Metaphyseal chondrodysplasia type Schmid mutations are predicted to occur in two distinct three-dimensional clusters within type X collagen NC1 domains that retain the ability to trimerize.

Metaphyseal chondrodysplasia type Schmid (MCDS) is caused by mutations in COL10A1 that are clustered in the carboxyl-terminal non-collagenous (NC1) encoding domain. This domain is responsible for initiating trimerization of type X collagen during biosynthesis. We have built a molecular model of the NC1 domain trimer based on the crystal structure coordinates of the highly homologous trimeric domain of ACRP30 (adipocyte complement-related protein of 30 kDa or AdipoQ). Mapping of the MCDS mutations onto the structure reveals two specific clusters of residues as follows: one on the surface of the monomer which forms a tunnel through the center of the assembled trimer and the other on a patch exposed to solvent on the exterior surface of each monomeric unit within the assembled trimer. Biochemical studies on recombinant trimeric NC1 domain show that the trimer has an unusually high stability not exhibited by the closely related ACRP30. The high thermal stability of the trimeric NC1 domain, in comparison with ACRP30, appears to be the result of a number of factors including the 17% greater total buried solvent-accessible surface and the increased numbers of hydrophobic contacts formed upon trimerization. The 27 amino acid sequence present at the amino terminus of the NC1 domain, which has no counterpart in ACRP30, also contributes to the stability of the trimer. We have also shown that NC1 domains containing the MCDS mutations Y598D and S600P retain the ability to homotrimerize and heterotrimerize with wild type NC1 domain, although the trimeric complexes formed are less stable than those of the wild type molecule. These studies suggest strongly that the predominant mechanism causing MCDS involves a dominant interference of mutant chains on wild type chain assembly.