Mutations within the gene encoding the α1 (X) chain of type X collagen (COL1OA1) cause metaphyseal chondrodysplasia type Schmid but not several other forms of metaphyseal chondrodysplasia

Abstract

Type X collagen is a homotrimer of α1(X) chains encoded by the COL1OA1 gene. It is synthesised specifically and transiently by hypertrophic chondrocytes at sites of endochondral ossification. Point mutations and deletions in the region of the COL1OA1 gene encoding the α1(X) carb-oxyl-terminal (NC1) domain have previously been identified in subjects with metaphyseal chondrodysplasia type Schmid (MCDS). To determine whether mutations in other regions of the gene caused MCDS or comparable phenotypes, we used PCR followed by SSCP to analyse the coding and promoter regions of the COL1OA1 gene, as well as the intron/exon boundaries of five further subjects with MCDS, one subject with atypical MCDS, and nine subjects with other forms of metaphyseal chondrodysplasia. Using this appproach, three of the subjects with MCDS were found to be heterozygous for the deletions lS64delACfl, l9S6delT, and 2O29delAC in the region of COL1OA1 encoding the NC1 domain. These deletions would lead to alterations in the reading frame, premature stop codons, and the translation of truncated protein products. A fourth subject with MCDS was found to be heterozygous for a single base pair transition, T1894C, that would lead to the substitution of the amino acid residue serine at position 600 by proline within the NC1 domain. We did not, however, detect mutations in the coding and non-coding regions of COL1OA1 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 COL1OA1 causing MCDS argues against the hypothesis that the phenotype arises simply through haploinsufficiency but that an, as yet, unexplained mutation mechanism underlies this phenotype.