To identify modifier genes in junctional EB that affect the severity of symptoms experienced by different patients with the same primary gene defect


Modelling the Genetics of epidermolysis bullosa

Investigator: Dr Derry Roopenian

Institution: The Jackson Laboratory, Maine, USA

Grant: $302,433 - Completed

Lay Summary

Epidermolysis bullosa (EB) is characterised by structural weaknesses in the skin and the membranes of the mouth and gastro-intestinal tract (gut). It encompasses a number of different types that have been related to mutations (or mistakes) in different genes, of which 18 have been identified so far. It is increasingly apparent that the genetic causes of all forms of EB are more complex than originally thought.

EB is not easily attributed to single genetic defects but there was essentially no knowledge as to how other genes contribute to these disorders i.e. affecting severity of symptoms. The rarity of all forms of EB makes it difficult to establish which genes are involved, how these genes will affect prognosis or outcome, and to inform studies that will help to develop effective treatments.

Our primary goal has been to develop methods and tools to develop avatars or models of human EB. In this way, we are able to model each form of EB.

Our research has been able to address issues directly pertinent to junctional form of EB (JEB) but with lessons learnt that inform on EB more generally. We have created multiple models of this disease and we have taken advantage of the most advanced methods of analysis and genetic engineering to understand the genetic basis of JEB.

This work has lead to unexpected insights into the genetic causes of EB that could not have been revealed by clinical studies in humans. Diagnosis of EB is typically made based on the manifestations of disease in combination with the molecular identification of a defect in an EB gene. Our work shows that this is only part of the story. Our studies show that JEB is heavily influenced by genetic variation in genes that by themselves do not cause abnormalities, but can strongly influence (or modify) the severity of disease Thus, JEB, and likely many other forms of EB, are genetically complex diseases.

Our studies support the existence of at least 7 genes distinct from the primary “mistake” that significantly impact the severity of JEB. The two that exert the most powerful effects produce proteins that are critical for maintaining the integrity of the skin. Our results have identified sites in these genes that are most likely to encode these so called modifier effects. Thus genetic screening to include those sites may improve genetic prognosis. Four of the 7 modifiers are in locations that have not been associated with EB and are not structural components of the skin.

We believe that the identification of these genes has the potential to reveal new therapeutic targets for treatment of EB.

What is important about this research?

The rarity of all forms of EB in humans makes it difficult to unravel its genetic causes, predict long-term outcomes, and devise treatments. By creating models it is possible to identify the genetic risk factors that connect to clinical consequences in a coherent manner.  

Dr Derry Roopenian

Investigator Biography

Dr Derry Roopenian is a Professor at The Jackson Laboratory, in Bar Harbor, Maine. His program addresses fundamental questions into genetic and mechanistic causes of human diseases. While his historic focus has been autoimmune diseases, Dr Roopenian and his team were first drawn into the field of EB through their serendipitous discovery of an important new model of Junctional epidermolysis bullosa (JEB) and further attracted by realizing that their expertise could have a significant impact on advancing the understanding of this and related disorders. They are applying a number of advanced methods to investigate the genetic causes of JEB and creating new models that will broadly enable investigations into the causes and treatments of EB.