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000893173 1001_ $$00000-0002-0363-8865$$aKimura, Kenichi$$b0
000893173 245__ $$aOverexpression of human BAG3P209L in mice causes restrictive cardiomyopathy
000893173 260__ $$a[London]$$bNature Publishing Group UK$$c2021
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000893173 520__ $$aAn amino acid exchange (P209L) in the HSPB8 binding site of the human co-chaperone BAG3 gives rise to severe childhood cardiomyopathy. To phenocopy the disease in mice and gain insight into its mechanisms, we generated humanized transgenic mouse models. Expression of human BAG3P209L-eGFP in mice caused Z-disc disintegration and formation of protein aggregates. This was accompanied by massive fibrosis resulting in early-onset restrictive cardiomyopathy with increased mortality as observed in patients. RNA-Seq and proteomics revealed changes in the protein quality control system and increased autophagy in hearts from hBAG3P209L-eGFP mice. The mutation renders hBAG3P209L less soluble in vivo and induces protein aggregation, but does not abrogate hBAG3 binding properties. In conclusion, we report a mouse model mimicking the human disease. Our data suggest that the disease mechanism is due to accumulation of hBAG3P209L and mouse Bag3, causing sequestering of components of the protein quality control system and autophagy machinery leading to sarcomere disruption.
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000893173 7001_ $$0P:(DE-HGF)0$$aOoms, Astrid$$b1
000893173 7001_ $$0P:(DE-HGF)0$$aGraf-Riesen, Kathrin$$b2
000893173 7001_ $$0P:(DE-Juel1)176604$$aKuppusamy, Maithreyan$$b3
000893173 7001_ $$0P:(DE-HGF)0$$aUnger, Andreas$$b4
000893173 7001_ $$0P:(DE-HGF)0$$aSchuld, Julia$$b5
000893173 7001_ $$0P:(DE-HGF)0$$aDaerr, Jan$$b6
000893173 7001_ $$0P:(DE-HGF)0$$aLother, Achim$$b7
000893173 7001_ $$0P:(DE-HGF)0$$aGeisen, Caroline$$b8
000893173 7001_ $$00000-0003-1297-0007$$aHein, Lutz$$b9
000893173 7001_ $$00000-0002-8540-7760$$aTakahashi, Satoru$$b10
000893173 7001_ $$0P:(DE-HGF)0$$aLi, Guang$$b11
000893173 7001_ $$0P:(DE-HGF)0$$aRöll, Wilhelm$$b12
000893173 7001_ $$0P:(DE-HGF)0$$aBloch, Wilhelm$$b13
000893173 7001_ $$00000-0002-9750-8913$$avan der Ven, Peter F. M.$$b14
000893173 7001_ $$00000-0003-0801-3773$$aLinke, Wolfgang A.$$b15
000893173 7001_ $$00000-0002-0000-3821$$aWu, Sean M.$$b16
000893173 7001_ $$0P:(DE-Juel1)162356$$aHuesgen, Pitter F.$$b17
000893173 7001_ $$0P:(DE-HGF)0$$aHöhfeld, Jörg$$b18
000893173 7001_ $$0P:(DE-HGF)0$$aFürst, Dieter O.$$b19
000893173 7001_ $$00000-0002-9202-8363$$aFleischmann, Bernd K.$$b20$$eCorresponding author
000893173 7001_ $$00000-0002-7518-0224$$aHesse, Michael$$b21$$eCorresponding author
000893173 773__ $$0PERI:(DE-600)2553671-0$$a10.1038/s41467-021-23858-7$$gVol. 12, no. 1, p. 3575$$n1$$p3575$$tNature Communications$$v12$$x2041-1723$$y2021
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