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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.

Pubmed ID: 11440982

Authors

  • Wang X
  • Osinska H
  • Klevitsky R
  • Gerdes AM
  • Nieman M
  • Lorenz J
  • Hewett T
  • Robbins J

Journal

Circulation research

Publication Data

July 6, 2001

Associated Grants

  • Agency: NHLBI NIH HHS, Id: HL41496
  • Agency: NHLBI NIH HHS, Id: HL52318
  • Agency: NHLBI NIH HHS, Id: HL56370
  • Agency: NHLBI NIH HHS, Id: HL56620
  • Agency: NHLBI NIH HHS, Id: HL60546
  • Agency: NHLBI NIH HHS, Id: HL62459

Mesh Terms

  • Animals
  • Cardiomegaly
  • Crystallins
  • Desmin
  • Mice
  • Mice, Transgenic
  • Mutation, Missense
  • Myocardial Contraction
  • Myocardium
  • RNA, Messenger
  • Survival Rate