Journal Article

DKFZ-2017-02388

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png The toxic effect of R350P mutant desmin in striated muscle of man and mouse.

Clemen, C. S. ; Stöckigt, F. ; Strucksberg, K.-H. ; Chevessier, F. ; Winter, L. ; Schütz, J. ; Bauer, R. ; Thorweihe, J.-M. ; Wenzel, D. ; Schlötzer-Schrehardt, U. ; Rasche, V. ; Krsmanovic, P.DKFZ* ; Katus, H. A. ; Rottbauer, W. ; Just, S. ; Müller, O. J. ; Friedrich, O. ; Meyer, R. ; Herrmann, H.DKFZ* ; Schrickel, J. W. ; Schröder, R.

2015
Springer Berlin

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Please use a persistent id in citations: doi:10.1007/s00401-014-1363-2

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.

Keyword(s): Desmin ; RNA, Messenger ; Recombinant Proteins

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Contributing Institute(s):

1. Funktionelle Zellarchitektur (B065)

Research Program(s):

1. 312 - Functional and structural genomics (POF3-312) (POF3-312)

Appears in the scientific report 2015

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Database coverage:
; BIOSIS Previews ; Current Contents - Life Sciences ; Ebsco Academic Search ; IF >= 10 ; JCR ; NCBI Molecular Biology Database ; Nationallizenz ; SCOPUS ; Science Citation Index ; Science Citation Index Expanded ; Thomson Reuters Master Journal List ; Web of Science Core Collection

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