Modelling the Genetics of Epidermolysis Bullosa in mice (Roopenian 2)

Short 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. Mice share their skin biology with humans and their genetic “make up” can be altered so that they have defects in the same genes as those causing EB in humans. 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. 

Strategic relevance

“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 mouse models it is possible to identify the genetic risk factors that connect to clinical consequences in a coherent manner.” 

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