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A New Model for Junctional Epidermolysis Bullosa

Completed
Project lead Dr John Paul Sundberg
Organisation The Jackson Laboratory, Main
Project budget GBP 206,187.00 + USD 34,000.00 (Extension funded by DEBRA Austria)
Start date / Duration 01. Jan 2007 / 40 months
Funder(s) / Co-Funder(s) DEBRA UK, DEBRA Austria, MSAP/EBEP Recommended
Research area Molecular therapy, EB genetics, epigenetics & biology

Project details

Short lay summary

A spontaneous mutation arose in our mouse colony that resulted in a blistering skin disease. A colony of mice carrying this mutation, referred to as jeb, was established. These mice are essentially normal and live well into adulthood. However, their skin develops blisters that never fully heal. Pathologic analysis of biopsies confirmed that this mouse disease is very similar to one form of the human disease epidermolysis bullosa (EB). We mapped the location of the mutant gene to the part of the genome that contains the mouse equivalent of the human LAMC2 gene. Mutations in this human gene are associated with Junctional EB (JEB), and there is a high probability that our mouse jeb mutation mimics the form of JEB in which affected people survive beyond the neonatal phase into adulthood.
We intend to further characterize this mouse to determine the specific subtype of JEB that these mice develop, define the specific mutation in the DNA that causes JEB in mice, and search for other genes that change the clinical features and especially severity in patients. An important use of these jeb mice that survive into adulthood is that they provide an ideal model to test new therapeutic approaches for EB. Since The Jackson Laboratory is not only a basic science research institution but a repository and distribution center for mutant mice and has a new program to develop interactions with pharmaceutical companies to use this and other mouse models for specific human disease to screen new drugs, we are in an ideal position to make these mice available to the biomedical research community once they are characterized to encourage rapid progress on understanding and better treating this disease.

What did this project achieve?

Junctional Epidermolysis Bullosa is a devastating, genetic based, blistering disease. Patients also develop pitting of their teeth, decreased bone mineralization, and have various degrees of respiratory disease. Although this disease does occur in a variety of animals, not just humans, it can be fatal at an early age. Genetically engineered mice provide useful tools to study these diseases but the ones created to date also die at an early age. We identified a naturally occurring disease in one of our mouse colonies that is an extraordinarly close copy of the human disease. We identified a mutation in the laminin gamma 2 (Lamc2) gene in these mice which is known to be mutated in some forms of this disease in humans as well. Unlike the genetically engineered mouse that lacks function of this gene, in our model the gene is partially functional. As a result the mice live to the equivalent of middle age. This provides us with a workable tool to test the efficacy of standard and novel treatments but also a means to dissect out the complex genetics of how other genes, be they normal or mutated, affect the severity or even the onset of disease. In order to investigate this we moved the Lamc2 mutated gene from the original strain onto several other inbred strains of laboratory mice by controlled breeding. We obtained strains that when carrying two copies of the mutated gene instead of getting junctional epidermolysis bullosa they appeared to be perfectly normal. Other strains developed ulcers early in life that were more severe than those found in the original strain. This marked difference provided us with the tools to find the genes responsible. We identified several areas in the mouse genome that contain one or more genes that affect the onset and severity of junctional epidermolysis bullosa. We are currently screening candidate genes within these areas and in so doing we will use this mouse model to further dissect out the molecular mechanisms of this disease. It is possible that some of these genes will provide new ideas on novel ways to treat patients or at least screen for other genetic influences that can predict prognosis or even response to treatments already available. This work would not have been possible without the support of DEBRA. As a result of these initial investigations we successfully obtained a grant from the National Institutes of Health to continue the genetic studies.


Keywords

JEB
Sundberg
The Jackson Laboratory
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