Functional deficiency in the 67-kD elastin binding protein is a crucial component of the pathomechanism of Costello syndrome

grantor: University of TorontoCostello syndrome is characterized by mental retardation, loose skin, coarse face, skeletal deformations, as well as cardiomyopathy and predisposition to numerous malignancies. The genetic origin of Costello syndrome has not yet been defined. Using immunohistochemistry and metabolic labeling with [ 3H]-valine, we have established that cultured skin fibroblasts obtained from patients with Costello syndrome did not assemble elastic fibers despite an adequate synthesis of tropoelastin and normal deposition of the microfibrillar scaffold. We found that impaired production of elastic fibers by these fibroblasts is associated with a functional deficiency of the 67-kD elastin binding protein (EBP), normally required to chaperone tropoelastin through the secretory pathways and to its extracellular assembly. Metabolic pulse labeling of the 67-kD EBP with radioactive serine and further chase of this tracer indicated that both normal fibroblasts and fibroblasts from Costello syndrome patients initially synthesized comparable amounts of this protein, however, the fibroblasts from Costello syndrome patients quickly lost it into the conditioned media. Since the normal association between EBP and tropoelastin can be disrupted upon contact with galactosugar-bearing moieties, and the fibroblasts from Costello syndrome patients revealed an unusual accumulation of chondroitin sulfate-bearing proteoglycans (CD44 and biglycan), we postulate that a chondroitin sulfate may be responsible for shedding EBP from Costello cells and in turn for their impaired elastogenesis. This was further supported by the fact that exposure to chondroitinase ABC, an enzyme capable of chondroitin sulfate degradation, restored normal production of elastic fibers by fibroblasts from Costello syndrome patients. We also present evidence that loss of EBP from fibroblasts of Costello syndrome patients is associated with an unusually high rate of cellular proliferation.M.Sc