Wang X, Osinska H, Klevitsky R, Gerdes A M, Nieman M, Lorenz J, Hewett T, Robbins J
Division of Molecular Cardiovascular Biology, Children's Hospital Research Foundation, Cincinnati, Ohio 45229, USA.
Circ Res. 2001 Jul 6;89(1):84-91. doi: 10.1161/hh1301.092688.
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.
小分子热休克蛋白αB-晶状体蛋白（CryAB）的上调与多种疾病相关，包括结蛋白相关的肌病。CryAB既能与结蛋白结合，也能与细胞质肌动蛋白结合，可能作为分子伴侣参与中间丝的形成和维持，但其上调的生理后果尚不清楚。CryAB的R120G突变与一种家族性结蛋白病有关。然而，尚不清楚该突变是否直接致病。我们创建了多个转基因小鼠品系，这些品系在心肌细胞中过表达小鼠野生型CryAB或R120G突变体。野生型CryAB的过表达相对无害，即使在一个CryAB mRNA表达增加约104倍且蛋白质水平增加11倍的品系中，死亡率也没有增加，也没有诱发结蛋白相关的心肌病。相比之下，表达R120G突变的品系出现了问题，一个高表达品系在成年早期表现出100%的死亡率。适度的表达水平导致了一种与结蛋白相关心肌病极为相似的表型。心肌细胞中的结蛋白丝明显受到影响，肌原纤维排列显著受损，并且在分子和细胞水平上都出现了肥大反应。数据表明，R120G突变导致结蛋白病，具有显性负效应，并导致心脏肥大。
