Decreased elastin deposition and high proliferation of fibroblasts from Costello syndrome are related to functional deficiency in the 67-kD elastin-binding protein

Costello syndrome is characterized by mental retardation, loose skin, coars e face, skeletal deformations, cardiomyopathy, and predisposition to numero us malignancies. The genetic origin of Costello syndrome has not yet been d efined. Using immunohistochemistry and metabolic labeling with [H-3]-valine , we have established that cultured skin fibroblasts obtained from patients with Costello syndrome did not assemble elastic fibers, despite an adequat e synthesis of tropoelastin and normal deposition of the microfibrillar sca ffold. We found that impaired production of elastic fibers by these fibrobl asts is associated with a functional deficiency of the 67-kD elastin-bindin g protein (EBP), which is normally required to chaperone tropoelastin throu gh the secretory pathways and to its extracellular assembly. Metabolic puls e labeling of the 67-kD EBP with radioactive serine and further chase of th is tracer indicated that both normal fibroblasts and fibroblasts from patie nts with Costello syndrome initially synthesized comparable amounts of this protein; however, the fibroblasts from Costello syndrome patients quickly lost it into the conditioned media. Because the normal association between EBP and tropoelastin can be disrupted on contact with galactosugarbearing m oieties, and the fibroblasts from patients with Costello syndrome revealed an unusual accumulation of chondroitin sulfate-bearing proteoglycans (CD44 and biglycan), we postulate that a chondroitin sulfate may be responsible f or shedding EBP from Costello cells and in turn for their impaired elastoge nesis. This was further supported by the fact that exposure to chondroitina se ABC, an enzyme capable of chondroitin sulfate degradation, restored norm al production of elastic fibers by fibroblasts from patients with Costello syndrome. We also present evidence that loss of EBP from fibroblasts of Cos tello syndrome patients is associated with an unusually high rate of cellul ar proliferation.