MUTATIONS WITHIN THE GENE ENCODING THE ALPHA-1(X) CHAIN OF TYPE-X COLLAGEN (COL10A1) CAUSE METAPHYSEAL CHONDRODYSPLASIA TYPE SCHMID BUT NOTSEVERAL OTHER FORMS OF METAPHYSEAL CHONDRODYSPLASIA

Type X collagen is a homotrimer of alpha 1(X) chains encoded by the CO L10A1 gene. It is synthesised specifically and transiently by hypertro phic chondrocytes at sites of endochondral ossification. Point mutatio ns and deletions in the region of the COL10A1 gene encoding the alpha 1(X) carboxyl-terminal (NC1) domain have previously been identified in subjects with metaphyseal chondrodysplasia type Schmid (MCDS). To det ermine whether mutations in other regions of the gene caused MCDS or c omparable phenotypes, we used PCR followed by SSCP to analyse the codi ng and promoter regions of the COL10A1 gene, as well as the intron/exo n boundaries of five further subjects with MCDS, one subject with atyp ical MCDS, and nine subjects with other forms of metaphyseal chondrody splasia. Using this approach, three of the subjects with MCDS were fou nd to be heterozygous for the deletions 1864delACTT, 1956delT, and 202 9delAC in the region of COL10A1 encoding the NC1 domain. These deletio ns would lead to alterations in the reading frame, premature stop codo ns, and the translation of truncated protein products. A fourth subjec t with MCDS was found to be heterozygous for a single base pair transi tion, T1894C, that would lead to the substitution of the amino acid re sidue serine at position 600 by proline within the NC1 domain. We did not, however, detect mutations in the coding and non-coding regions of COL10A1 in one subject with MCDS, the subject with atypical MCDS, and in the nine subjects with other forms of metaphyseal chondrodysplasia . We propose that the nature and distribution of mutations within the NC1 domain of COL10A1 causing MCDS argues against the hypothesis that the phenotype arises simply through haploinsufficiency but that an, as yet, unexplained mutation mechanism underlies this phenotype.