Genetic compensation prevents myopathy and heart failure in an in vivo model of Bag3 deficiency

Mutations in the molecular co-chaperone Bcl2-associated athanogene 3 (BAG3) are found to cause dilated cardiomyopathy (DCM), resulting in systolic dysfunction and heart failure, as well as myofibrillar myopathy (MFM), which is characterized by protein aggregation and myofibrillar disintegration in s...

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Published in:PLoS genetics 2020-11, Vol.16 (11), p.e1009088-e1009088
Main Authors: Diofano, Federica, Weinmann, Karolina, Schneider, Isabelle, Thiessen, Kevin D, Rottbauer, Wolfgang, Just, Steffen
Format: Article
Language:English
Subjects:
Adaptor Proteins, Signal Transducing - deficiency
Adaptor Proteins, Signal Transducing - genetics
Adaptor Proteins, Signal Transducing - metabolism
Animals
Apoptosis - genetics
Apoptosis Regulatory Proteins - deficiency
Apoptosis Regulatory Proteins - genetics
Apoptosis Regulatory Proteins - metabolism
Biology and Life Sciences
Cardiomyopathies - genetics
Cardiomyopathies - metabolism
Cardiomyopathies - pathology
Cardiomyopathy
Cardiomyopathy, Dilated - genetics
Cardiomyopathy, Dilated - metabolism
Cardiomyopathy, Dilated - pathology
Compensation
Congestive heart failure
CRISPR
Dilated cardiomyopathy
Disease
Disease Models, Animal
Embryos
Gene deletion
Gene expression
Genetic aspects
Genetic disorders
Genomes
Heart failure
Heart Failure - genetics
Heart Failure - metabolism
Heart Failure - pathology
Medicine and Health Sciences
Molecular Chaperones - genetics
Molecular Chaperones - metabolism
mRNA turnover
Muscle Fibers, Skeletal - metabolism
Muscle function
Muscular diseases
Muscular Diseases - genetics
Muscular Diseases - metabolism
Muscular Diseases - pathology
Musculoskeletal system
Mutants
Mutation
Myocardium - metabolism
Myopathies, Structural, Congenital - metabolism
Myopathy
Nonsense mutation
Nonsense-mediated mRNA decay
Nucleotides
Phenotype
Physical Sciences
Prevention
Protein interaction
Proteins
Proteomics
Research and Analysis Methods
Skeletal muscle
Stop codon
Transcription
Zebrafish
Zebrafish Proteins - deficiency
Zebrafish Proteins - genetics
Zebrafish Proteins - metabolism
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Summary:Mutations in the molecular co-chaperone Bcl2-associated athanogene 3 (BAG3) are found to cause dilated cardiomyopathy (DCM), resulting in systolic dysfunction and heart failure, as well as myofibrillar myopathy (MFM), which is characterized by protein aggregation and myofibrillar disintegration in skeletal muscle cells. Here, we generated a CRISPR/Cas9-induced Bag3 knockout zebrafish line and found the complete preservation of heart and skeletal muscle structure and function during embryonic development, in contrast to morpholino-mediated knockdown of Bag3. Intriguingly, genetic compensation, a process of transcriptional adaptation which acts independent of protein feedback loops, was found to prevent heart and skeletal muscle damage in our Bag3 knockout model. Proteomic profiling and quantitative real-time PCR analyses identified Bag2, another member of the Bag protein family, significantly upregulated on a transcript and protein level in bag3-/- mutants. This implied that the decay of bag3 mutant mRNA in homozygous bag3-/- embryos caused the transcriptional upregulation of bag2 expression. We further demonstrated that morpholino-mediated knockdown of Bag2 in bag3-/- embryos evoked severe functional and structural heart and skeletal muscle defects, which are similar to Bag3 morphants. However, Bag2 knockdown in bag3+/+ or bag3+/- embryos did not result in (cardio-)myopathy. Finally, we found that inhibition of the nonsense-mediated mRNA decay (NMD) machinery by knockdown of upf1, an essential NMD factor, caused severe heart and skeletal muscle defects in bag3-/- mutants due to the blockade of transcriptional adaptation of bag2 expression. Our findings provide evidence that genetic compensation might vitally influence the penetrance of disease-causing bag3 mutations in vivo.
ISSN:1553-7404
1553-7390
1553-7404
DOI:10.1371/journal.pgen.1009088