Domain-specific Mutations of a Transforming Growth Factor (TGF)-β1 Latency-associated Peptide Cause Camurati-Engelmann Disease Because of the Formation of a Constitutively Active Form of TGF-β1

Transforming growth factor (TGF)-β1 is secreted as a latent form, which consists of its mature form and a latency-associated peptide (β1-LAP) in either the presence or the absence of additional latent TGF-β1-binding protein. We recently reported that three different missense mutations (R218H, R218C, and C225R) of β1-LAP cause the Camurati-Engelmann disease (CED), an autosomal dominant disorder characterized by hyperosteosis and sclerosis of the diaphysis of the long bones. Pulse-chase experiments using fibroblasts from CED patients and expression experiments of the mutant genes in an insect cell system suggest that these mutations disrupt the association of β1-LAP and TGF-β1 and the subsequent release of the mature TGF-β1. Furthermore, the cell growth of fibroblasts from a CED patient and mutant gene-transfected fibroblasts was suppressed via TGF-β1. The growth suppression observed was attenuated by neutralizing antibody to TGF-β1 or by treatment of dexamethasone. On the other hand, the proliferation of human osteoblastic MG-63 cells was accelerated by coculture with CED fibroblasts. These data suggest that the domain-specific mutations of β1-LAP result in a more facile activation of TGF-β1, thus causing CED.