| First Author | Robertson R | Year | 2020 |
| Journal | Am J Pathol | Volume | 190 |
| Issue | 3 | Pages | 554-562 |
| PubMed ID | 31953038 | Mgi Jnum | J:290387 |
| Mgi Id | MGI:6435338 | Doi | 10.1016/j.ajpath.2019.11.005 |
| Citation | Robertson R, et al. (2020) BAG3(P215L/KO) Mice as a Model of BAG3(P209L) Myofibrillar Myopathy. Am J Pathol 190(3):554-562 |
| abstractText | BCL-2-associated athanogene 3 (BAG3) is a co-chaperone to heat shock proteins important in degrading misfolded proteins through chaperone-assisted selective autophagy. The recurrent dominant BAG3-P209L mutation results in a severe childhood-onset myofibrillar myopathy (MFM) associated with progressive muscle weakness, cardiomyopathy, and respiratory failure. Because a homozygous knock-in (KI) strain for the mP215L mutation homologous to the human P209L mutation did not have a gross phenotype, compound heterozygote knockout (KO) and KI mP215L mice were generated to establish whether further reduction in BAG3 expression would lead to a phenotype. The KI/KO mice have a significant decrease in voluntary movement compared with wild-type and KI/KI mice in the open field starting at 7 months. The KI/KI and KI/KO mice both have significantly smaller muscle fiber cross-sectional area. However, only the KI/KO mice have clear skeletal muscle histologic changes in MFM. As in patient muscle, there are increased levels of BAG3-interacting proteins, such as p62, heat shock protein B8, and alphaB-crystallin. The KI/KO mP215L strain is the first murine model of BAG3 myopathy that resembles the human skeletal muscle pathologic features. The results support the hypothesis that the pathologic development of MFM requires a significant decrease in BAG3 protein level and not only a gain of function caused by the dominant missense mutation. |
