Epigenetic modifiers of disease phenotypes: EB as a paradigm

Patients with epidermolysis bullosa (EB) often also referred to as butterfly children suffer from a rare, heritable skin disorder. Due to distinct gene mutations, skin layers lack sufficient adherence and consequently separate already after minor trauma (e.g. friction of a T-shirt, bumping against edges), which leads to blister formation and wounding. These injuries are frequently accompanied by persisting pain and itch, and in some patients also mucous membranes (e.g. mouth) are affected. Over time, recurring wounds can lead to severe complications, like infections and the development of particularly aggressive skin tumours. Even though in most patients the cause of the disease i.e. the respective gene mutation in an EB- associated gene - is known, for some patients they could not be identified. As a proper diagnosis is crucial to making the best treatment decisions, an important part of this project is to identify disease- causing gene mutations in cases where these have not yet been resolved. To do this, we will apply up- to-date technologies such as next generation sequencing. Another phenomenon observed in EB, is that patients present with diverse symptoms, even though they harbour the same gene mutation. Even in identical twins it was reported that one sibling showed a rather mild phenotype while the other was much more severely affected. Finding out what causes these differences is another major aim of this project. In this context, we will focus on the investigation of epigenetic events. These are changes that do not directly affect the genetic sequence, but rather refer to the additional layer of regulation that exists, which in part determines which genes become expressed and which do not. Epigenetic mechanisms can be linked to external factors. Therefore, tracing the events that lead to such differences in disease severity can provide important new information that will direct patient care and support the development of novel therapies. Finally, we will also investigate epigenetic changes as a direct consequence of EB mutation that impact the ability of skin cells to self-renew. This consequently affects skin repair and therefore disease severity. We will study these especially in the context of patient cells that have been repaired. Clarifying these aspects should also help guide the improvement of gene therapeutic approaches. A notable aspect of this project is that it falls within the framework of the recently established Austrian- Israeli scientific research program, and represents the first time a project of this scale, which is conducted in collaboration with two leading research institutes in Israel, is (co-)funded by the Austrian Science Fund (FWF).

No additional funding sources recorded.