Introduction

Dystrophic Epidermolysis Bullosa is a severe form of EB affecting an estimated 1 in 35,000 of the world’s population. Dystrophic EB is a genetic condition where the skin is extremely fragile and blisters very easily. It is always painful and is increasingly disabling and disfiguring.

Dystrophic EB is an inherited genetic disorder caused by alterations (mutations) affecting the correct function of the collagen type VII gene (COL7A1). This gene encodes for a protein forming micro structures which are responsible for keeping the layers of the skin together ie anchoring the epidermis to the dermis. Defects in the gene result in defective adhesion and in the formation of blisters.

Abstract of Research

The objective of the proposed study is to understand how mutations in the collagen VII gene COL7A1 lead to Dystrophic EB (DEB) and to use this knowledge as a basis for development and evaluation of novel therapeutic strategies for Dystrophic EB. At present it is well established that COL7A1 mutations cause DEB, however, the consequences of the different mutations for the structure of collagen VII protein at the molecular will remain unknown.

This research project attempts to understand these pathomechanisms by investigating naturally occurring mutated collagen VII molecules with substitution of a glycine by another amino acid. Glycine in every third position of the polypeptide chain in any collagen is very important for proper folding of the protein. In concert with this, the prediction is that COL7A1 gene mutations leading to a glycine substitution delay and inhibit the folding of collagen VII and, therefore, the production of a functional anchoring fibrils.

Professor Bruckner-Tuderman has disclosed several glycine substitution mutations in COL7A1 in DEB families and will study the effects of these mutations. Keratinocytes derived from diagnostic skin biopsies from these patients will be cultured, and the abnormal collagen VII synthesized by these cells with a number of biochemical techniques. With these studies the research will gain new information on the ability of different altered collagen VII molecules in DEB patients’ skin to form anchoring fibrils and to function in adhering the epidermis to the dermis.

Puzzlingly, some glycine substitution mutations in COL7A1 do not cause DEB. In several families with recessive DEB, such mutations have been found: the carriers of the mutations (e.g. parents of siblings of affected children) are healthy. By comparing collagen VII isolated from skin cells of such carriers with collagen VII from DEB patients’ cells the research expects to establish certain rules about which mutations cause more harmful effects and which mutations can be tolerated, at least in part.