Costello syndrome is characterized by
mental retardation, loose skin,
coarse face, skeletal deformations,
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), which is 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 patients 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 galactosugar-bearing moieties, 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 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 patients with
Costello syndrome. We also present evidence that loss of EBP from fibroblasts of
Costello syndrome patients is associated with an unusually high rate of cellular proliferation.