Epidermolysis Bullosa (EB) is a devastating, heritable blistering skin disease characterized by widespread epithelial fragility, blistering, and ulceration. Rodent models that faithfully recapitulate EB-like skin diseases are sorely needed to understand the underlying genetics of EB and to develop therapeutic interventions. We identified a novel, spontaneous, autosomal recessive, hypomorphic mutation in the gene Lamc2, which results in mice that progressively develop a blistering skin disease throughout their life that is remarkably similar to human generalized non-Herlitz junctional epidermolysis bullosa (JEB). Our Lamc2jeb homozygous mutant mice faithfully recapitulate the pathological features of the human disease, including progressive dermal/epidermal separation, tooth enamel hypoplasia, lowered bone mineralization, dyspenia, and premature morbidity. Importantly, our preliminary data show that the strain background onto which the Lamc2jeb mutant allele is introgressed can have remarkably strong effects on the severity of JEB. Thus, genetic modifier loci can determine whether mice succumb to devastating disease or are minimally affected. We propose to elucidate the genetic basis of this differential susceptibility. Our overall hypothesis is that allelic variants of certain modifier genes have a major impact in controlling the phenotypic severity of JEB. To test this hypothesis, our first goal is to define quantitative trait locus (QTL) patterns for genetic modifiers of JEB. We will perform QTL analyses of crosses between resistant and susceptible mouse strains to identify the QTL(s) responsible for these effects. Our second goal is to fine map major QTL intervals to identify candidate gene(s). We identified a major Chromosome 19 modifier QTL that affects the time of onset of skin blistering in a 129X1/SvJ X DBA/1J F2-Lamc2jeb/Lamc2jeb cross. We will use a combination of congenic reduction, subphenotypic, and haplotype analyses to hone-in on the genes responsible for the Chromosome 19 QTL and possibly others that emerge. These studies will make it possible to ascribe functional attributes to QTLs that increase or reduce risk for JEB in our mouse model, to suggest the candidate gene(s) responsible, and to characterize their mechanism(s) of action. Overall, the work will open the door for assessment of whether the same genes, encoded proteins, and associated pathways pose risk in human JEB patients and for designing therapeutic approaches based on the modifier gene effects or even as primary pharmaceutical targets.
We have developed mice carrying a spontaneous mouse mutation that is an important preclinical tool for understanding why junctional epidermolysis bullosa (JEB) develops in humans. Characterization of the genetic basis of JEB in this unique model promises to identify novel prognostic tools, pharmacological targets, and, once the mechanism is understood, potential ways to modify lifestyle to moderate the clinical effects of JEB in humans.
