EBS is an inherited skin disorder which is caused by
point mutations in keratin genes 5 or 14. These keratins form the essential cytoskeleton
of basal skin keratinocytes and are responsible for the mechanical strength of the
epidermis. Due to the severity of the disease, the mechanisms of blistering and wound
repair as well as the development of therapy approaches cannot be studied in patients.
In order to understand the molecular mechanisms by which keratin mutations lead to EBS
and to have a model suitable for therapy evaluations, it is proposed to develop a mouse
model of EBS based on a novel strategy. The proposal is based on a method of gene
targeting, which can introduce precise alterations into the genome of the mouse, in
combination with a technique which allows the reversible switching on and off of the
expression of the altered gene at any time and place. Using this combined approach, Dr
Magin will introduce a known point mutation, which in humans causes the life-threatening
Dowling Meara form of EBS, into the mouse keratin 5 gene. This should enable the induction
and repression of the expression of a point-mutated keratin 5 gene in the epidermis of
mice by the local or systemic application of a specific drug. The animal model; will allow
the study of the extent of skin blistering depending on the body site, the relationship of
mechanical stress and blistering, wound repair, the role of ageing and other clinically
relevant parameters. Ultimately, this animal model will be used for the evaluation of
genetically modified keratinocytes in transplantation studies.
