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Genetic Modifiers of Junctional Epidermolysis Bullosa

Completed
Project leadDr. Derry Roopenian
Organisation The Jackson Laboratory
Project budgetUSD 130,722.00
Start date / Duration01. Feb 2012 / 12 months
Funder(s) / Co-Funder(s) DEBRA Austria
Research area EB genetics, epigenetics & biology

Project details

Short lay summary

Our project directly addresses the underlying genetic basis for the high degree of variability of the severely disfiguring and often lethal group of blistering diseases collectively known as Epidermolysis Bullosa (EB). This is a complex group of diseases that result from a failure of particular proteins to form the “glue” that holds the surface of the skin to the connective tissue below it. This glue consists of at least 10 interlinked proteins any one of which, when abnormal, can result in skin fragility, blister formation, and ulceration. The current dogma is that forms of EB are caused by rare genetic mutations that result in abnormalities in the protein components of the glue. We have developed a mouse model that develops a disorder with remarkable similarity to human Junctional Epidermylosis Bullosa (JEB).

 

What did this project achieve?

Through study of this model we have provided data indicating that the rare mutations are only part of the story, and that normal allelic variation of other genes that distinguish individuals can have a major impact on the severity of each form of EB. The major implication of our mouse studies is that they will provide unique information into the genetics of EB, which could not come from human research because of the logistical and technological limitations involved. Our mouse model allows us to perform genetic experiments rapidly, to compare disease information with genome sequences from the mice in an efficient manner, and to determine if the modifier genes we predicted have a clinical effect. This information will show how to more accurately predict the severity of EB diseases in humans and potentially identify novel therapeutic targets. This has the prognostic advantage that babies born with these diseases can be screened genetically to determine not only which primary gene is mutated but also the allelic state of modifier genes to help the physicians make a definitive diagnosis. It is also possible that, with the knowledge of which modifier genes are involved, those genes and their protein products can be targeted for therapy rather than the primary mutated gene. This would open many new opportunities that may be more fruitful than current therapeutic approaches.


Keywords

Junctional Epidermolysis bullosa
genetic modifiers
Roopenian
Sundberg
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