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Editor—Type X collagen is a short chain collagen consisting of three α1(X) chains encoded by theCOL10A1 gene. The α1(X) chains are composed of three structurally distinct domains, an amino-terminal globular domain (NC2), a triple helical region, and a carboxyl-terminal globular domain (NC1).1 Type X collagen is predominantly synthesised by the hypertrophic chondrocytes of the vertebrate growth plate but its precise function during development remains unclear.2 To date, 27 naturally occurring mutations within specific regions of COL10A1 have been reported to cause the autosomal dominant human disorder metaphyseal chondrodysplasia type Schmid (MCDS), which is characterised by short stature, a waddling gait, and coxa vara.2 Of these 27COL10A1 mutations, two occur within a single codon and cause single amino acid substitutions at the putative signal sequence cleavage site within NC2,3 12 mutations cause amino acid substitutions that map to two distinct regions of the predicted structure of the NC1 domain,4 and the remaining mutations introduce stop codons or frameshifts plus premature stop codons that affect, at most, 40% of the carboxyl-terminal region of the NC1 domain. No mutations causing MCDS have yet been found altering the collagenous region of type X collagen, and in two unrelated families with MCDS we have not been able to find mutations in the entire coding region of COL10A1 (unpublished data). The probability of all 27 MCDS mutations clustering within the NC1 and NC2 encoding portions of the gene by chance alone is approximately 1 in 7.6 × 108 and for mutations predicted to truncate the α1(X) chains is approximately 1 in 106. This restricted distribution of the COL10A1mutations causing MCDS strongly suggests that these mutations alter specific function(s) of the encoded α1(X) chains.
The molecular mechanism(s) by which mutations inCOL10A1 cause MCDS …
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