On genetics of dilated cardiomyopathy and transgenic models: all is not crystal clear in myopathic hearts.

The aB-crystallin protein, the predominant structural protein of the ocular lens, is a member of the small heat shock proteins that is also expressed abundantly in the heart and skeletal muscle.1 The aB-crystallin was initially discovered in the vertebrate ocular lens and was dubbed crystallin because of its role in maintenance of lens transparency.2 It is also essential for maintenance of microtubular integrity in striated muscles.3 In the heart, as in the ocular lens, aB-crystallin forms soluble multimeres that function as chaperone molecules, facilitating protein folding and translocation.4 Thus, the principal function of aBcrystallin protein is to prevent unfolding of cellular proteins damaged by all forms of stress. Ischemia and oxidative stress increase the expression of aB-crystallin in the heart.5 In response to stress, intracellular kinases phosphorylate aBcrystallin,6 leading to its translocation from the cytosolic pool to Z lines and intercalated disks. Translocated aB-crystallin binds to the components of the intermediary filaments and cytoskeletal proteins, such as actin and desmin, and prevents their aggregation.3,7 The protective role of aB-crystallin in the maintenance of cytoskeletal integrity has been confirmed in gene transfer studies in cultured cardiac myocytes8 and in transgenic mice.9 Overexpression of aB-crystallin protects cardiac myocytes against apoptosis and reperfusion injury.8,9 Interest in aB-crystallin has been heightened because of recent elucidation of the genetic basis of desmin-related myopathy (DRM), a familial muscular disorder characterized by skeletal myopathy, heart failure, conduction defect, and arrhythmias. Pathologically, DRM is characterized by the presence of protein aggregates containing desmin in the cytoplasm of striated muscles. For this reason, the initial genetic studies in families with DRM focused on identification of mutations in the desmin gene (DES).10,11 However, genetic heterogeneity of DRM was soon recognized and substantiated by the discovery of the R120G mutation in the CRYAB gene in patients with DRM and lens cataract.12 In this issue of Circulation Research, Wang et al13 describe a transgenic mouse model whereby cardiac-restricted expression of the aB-crystallin–R120G protein leads to a phenotype similar to DRM in humans.12 The aB-crystallin–R120G mice exhibit early mortality, aberrant desmin and aB-crystallin aggregation in the heart, and cardiac hypertrophy and dysfunction. The observed phenotypes are similar to those reported in the mutant desmin transgenic mice,14 which emphasize the intricate interactions between aB-crystallin and desmin. In contrast to the mutant protein, overexpression of wild-type aB-crystallin in the heart did not produce a significant phenotype. This finding corroborates the results of studies in a previous aB-crystallin transgenic mouse model9 and in transgenic mice overexpressing wild-type desmin.14 A striking feature of the aB-crystallin–R120G mice is the high rate of premature death from congestive heart failure leading to 100% fatality at 32 weeks of age. In humans, the R120G mutation has been described only in a single large family with an apparently low rate of premature death. This apparent discrepancy may reflect the relatively higher than natural levels of the mutant protein in the hearts of transgenic mice. The effects of the excess mutant protein on survival could also explain the lower copy number and expression levels observed in the mutant transgenic mice compared with the wild-type mice, ie, conferring an embryonic survival disadvantage. Other factors, such as the genetic background, known to affect the phenotypic expression of cardiomyopathies in humans, also could account for the observed differences in survival rates. The mutant aB-crystallin mice, despite having deposits of desmin/aB-crystallin aggregates in the heart, exhibited an enhanced 1dP/dt at 3 months of age. The latter may reflect the presence of left ventricular hypertrophy, although it should be recognized that 1dp/dt is a load-dependent index, which varies significantly from mouse to mouse. It is interesting that the initial description of the phenotype in the family with the aB-crystallin R120G mutation was that of hypertrophic cardiomyopathy.15 Despite apparent dissociation of the contractile function and cardiac hypertrophy, it is likely that hypertrophy, as in other forms of cardiomyopathy, is a secondary phenotype because of impaired myocyte function and activation of stress-responsive transcription machinery. The primary purpose of transgenesis is to develop models that provide opportunity to delineate the pathogenesis of the disease of interest so that new targets for treatment and prevention of human disease might be developed. In this regard, the report by Wang et al12 provides some insight into the pathogenesis of DRM and supports the results of previous in vitro cell culture studies.12,16,17 The results in transgenic mice suggest that the aB-crystallin–R120G is less soluble and its expression leads to formation of protein aggregates, The opinions expressed in this editorial are not necessarily those of the editors or of the American Heart Association. From Baylor College of Medicine, Department of Medicine, Section of Cardiology, Houston, Tex. Correspondence to A.J. Marian, MD, Associate Professor of Medicine, Section of Cardiology, One Baylor Plaza, 543E, Houston, TX 77030. E-mail [email protected] (Circ Res. 2001;89:3-5.) © 2001 American Heart Association, Inc.