Expression of R120G-alphaB-crystallin causes aberrant desmin and alphaB-crystallin aggregation and cardiomyopathy in mice.
Upregulation of alphaB-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 approximately 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.
Wang
X
X
Division of Molecular Cardiovascular Biology, Children's Hospital Research Foundation, Cincinnati, Ohio 45229, USA.
Osinska
H
H
Klevitsky
R
R
Gerdes
A M
AM
Nieman
M
M
Lorenz
J
J
Hewett
T
T
Robbins
J
J
D000818:Animals; D006332:Cardiomegaly / Q000235:genetics* / Q000473:pathology / Q000503:physiopathology; D003459:Crystallins / Q000235:genetics* / Q000378:metabolism*; D003893:Desmin / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D020125:Mutation, Missense; D009200:Myocardial Contraction; D009206:Myocardium / Q000378:metabolism / Q000473:pathology / Q000648:ultrastructure; D012333:RNA, Messenger / Q000096:biosynthesis; D015996:Survival Rate
D003459:Crystallins; D003893:Desmin; D012333:RNA, Messenger