Stability related bias in residues replacing glycines within the collagen triple helix (Gly-Xaa-Yaa) in inherited connective tissue disorders
A missense mutation leading to the replacement of one Gly in the (Gly-Xaa-Yaa)n repeat of the collagen triple helix can cause a range of heritable connective tissue disorders that depend on the gene in which the mutation occurs. Osteogenesis imperfecta results from mutations in type I collagen, Ehlers-Danlos syndrome type IV from mutations in type III collagen, Alport syndrome from mutations in type IV collagen, and dystrophic epidermolysis bullosa from mutations in type VII collagen. The predicted rates of substitutions by different amino acids for glycine in the α1(I), α2(I), α1(III), α5(IV), and α1(VII) chains (encoded by COL1A1, COL1A2, COL3A1, COL4A5, and COL7A1, respectively) were compared with missense mutations in those chains that have been observed to cause disease. The spectrum of amino acids replacing Gly was not significantly different from that expected for the α1(VII) chains, suggesting that any Gly replacement will cause disease. The distribution of residues replacing Gly was significantly different from that expected for all other collagen chains studied, with a particularly strong bias seen for α1(I) and α1(III) collagen chains. The bias did not correlate with the degree of chemical dissimilarity between Gly and the replacement residues, but in some cases a relationship was observed with the predicted extent of destabilization of the triple helix. For α1(III) collagen chains, the more destabilizing mutations were identified more often than expected. For α1(I), the most destabilizing residues, Val, Glu, and Asp, and the least destabilizing residue, Ala, were underrepresented. This bias supports the hypothesis that the level of triple-helix destabilization determines clinical outcome. Hum Mutat 24:330–337, 2004. © 2004 Wiley-Liss, Inc.