Abnormal growth plate function in pigs carrying a dominant mutation in type X collagen

We have identified a naturally occurring, dominant mutation that causes dwa rfism in domestic pigs (Sus scrofa). With a positional candidate gene appro ach, the dwarf phenotype was shown to be a result of a single amino acid ch ange, G590R, in the alpha1(X) chain of type X collagen. Type X collagen is a homotrimer of alpha1(X) chains encoded by the COL10A1 gene, which is expr essed in hypertrophic chondrocytes during the process of endochondral ossif ication. An amino acid substitution at the equivalent position in human typ e X collagen, G595E, has previously been shown to cause Schmid metaphyseal chondrodysplasia (SMCD), which is a relatively mild skeletal disorder assoc iated with dwarfism and growth plate abnormality. Consistent with the clini cal phenotype of SMCD patients, radiological and histological examination o f the dwarf pigs revealed metaphyseal chondrodysplasia in the long bones. Y east-based, two-hybrid protein interaction studies and in vitro assembly ex periments demonstrated that the amino acid substitution interfered with the ability of the mutated collagen molecules to engage in trimerization. This work establishes that the chondrodysplastic dwarf pigs by genetic, biochem ical, radiological and histological criteria provide a valid animal model o f SMCD.