Jagadeesan C, Jason E. Gestwicki, Harm H. Kampinga et al., 2018: Myopathy associated BAG3 mutations lead to protein aggregation by stalling Hsp70 networks

17. Serena Carrara, Angelo Poletti, Vincent Timmerman et al., 2020: BAG3 Pro209 mutants associated with myopathy and neuropathy relocate chaperones of the CASA-complex to aggresomes

18. Avnika A. Ruparelia et al., 2019: Metformin rescues muscle function in BAG3 myofibrillar myopathy models

19. Nitya Yerabandi et al., 2022: The role of BAG3 in dilated cardiomyopathy and its association with CharcotMarie-Tooth disease type 2

20. Rebecca Robertson et al., 2020: BAG3P215L/KO Mice as a Model of BAG3P209L Myofibrillar Myopathy

21. Megan T. Quintana, Traci L. Parry, Jun He, Cecelia C. Yates, Tatiana N. Sidorova, Katherine T. Murray, James R. Bain, Christopher B. Newgard, Michael J. Muehlbauer, Samuel C. Eaton, Akinori Hishiya, Shin Takayama & Monte S. Willis, 2016: Cardiomyocyte-Specific Human Bcl2-Associated Anthanogene 3 P209L Expression Induces Mitochondrial Fragmentation, Bcl2-Associated Anthanogene 3 Haploinsufficiency, and Activates p38 Signaling

• Discovery of Bag3-P209L signaling mechanism brings hope for therapeutic options currently in development

22. Ashley R. Hacker et al., 2019: Bag3 P209L myopathies and efficacy of blocking signaling pathways with the therapeutic peptide, MMI-0100

23. Aakarsh Vermani, Valentina L. Kouznetsova & Igor F. Tsigelny, 2022: New Inhibitors of the P38 Mitogen-Activated Protein Kinase: Repurposing Existing Drugs with Deep Learning

24. Rebecca Robertson, 2022: BAG3 myofibrillar myopathy: model creation and characterization of a defect in mechanotransduction 

25. Avnika A. Ruparelia, Viola Oorschot, Raquel Vaz, Georg Ramm & Robert J. Bryson-Richardson, 2014: Zebrafish models of BAG3 myofibrillar myopathy suggest a toxic gain of function leading to BAG3 insufficiency

About BAG3, it's role in the muscle, and the Chaperone-Assisted Selective Autophagy (CASA)

26. Homma S, Iwasaki M, Shelton GD, et al., 2006: BAG3 Deficiency Results in Fulminant Myopathy and Early Lethality

27. Elisabeth Stürner & Christian Behl, 2017: The Role of the Multifunctional BAG3 Protein in Cellular Protein Quality Control and in Disease

28. Solenn M. Guilbert, Herman Lambert, Marc-Antoine Rodrigue, Margit Fuchs, Jacques Landry, Josée N. Lavoie, 2018: HSPB8 and BAG3 cooperate to promote spatial sequestration of ubiquitinated proteins and coordinate the cellular adaptive response to proteasome insufficiency

29. Heng Lin, Shon A. Koren, Gregor Cvetojevic, Peter Girardi & Gail V.W. Johnson, 2021: The Role of BAG3 in Health and Disease: A “Magic BAG of Tricks”

30. Thomas G. Martin, Valerie D. Myers, Praveen Dubey, Shubham Dubey, Edith Perez, Christine S. Moravec, Monte S. Willis, Arthur M. Feldman & Jonathan A. Kirk, 2021: Cardiomyocyte contractile impairment in heart failure results from reduced BAG3-mediated sarcomeric protein turnover

31. Barbara Tedesco, Leen Vendredy, Vincent Timmerman, Angelo Poletti, 2023: The chaperone-assisted selective autophagy complex dynamics and dysfunctions