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Papers In Press, published online ahead of print December 13, 2000
Biochemistry, University of Hong Kong, Hong Kong
Corresponding Author: chand{at}hkusua.hku.hk
Schmid metaphyseal chondrodysplasia (SMCD) results from mutations in the collagen X (COL10A1) gene. With the exception of two cases, the known mutations are clustered in the C-terminal non-helical (NC1) domain of the collagen X. In vitro and cell culture studies have shown that the NC1 mutations result in impaired collagen X trimer assembly and secretion. In the two other cases, missense mutations which alter Gly18 at the -1 position of the "putative" signal peptide cleavage site were identified [Ikegawa,S.,Nakamura,K., Nagano,A., Haga,N. and Nakamura,Y (1997) Hum. Mutat. 9, 131-135]. To study their impact on collagen X biosynthesis using in vitro cell-free translation in the presence of microsomes, and cell transfection assays, these two mutations were created in COL10A1 by site-directed mutagenesis. The data suggest that translocation of the mutant pre-a1(X) chains into the microsomes is not affected, but cleavage of the signal peptide is inhibited and the mutant chains remain anchored to the membrane of microsomes. Cell-free translation and transfection studies in cells showed that the mutant chains associate into trimers, but cannot form a triple helix. The combined effect of both the lack of signal peptide cleavage and helical configuration is impaired secretion. Thus, despite the different nature of the NC1 and signal peptide mutations in collagen X, both result in impaired collagen X secretion, probably followed by intracellular retention and degradation of mutant chains, causing the SMCD phenotype.
J. Biol. Chem, 10.1074/jbc.M003361200
Submitted on April 18, 2000
Revised on November 26, 2000
Accepted on December 13, 2000
Aberrrant signal peptide cleavage of collage x in Schmid metaphyseal chondrodysplasia: implications for the molecular basis of the disease
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