Seven naturally variant loci serve as genetic modifiers of Lamc2(jeb) induced non-Herlitz junctional Epidermolysis Bullosa in mice

Epidermolysis 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. The Lamc2(jeb) mouse 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 of Lamc2(jeb). This work identifies six additional Quantitative Trait Loci (QTL) that modify disease in Lamc2(jeb/jeb) mice. 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 coactivator Ppargc1a as its primary candidate and the others contain related genes Pparg and Igf1, 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.

Automated summary

Epidermolysis Bullosa (EB) is a rare genetic disorder that causes skin blistering and erosions after minor trauma. The severity and clinical presentations of EB can vary greatly, indicating the presence of genetic modifiers. A mouse model of non-Herlitz junctional EB (JEB-nH) showed that genetic modifiers, including the gene Col17a1, can significantly contribute to the phenotypic variability of EB. This study identified six additional Quantitative Trait Loci (QTL) that modify the disease in the mouse model, including known EB-related genes and genes related to modifier pathways. These findings expand our understanding of genetic modifiers of EB and potential therapeutic approaches.