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000126273 0247_ $$2ISSN$$a1432-0533
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000126273 037__ $$aDKFZ-2017-02388
000126273 041__ $$aeng
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000126273 1001_ $$aClemen, Christoph S$$b0
000126273 245__ $$aThe toxic effect of R350P mutant desmin in striated muscle of man and mouse.
000126273 260__ $$aBerlin$$bSpringer$$c2015
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000126273 520__ $$aMutations of the human desmin gene on chromosome 2q35 cause autosomal dominant, autosomal recessive and sporadic forms of protein aggregation myopathies and cardiomyopathies. We generated R349P desmin knock-in mice, which harbor the ortholog of the most frequently occurring human desmin missense mutation R350P. These mice develop age-dependent desmin-positive protein aggregation pathology, skeletal muscle weakness, dilated cardiomyopathy, as well as cardiac arrhythmias and conduction defects. For the first time, we report the expression level and subcellular distribution of mutant versus wild-type desmin in our mouse model as well as in skeletal muscle specimens derived from human R350P desminopathies. Furthermore, we demonstrate that the missense-mutant desmin inflicts changes of the subcellular localization and turnover of desmin itself and of direct desmin-binding partners. Our findings unveil a novel principle of pathogenesis, in which not the presence of protein aggregates, but disruption of the extrasarcomeric intermediate filament network leads to increased mechanical vulnerability of muscle fibers. These structural defects elicited at the myofiber level finally impact the entire organ and subsequently cause myopathy and cardiomyopathy.
000126273 536__ $$0G:(DE-HGF)POF3-312$$a312 - Functional and structural genomics (POF3-312)$$cPOF3-312$$fPOF III$$x0
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000126273 650_7 $$2NLM Chemicals$$aDesmin
000126273 650_7 $$2NLM Chemicals$$aRNA, Messenger
000126273 650_7 $$2NLM Chemicals$$aRecombinant Proteins
000126273 7001_ $$aStöckigt, Florian$$b1
000126273 7001_ $$aStrucksberg, Karl-Heinz$$b2
000126273 7001_ $$aChevessier, Frederic$$b3
000126273 7001_ $$aWinter, Lilli$$b4
000126273 7001_ $$aSchütz, Johanna$$b5
000126273 7001_ $$aBauer, Ralf$$b6
000126273 7001_ $$aThorweihe, José-Manuel$$b7
000126273 7001_ $$aWenzel, Daniela$$b8
000126273 7001_ $$aSchlötzer-Schrehardt, Ursula$$b9
000126273 7001_ $$aRasche, Volker$$b10
000126273 7001_ $$0P:(DE-HGF)0$$aKrsmanovic, Pavle$$b11
000126273 7001_ $$aKatus, Hugo A$$b12
000126273 7001_ $$aRottbauer, Wolfgang$$b13
000126273 7001_ $$aJust, Steffen$$b14
000126273 7001_ $$0P:(DE-HGF)0$$aMüller, Oliver J$$b15
000126273 7001_ $$aFriedrich, Oliver$$b16
000126273 7001_ $$aMeyer, Rainer$$b17
000126273 7001_ $$0P:(DE-He78)7892a89fee19b8e3912c7423d660765d$$aHerrmann, Harald$$b18$$udkfz
000126273 7001_ $$aSchrickel, Jan Wilko$$b19
000126273 7001_ $$aSchröder, Rolf$$b20
000126273 773__ $$0PERI:(DE-600)1458410-4$$a10.1007/s00401-014-1363-2$$gVol. 129, no. 2, p. 297 - 315$$n2$$p297 - 315$$tActa neuropathologica$$v129$$x1432-0533$$y2015
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