Molecular identification of collagen 17a1 as a major genetic modifier of laminin gamma 2 mutation-induced junctional epidermolysis bullosa in mice.

[junctional epidermolysis bullosa]

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 (Lamc 2 ). 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 Lamc 2 (jeb ) mutation . Through an unbiased genetic approach involving a combination of QTL mapping and positional cloning , we demonstrate that Col 17 a 1 is a strong genetic modifier of the non-Herlitz JEB that develops in Lamc 2 (jeb ) 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 Lamc 2 (jeb ) 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 .

Diseases
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Diseases presenting "normally innocuous allelic variants" symptom

junctional epidermolysis bullosa

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