The toxic effect of R350P mutant desmin in striated muscle of man and mouse.
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.
Center for Biochemistry, Institute of Biochemistry I, Medical Faculty, University of Cologne, Joseph-Stelzmann-Str. 52, 50931, Cologne, Germany, christoph.clemen@uni-koeln.de.
Christoph S
CS
Clemen
Florian
F
Stöckigt
Karl-Heinz
KH
Strucksberg
Frederic
F
Chevessier
Lilli
L
Winter
Johanna
J
Schütz
Ralf
R
Bauer
José-Manuel
JM
Thorweihe
Daniela
D
Wenzel
Ursula
U
Schlötzer-Schrehardt
Volker
V
Rasche
Pavle
P
Krsmanovic
Hugo A
HA
Katus
Wolfgang
W
Rottbauer
Steffen
S
Just
Oliver J
OJ
Müller
Oliver
O
Friedrich
Rainer
R
Meyer
Harald
H
Herrmann
Jan Wilko
JW
Schrickel
Rolf
R
Schröder
D000818:Animals; D001145:Arrhythmias, Cardiac / Q000473:pathology / Q000503:physiopathology; D009202:Cardiomyopathies / Q000473:pathology / Q000503:physiopathology; D002311:Cardiomyopathy, Dilated / Q000473:pathology / Q000503:physiopathology; D003599:Cytoskeleton / Q000378:metabolism / Q000473:pathology; D003893:Desmin / Q000235:genetics* / Q000378:metabolism*; D004195:Disease Models, Animal; D004926:Escherichia coli; D055879:Gene Knock-In Techniques; D006352:Heart Ventricles / Q000473:pathology / Q000503:physiopathology; D006801:Humans; D008822:Mice, Transgenic; D018908:Muscle Weakness / Q000473:pathology / Q000503:physiopathology; D018482:Muscle, Skeletal / Q000473:pathology* / Q000503:physiopathology*; D009136:Muscular Dystrophies / Q000473:pathology / Q000503:physiopathology; D020125:Mutation, Missense; D009206:Myocardium / Q000473:pathology*; D012333:RNA, Messenger / Q000378:metabolism; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism; D061987:Sf9 Cells; D018411:Spodoptera
D003893:Desmin; D012333:RNA, Messenger; D011994:Recombinant Proteins