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


Autoři: Federica Diofano aff001;  Karolina Weinmann aff001;  Isabelle Schneider aff001;  Kevin D. Thiessen aff001;  Wolfgang Rottbauer aff002;  Steffen Just aff001
Působiště autorů: Molecular Cardiology, Department of Internal Medicine II, University of Ulm, Ulm, Germany aff001;  Department of Internal Medicine II, University of Ulm, Ulm, Germany aff002
Vyšlo v časopise: Genetic compensation prevents myopathy and heart failure in an in vivo model of Bag3 deficiency. PLoS Genet 16(11): e1009088. doi:10.1371/journal.pgen.1009088
Kategorie: Research Article
doi: https://doi.org/10.1371/journal.pgen.1009088

Souhrn

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.

Klíčová slova:

Heart – Analysis of variance – Embryos – Genetics – Messenger RNA – Phenotypes – Skeletal muscles – Zebrafish


Zdroje

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