Seven naturally variant loci serve as genetic modifiers ofLamc2^jebinduced non-Herlitz Junctional Epidermolysis Bullosa in mice

AbstractEpidermolysis Bullosa (EB) is a group of rare genetic disorders that compromise the structural integrity of the skin such that blisters and subsequent erosions occur after minor trauma. While primary genetic risk of all subforms of EB adhere to Mendelian patterns of inheritance, their clinical presentations and severities can vary greatly, implying genetic modifiers. TheLamc2jebmouse model of non-Herlitz junctional EB (JEB-nH) demonstrated that genetic modifiers can contribute substantially to the phenotypic variability of JEB and likely other forms of EB. The innocuous changes in an ‘EB related gene’,Col17a1, have shown it to be a dominant modifier ofLamc2jeb. This work identifies six additional Quantitative Trait Loci (QTL) that modify disease inLamc2jeb/jebmice. Three QTL include other known ‘EB related genes’, with the strongest modifier effect mapping to a region including the epidermal hemi-desmosomal structural gene dystonin (Dst-e/Bpag1-e). Three other QTL map to intervals devoid of known EB-associated genes. Of these, one contains the nuclear receptor coactivatorPpargc1aas its primary candidate and the others contain related genesPpargandIgf1, suggesting modifier pathways. These results, demonstrating the potent disease modifying effects of normally innocuous genetic variants, greatly expand the landscape of genetic modifiers of EB and therapeutic approaches that may be applied.