title: Decreased elastin deposition and high proliferation of fibroblasts from Costello syndrome are related to functional deficiency in the 67-kD elastin-binding protein.
abstract: 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.
authors.affiliation: Division of Cardiovascular Research, The Hospital for Sick Children, Toronto, ON M5G 1X8 Canada. alek.hinek@sickkids.on.ca
authors.forename: A
authors.initials: A
authors.lastname: Hinek
authors.forename: A C
authors.initials: AC
authors.lastname: Smith
authors.forename: E M
authors.initials: EM
authors.lastname: Cutiongco
authors.forename: J W
authors.initials: JW
authors.lastname: Callahan
authors.forename: K W
authors.initials: KW
authors.lastname: Gripp
authors.forename: R
authors.initials: R
authors.lastname: Weksberg
mesh_terms: D000015:Abnormalities, Multiple / Q000235:genetics / Q000378:metabolism* / Q000473:pathology* / Q000503:physiopathology; D000293:Adolescent; D058578:Biglycan; D001704:Biopolymers / Q000378:metabolism; D002455:Cell Division; D002478:Cells, Cultured; D002648:Child; D002675:Child, Preschool; D019765:Chondroitin ABC Lyase / Q000378:metabolism; D002809:Chondroitin Sulfates / Q000378:metabolism; D017077:Culture Media, Conditioned / Q000378:metabolism; D004549:Elastin / Q000378:metabolism*; D016326:Extracellular Matrix Proteins; D005347:Fibroblasts / Q000378:metabolism* / Q000473:pathology*; D006801:Humans; D018960:Hyaluronan Receptors / Q000737:chemistry / Q000378:metabolism; D007223:Infant; D007231:Infant, Newborn; D018832:Molecular Chaperones / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D008970:Molecular Weight; D011509:Proteoglycans / Q000737:chemistry / Q000378:metabolism; D011956:Receptors, Cell Surface / Q000737:chemistry / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D013577:Syndrome; D014333:Tropoelastin / Q000378:metabolism
chemical_list: C546884:BGN protein, human; D058578:Biglycan; D001704:Biopolymers; D017077:Culture Media, Conditioned; D016326:Extracellular Matrix Proteins; D018960:Hyaluronan Receptors; D018832:Molecular Chaperones; D011509:Proteoglycans; D011956:Receptors, Cell Surface; D014333:Tropoelastin; C054901:elastin-binding proteins; D002809:Chondroitin Sulfates; D004549:Elastin; D019765:Chondroitin ABC Lyase