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

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dc.contributor.authorSproule, Thomas J.en
dc.contributor.authorBubier, Jason A.en
dc.contributor.authorGrandi, Fiorella C.en
dc.contributor.authorSun, Victor Z.en
dc.contributor.authorPhilip, Vivek M.en
dc.contributor.authorMcPhee, Caroline G.en
dc.contributor.authorAdkins, Elisabeth B.en
dc.contributor.authorSundberg, John P.en
dc.contributor.authorRoopenian, Derry C.en
dc.contributor.departmentAnimal and Poultry Sciencesen
dc.date.accessioned2017-07-28T18:37:06Zen
dc.date.available2017-07-28T18:37:06Zen
dc.date.issued2014-02en
dc.description.abstractEpidermolysis 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 Lamc2(jeb) 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 Lamc2(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 Lamc2(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.en
dc.description.versionPublished versionen
dc.format.mimetypeapplication/pdfen
dc.identifier.doihttps://doi.org/10.1371/journal.pgen.1004068en
dc.identifier.eissn1553-7404en
dc.identifier.issue2en
dc.identifier.orcidMcPhee, CG [0000-0002-5909-7623]en
dc.identifier.urihttp://hdl.handle.net/10919/78463en
dc.identifier.volume10en
dc.language.isoenen
dc.relation.urihttps://www.ncbi.nlm.nih.gov/pubmed/24550734en
dc.rightsCreative Commons Attribution 4.0 Internationalen
dc.rights.holderThe Author(s)en
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/en
dc.subjectAnimalsen
dc.subjectAutoantigensen
dc.subjectDisease Models, Animalen
dc.subjectEpidermolysis Bullosa, Junctionalen
dc.subjectEpistasis, Geneticen
dc.subjectGenetic Variationen
dc.subjectLamininen
dc.subjectMiceen
dc.subjectMutationen
dc.subjectNon-Fibrillar Collagensen
dc.titleMolecular identification of collagen 17a1 as a major genetic modifier of laminin gamma 2 mutation-induced junctional epidermolysis bullosa in miceen
dc.title.serialPLoS Geneticsen
dc.typeArticle - Refereeden
dc.type.dcmitypeTexten
dc.type.otherResearch Support, N.I.H., Extramuralen
dcterms.dateAccepted2013-11-11en
pubs.organisational-group/Virginia Techen
pubs.organisational-group/Virginia Tech/Agriculture & Life Sciencesen
pubs.organisational-group/Virginia Tech/Agriculture & Life Sciences/Animal and Poultry Sciencesen
pubs.organisational-group/Virginia Tech/Agriculture & Life Sciences/CALS T&R Facultyen
pubs.organisational-group/Virginia Tech/All T&R Facultyen

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