TY  - JOUR
AU  - Clemen, Christoph S
AU  - Stöckigt, Florian
AU  - Strucksberg, Karl-Heinz
AU  - Chevessier, Frederic
AU  - Winter, Lilli
AU  - Schütz, Johanna
AU  - Bauer, Ralf
AU  - Thorweihe, José-Manuel
AU  - Wenzel, Daniela
AU  - Schlötzer-Schrehardt, Ursula
AU  - Rasche, Volker
AU  - Krsmanovic, Pavle
AU  - Katus, Hugo A
AU  - Rottbauer, Wolfgang
AU  - Just, Steffen
AU  - Müller, Oliver J
AU  - Friedrich, Oliver
AU  - Meyer, Rainer
AU  - Herrmann, Harald
AU  - Schrickel, Jan Wilko
AU  - Schröder, Rolf
TI  - The toxic effect of R350P mutant desmin in striated muscle of man and mouse.
JO  - Acta neuropathologica
VL  - 129
IS  - 2
SN  - 1432-0533
CY  - Berlin
PB  - Springer
M1  - DKFZ-2017-02388
SP  - 297 - 315
PY  - 2015
AB  - Mutations 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.
KW  - Desmin (NLM Chemicals)
KW  - RNA, Messenger (NLM Chemicals)
KW  - Recombinant Proteins (NLM Chemicals)
LB  - PUB:(DE-HGF)16
C6  - pmid:25394388
C2  - pmc:PMC4309020
DO  - DOI:10.1007/s00401-014-1363-2
UR  - https://inrepo02.dkfz.de/record/126273
ER  -