Mouse model of desmin-related cardiomyopathy.
BACKGROUND
The consequence of upregulation of desmin in the heart is unknown. Mutations in desmin have been linked to desmin-related myopathy (DRM), which is characterized by abnormal intrasarcoplasmic accumulation of desmin, but direct causative evidence that a desmin mutation leads to aberrant intrasarcoplasmic desmin accumulation, aggregation, and cardiomyopathy is lacking.


RESULTS
Multiple transgenic mouse lines that expressed either murine wild-type desmin or a 7-amino acid deletion (R173 through E179) desmin (D7-des) mutation linked to DRM were made. The distribution of desmin protein was unchanged, and no overt phenotype was detected in the wild-type desmin transgenic mice. In contrast, the D7-des mouse heart showed aberrant intrasarcoplasmic and electron-dense granular filamentous aggregates that were desmin-positive and characteristic of human DRM. The desmin filament network was significantly disrupted, and myofibril alignment was visibly compromised. Although systolic function at the whole-organ level was substantially conserved in the young adult animals, the ability of the heart to respond to beta-agonist stimulation, as measured in the intact animal, was significantly blunted.


CONCLUSIONS
Upregulation of desmin protein at moderate levels is not detrimental. However, the D7-des mutation is dominant negative, and expression of the mutant protein leads to the appearance of aggregates that are characteristic of and diagnostic for human desmin-related cardiomyopathy.
Wang
X
X
Divisions of Molecular Cardiovascular Biology, Children's Hospital Research Foundation, Cincinnati, Ohio, USA.
Osinska
H
H
Dorn
G W
GW
Nieman
M
M
Lorenz
J N
JN
Gerdes
A M
AM
Witt
S
S
Kimball
T
T
Gulick
J
J
Robbins
J
J
D000595:Amino Acid Sequence; D000818:Animals; D009202:Cardiomyopathies / Q000235:genetics* / Q000473:pathology / Q000503:physiopathology; D003893:Desmin / Q000235:genetics* / Q000378:metabolism; D004195:Disease Models, Animal; D006352:Heart Ventricles / Q000378:metabolism / Q000473:pathology / Q000648:ultrastructure; D006984:Hypertrophy / Q000235:genetics; D051379:Mice; D008822:Mice, Transgenic; D018613:Microscopy, Confocal; D008854:Microscopy, Electron; D008969:Molecular Sequence Data; D009154:Mutation; D009200:Myocardial Contraction / Q000235:genetics
D003893:Desmin