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@ARTICLE{Clemen:126273,
author = {C. S. Clemen and F. Stöckigt and K.-H. Strucksberg and F.
Chevessier and L. Winter and J. Schütz and R. Bauer and
J.-M. Thorweihe and D. Wenzel and U. Schlötzer-Schrehardt
and V. Rasche and P. Krsmanovic$^*$ and H. A. Katus and W.
Rottbauer and S. Just and O. J. Müller and O. Friedrich and
R. Meyer and H. Herrmann$^*$ and J. W. Schrickel and R.
Schröder},
title = {{T}he toxic effect of {R}350{P} mutant desmin in striated
muscle of man and mouse.},
journal = {Acta neuropathologica},
volume = {129},
number = {2},
issn = {1432-0533},
address = {Berlin},
publisher = {Springer},
reportid = {DKFZ-2017-02388},
pages = {297 - 315},
year = {2015},
abstract = {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.},
keywords = {Desmin (NLM Chemicals) / RNA, Messenger (NLM Chemicals) /
Recombinant Proteins (NLM Chemicals)},
cin = {B065},
ddc = {610},
cid = {I:(DE-He78)B065-20160331},
pnm = {312 - Functional and structural genomics (POF3-312)},
pid = {G:(DE-HGF)POF3-312},
typ = {PUB:(DE-HGF)16},
pubmed = {pmid:25394388},
pmc = {pmc:PMC4309020},
doi = {10.1007/s00401-014-1363-2},
url = {https://inrepo02.dkfz.de/record/126273},
}