Expression of R120G-alpha B-crystallin causes aberrant desmin and alpha B-crystallin aggregation and cardiomyopathy in mice

Upregulation of alphaB-crystallin (CryAB), a small heat shock protein, is a ssociated with a variety of diseases, including the desmin-related myopathi es. CryAB, which binds to both desmin and cytoplasmic actin, may participat e as a chaperone in intermediate filament formation and maintenance, but th e physiological consequences of CryAB upregulation are unknown. A mutation in CryAB, R120G, has been linked to a familiar desminopathy. However, it is unclear whether the mutation is directly causative. We created multiple tr ansgenic mouse lines that overexpressed either murine wild-type CryAB or th e R120G mutation in cardiomyocytes. Overexpression of wild-type CryAB was r elatively benign, with no increases in mortality and no induction of desmin -related cardiomyopathy even in a line in which CryAB mRNA expression was i ncreased approximate to 104-fold and the protein level increased by Ii-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 th at observed for the desmin-related cardiomyopathies. The desmin filaments i n the cardiomyocytes were overtly affected, myofibril alignment was signifi cantly impaired, and a hypertrophic response occurred at both the molecular and cellular levels. The data show that the R120G mutation causes a desmin opathy, is dominant negative, and results in cardiac hypertrophy.