Impaired secretion of type III procollagen in Ehlers-Danlos syndrome type IV fibroblasts: correction of the defect by incubation at reduced temperature and demonstration of subtle alterations in the triple-helical region of the molecule.

The amount of type III procollagen secreted by fibroblasts from two patients with type IV Ehlers-Danlos syndrome is reduced to 25% and 20%, respectively, of that of control cells after incubation at 37 degrees C, but reverts to 70% and 110% when cells are incubated at 32 degrees C. The type III procollagen molecules secreted only at the lower temperature are of normal size but apparently contain different mutations which disrupt the triple-helical region and lower the thermal stability of the molecule. These data suggest that subtle mutations in the pro alpha 1(III)-chains produce Ehlers-Danlos syndrome type IV by disrupting the triple-helical region of the molecule, lowering its thermal stability, and thus impairing its secretion. At the lower temperature, stabilization of the defective molecules result in more efficient secretion. This approach may be useful for the characterization of other unstable collagens.