We investigated the molecular bases of spondyloepiphyseal dysplasia (SED) associated with the R992C (p.R1192C) substitution in collagen II. At the protein level, we analyzed the structure and integrity of mutant molecules, and at the cellular level, we specifically studied the effects of the presence of the R992C collagen II on the biological processes taking place in host cells. Our studies demonstrated that mutant collagen II molecules were characterized by altered electrophoretic mobility, relatively low thermostability, the presence of atypical disulfide bonds, and slow rates of secretion into the extracellular space. Analyses of cellular responses to the presence of the mutant molecules showed that excessive accumulation of thermolabile collagen II was associated with the activation of an "unfolded protein response" and an increase in apoptosis of host cells. Collectively, these data suggest that molecular mechanisms of SED may be driven not only by structural changes in the architecture of extracellular collagenous matrices, but also by intracellular processes activated by the presence of mutant collagen II molecules.
Recommended CitationChung, Hye Jin; Jensen, Deborah A.; Gawron, Katarzyna; Steplewski, Andrzej; and Fertala, Andrzej, "R992C (p.R1192C) Substitution in collagen II alters the structure of mutant molecules and induces the unfolded protein response." (2009). Department of Dermatology and Cutaneous Biology Faculty Papers. Paper 5.