Circulation Research. 2001;89:84-91
Published online before print June 21, 2001, doi: 10.1161/hh1301.092688
Published online before print June 21, 2001, doi: 10.1161/hh1301.092688
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© 2001 American Heart Association, Inc.
Integrative Physiology |
Expression of R120G–
B-Crystallin Causes Aberrant Desmin and B-Crystallin Aggregation and Cardiomyopathy in Mice
From the Division of Molecular Cardiovascular Biology (X.W., H.O., R.K., T.H., J.R.), Children’s Hospital Research Foundation, Cincinnati, Ohio; South Dakota Health Research Foundation–Cardiovascular Research Institute (A.M.G.), Sioux Falls, SD; and Department of Molecular and Cellular Physiology (M.N., J.L.), University of Cincinnati Medical Center, Cincinnati, Ohio.
Correspondence to Jeffrey Robbins, Division of Molecular Cardiovascular Biology, Children’s Hospital Research Foundation, 3333 Burnet Ave, Cincinnati, OH 45229. E-mail jeff.robbins{at}chmcc.org
Abstract
Abstract—Upregulation
of 
B-crystallin (CryAB), a small heat shock protein, is associated
with a variety of diseases, including the desmin-related myopathies.
CryAB, which binds to both desmin and cytoplasmic actin, may
participate as a chaperone in intermediate filament formation and
maintenance, but the physiological
consequences of CryAB upregulation are unknown. A mutation in CryAB,
R120G, has been linked to a familial desminopathy. However, it is
unclear whether the mutation is directly causative. We created multiple
transgenic mouse lines that overexpressed either murine wild-type CryAB
or the R120G mutation in cardiomyocytes. Overexpression of
wild-type CryAB was relatively benign, with no increases in mortality
and no induction of desmin-related cardiomyopathy
even in a line in which CryAB mRNA expression was increased 
104-fold
and the protein level increased by 11-fold. In contrast, lines
expressing the R120G mutation were compromised, with a high-expressing
line exhibiting 100% mortality by early adulthood. Modest expression
levels resulted in a phenotype that was strikingly similar to
that observed for the desmin-related
cardiomyopathies. The desmin filaments in the
cardiomyocytes were overtly affected, myofibril alignment
was significantly impaired, and a hypertrophic response occurred at
both the molecular and cellular levels. The data show that the R120G
mutation causes a desminopathy, is dominant negative, and results in
cardiac hypertrophy.
Key Words: transgenic • heart disease • mouse • cardiac • genetics
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