Molecular Identification of Collagen 17a1 as a Major Genetic Modifier of Laminin Gamma 2 Mutation-Induced Junctional Epidermolysis Bullosa in Mice

Abstract

Epidermolysis Bullosa (EB) encompasses a spectrum of mechanobullous disorders caused by rare mutations that result in structural weakening of the skin and mucous membranes. While gene mutated and types of mutations present are broadly predictive of the range of disease to be expected, a remarkable amount of phenotypic variability remains unaccounted for in all but the most deleterious cases. This unexplained variance raises the possibility of genetic modifier effects. We tested this hypothesis using a mouse model that recapitulates a non-Herlitz form of junctional EB (JEB) owing to the hypomorphic jeb allele of laminin gamma 2 (Lamc2). By varying normally asymptomatic background genetics, we document the potent impact of genetic modifiers on the strength of dermal-epidermal adhesion and on the clinical severity of JEB in the context of the Lamc2jeb mutation. Through an unbiased genetic approach involving a combination of QTL mapping and positional cloning, we demonstrate that Col17a1 is a strong genetic modifier of the non-Herlitz JEB that develops in Lamc2jeb mice. This modifier is defined by variations in 1–3 neighboring amino acids in the non-collagenous 4 domain of the collagen XVII protein. These allelic variants alter the strength of dermal-epidermal adhesion in the context of the Lamc2jeb mutation and, consequentially, broadly impact the clinical severity of JEB. Overall the results provide an explanation for how normally innocuous allelic variants can act epistatically with a disease causing mutation to impact the severity of a rare, heritable mechanobullous disorder.

Juxta-articular joint-capsule mineralization in CD73 deficient mice: Similarities to patients withNT5Emutations

“…In addition, a number of genetic modifiers could differentially influence the expression of the phenotype in human and mice in diseases which are thought to be single gene disorders, yet demonstrate considerable phenotypic variability. 29 Nevertheless, this mouse model can be used to study the pathomechanistic features and metabolic pathways potentially involved in the development of mineralization in ACDC.…”

Skin fragility in the wild-derived, inbred mouse strain Mus pahari/EiJ

“…Mus pahari skin consistently separated at a low force, typically 7–12 Newtons, with no apparent age or sex difference (Figure 3a,b). For comparison, B6.129X1- Lamc2 jeb/jeb /Dcr, mutant mice with non-Herlitz junctional epidermolysis bullosa, 12 week old female skin was removed at 19–23 Newtons (Bubier et al, 2010; Sproule et al, 2014; Sproule et al, 2012). Histologic evaluation of the tails that required a great deal of tension, often without success, had normal attachment of the epidermis and dermis.…”

“…Modifier genes, such as collagen type XVII, alpha 1 ( Col17a1 ), can affect this fragility (Bubier et al, 2010; Sproule et al, 2014). Other genetic or autoimmune based defects in keratins and adhesion molecules between keratinocytes (epidermolysis bullosa complex of diseases and various forms of pemphigus and pemphigoid, can also cause blistering and loss of skin on the tail).…”

Skin Diseases in Laboratory Mice: Approaches to Drug Target Identification and Efficacy Screening

“…Many so-called single gene based diseases, including many of the epidermolysis bullosa blistering diseases [19], can be successfully reproduced using mouse models. Yet, even these vary due to background modifier genes [20]. However, similar modifier genes in the mouse genome [20] can be found as modifiers of the homologous human disease (Roopenian, Sproule, and Sundberg unpublished data), such that while difficult, it is still possible to model even specific subsets of human diseases.…”

“…Yet, even these vary due to background modifier genes [20]. However, similar modifier genes in the mouse genome [20] can be found as modifiers of the homologous human disease (Roopenian, Sproule, and Sundberg unpublished data), such that while difficult, it is still possible to model even specific subsets of human diseases. Some complex diseases, such as psoriasis, may never be adequately mimicked by mouse models as they lack some of the key anatomic structures or response features found in human patients (Table 1) [13,21].…”