Transforming growth factor-beta1 (TGF-beta1) is secreted as a latent precursor, consisting of a homodimer of the latency-associated
peptide and the mature
peptide. TGFbeta-1 can only exert its many functions after going from this latent to an active state, in which the binding site of the mature
peptide for its receptor is no longer shielded by the latency-associated
peptide. We and others reported that mutations in TGFB1 cause
Camurati-Engelmann disease, a rare bone disorder. Until now, seven mutations have been published. In this study, we investigate the effect of the LLL12-13ins, Y81H, R218C, H222D, and C225R mutations on the functioning of
TGF-beta1 in vitro. A
luciferase reporter assay specific for
TGF-beta-induced transcriptional response with wild type and mutant
TGF-beta1 constructs showed a positive effect of all mutations on
TGF-beta1 activity. By way of
enzyme-linked
immunosorbent assay, we found that in the R218C, H222D, and C225R mutant constructs, this effect is caused by an increase in active
TGF-beta1 in the medium of transfected cells. The LLL12-13ins and Y81H mutations on the contrary have a profound effect on secretion; a decreased amount of
TGF-beta1 is secreted, but the increased
luciferase activity shows that the intracellular accumulation of (aberrant)
TGF-beta1 can initiate an enhanced transcriptional response, suggesting the existence of an alternative signaling pathway. Our data indicate that the mutations in the
signal peptide and latency-associated
peptide facilitate
TGF-beta1 signaling, thus causing
Camurati-Engelmann disease.