Distribution of disease causing Gly → Zaa mutations in the fibrillar collagens related to stability and their putative location within fibrils

Abstract

Introduction: Collagens are the most abundant proteins in vertebrate and can be found in almost all tissues. Their structure and composition is unique with a triple helix caused be a Gly-Xaa-Yaa sequence repeat, where Xaa is frequently proline and Yaa is hydroxyproline. Collagens can form various arrays. Types I, II, and III are the major, and types V, XI, XXIV and XXVII the minor fibril forming collagens. Aim: The aim of this thesis is to expand understanding of the distribution of glycine mutations and their environment within the triple helix with respect to diseases and their severity. Methods: Existing databases were searched for Gly→Zaa missense mutations resulting from single nucleotide exchanges within the glycine codon observed in the fibrillar collagens. Their destabilizing effect was correlated to theoretical local melting temperatures. Using the Hodge/Petruska model of collagen fibril organization, the putative location of mutation sites within a fibril were mapped. Results: A total number of 1,516 Gly→Zaa missense mutations were found for the major fibrillar collagens. For type I collagen the mutations mainly result in lethal (OI-II) and milder forms of osteogenesis imperfecta. In type II and III collagens, mutations follow different patterns causing severe and non-severe chondrodysplasia and vesicular diseases. For the minor fibrillar collagens only 60 mutations were found thus making a generalization upon their distribution difficult. Generally, it appears that most of these mutations tend to occur in the gap zone. Conclusion: This work shows that Gly→Zaa mutations are by far reported more within collagen types I and III. These mutations seem to affect the correct collagen folding thus causing lethal or severe phenotypes affecting skeletal growth and strength of vascular tissues. Analysing non-glycine mutations within the collagen sequences could be done in the future to further our understanding of the effect of these mutations on the collagen structure.