Myopathy Causing Alpha B-Crystallin Mutants Have Distinct Properties In Myocytes

αB-crystallin is a small heat shock protein which is ubiquitously expressed and at high levels in muscle and eye lens. αB-crys consists of an N-terminal domain that contains the phosphorylated serines; a highly conserved “crystallin” domain, from a. a. 64 to 150; and a flexible c-terminal domain, which is involved in chaperone function and solubility. One mutation in the crystallin domain, R120G, causes a dominant desmin-related myopathy. The affected patients have desmin accumulation in skeletal and cardiac tissue, with progressive weakness, and develop cataracts. Recently, two mutations in αB-crys have been shown to cause progressive myopathy with myofibrillar degeneration at the z-disk. These mutations truncate the c-terminal domain of the protein. Adenovirus expressing wild-type human αB-crys (WT) as a cfp fusion protein, and the three mutated versions of crystallin: R120G-cfp, 464delCT-cfp, and Q151X-cfp were expressed in cardiomyocytes. Percentage of cells with aggregates, assessed by microscopy, are: R120G, 42.2; Q151X, 21.3; 464delCT, 20.2; WT, 11.0; GFP, 6.9. By IE focusing they all have different pIs from WT. Only the c-terminal mutants caused a downregulation of endogenous crystallin by immunoanalysis. We conclude the αB-crys mutants have unique and functionally significant properties in myocytes. This work was supported by the American Heart Association and the Falk Foundation.