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.
Highlights
Epidermolysis bullosa (EB) is a group of rare heritable disorders that result in mechanical fragility of the skin and mucosal membranes
Since mechanical weakness of the basement membrane (BM) is considered to be the cause of junctional EB (JEB), Lamc2jeb/jeb mice of each strain were subjected to a novel mechanical test that directly measures the force required to shear the tail skin epidermis from the dermis [21]
The shear force values correlated generally in an inverse manner with the overt skin lesion strain patterns and revealed phenotypic differences well before evidence of externally observable lesions (Figures 1E and S1B). Overall these results were consistent with the action of genetic background modifiers that act epistatically with the Lamc2jeb allele with varying strengths to alter the structural integrity of the skin, leading to substantial strain variation in the severity of clinical features of JEB
Summary
Epidermolysis bullosa (EB) is a group of rare heritable disorders that result in mechanical fragility of the skin and mucosal membranes. These disorders are caused by defects in any one of at least 18 genes whose encoded proteins control the integrity of the dermal and epidermal layers [1,2,3,4,5]. The more severe Herlitz type (JEB-H), which commonly results in death during infancy or early childhood, is usually characterized by recessively acting loss-of-function mutations leading to premature termination codons (PTCs) in any one of the three subunit genes encoding the laminin 332 protein complex. JEB-PA is in many ways phenotypically similar to JEB-nH but is caused by mutations in ITGA6 or ITGB4 and is classified separately based on the additional phenotype of pyloric atresia [6]
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
