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BAG3 P215L/KO Mice as a Model of BAG3 P209L Myofibrillar Myopathy.
- Source :
-
The American journal of pathology [Am J Pathol] 2020 Mar; Vol. 190 (3), pp. 554-562. Date of Electronic Publication: 2020 Jan 14. - Publication Year :
- 2020
-
Abstract
- 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 αB-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.<br /> (Copyright © 2020 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.)
- Subjects :
- Animals
Cardiomyopathies genetics
Cardiomyopathies pathology
Disease Models, Animal
Genes, Dominant
Humans
Mice
Mice, Inbred C57BL
Mice, Knockout
Microscopy, Electron, Transmission
Muscle Fibers, Skeletal pathology
Muscle, Skeletal pathology
Mutation
Myopathies, Structural, Congenital genetics
Phenotype
Adaptor Proteins, Signal Transducing genetics
Apoptosis Regulatory Proteins genetics
Myopathies, Structural, Congenital pathology
Subjects
Details
- Language :
- English
- ISSN :
- 1525-2191
- Volume :
- 190
- Issue :
- 3
- Database :
- MEDLINE
- Journal :
- The American journal of pathology
- Publication Type :
- Academic Journal
- Accession number :
- 31953038
- Full Text :
- https://doi.org/10.1016/j.ajpath.2019.11.005