Deletion of 24 amino acids from the Pro-α1(I) chain of type I procollagen in a patient with the Ehlers-Danlos syndrome type VII

Abstract

A child with the type VII form of the Ehlers-Danlos syndrome was shown to have a structural defect in the amino terminus of the pro-α1(I) chain of type I procollagen. Normal and mutant amino-terminal cyanogen bromide peptides (pN-α1(I) CB0,1 peptides) were purified from the medium of the patient's cultured fibroblasts. Amino acid sequencing of tryptic peptides derived from the mutant pN-α1(I) CB0,1 peptide showed that an expected sequence of 24 amino acids (positions 136-159 of the normal pN-α1(I) CB0,1 peptide) was deleted. The segment deleted from the mutant pro-α1(I) chain contains the small globular region of the NH 2-propeptide, the procollagen N-proteinase cleavage site, the NH 2-telopeptide, and first triplet of the helix of the αI(I) collagen chain (Chu, M.-L., de Wet, W., Bernard, M., Ding, J.F., Morabito, M., Myers, J., Williams, C., and Ramirez, F. (1984) Nature 310, 337-340). Loss of the procollagen N-proteinase cleavage site from the mutant pro-α1(I) chain accounted for the persistence of its NH 2-propeptide despite normal production of the N-proteinase by cultured mutant fibroblasts. Collagen production by mutant fibroblasts was doubled possibly due to reduced feedback inhibition by the NH 2-propeptides. The child appeared to be heterozygous for the peptide deletion and, as the parents did not show any evidence of the deletion, it is likely that the child had a new mutation of one allele of the pro-α1(I) gene. The deleted peptide corresponds precisely to the sequence coded by exon 46 of the normal pro-α1(I) gene (Chu, M.-L., de Wet, W., Bernard, M., Ding, J.F., Morabito, M., Myers, J., Williams, C., and Ramirez, F. (1984) Nature 310, 337-340).