{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,27]],"date-time":"2026-10-27T18:41:36Z","timestamp":1793126496784,"version":"4.5.0"},"reference-count":46,"publisher":"Public Library of Science (PLoS)","issue":"7","license":[{"start":{"date-parts":[[2023,7,12]],"date-time":"2023-07-12T00:00:00Z","timestamp":1689120000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100019725","name":"DEBRA Austria","doi-asserted-by":"publisher","award":["Roopenian 2"],"award-info":[{"award-number":["Roopenian 2"]}],"id":[{"id":"10.13039\/501100019725","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100008081","name":"Debra UK","doi-asserted-by":"crossref","award":["Roopenian 1"],"award-info":[{"award-number":["Roopenian 1"]}],"id":[{"id":"10.13039\/100008081","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100005946","name":"Jackson Laboratory","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100005946","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["www.plosone.org"],"crossmark-restriction":false},"short-container-title":["PLoS ONE"],"abstract":"<jats:p>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 <jats:italic>Lamc2<\/jats:italic><jats:sup><jats:italic>jeb<\/jats:italic><\/jats:sup> 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 \u2018EB related gene\u2019, <jats:italic>Col17a1<\/jats:italic>, have shown it to be a dominant modifier of <jats:italic>Lamc2<\/jats:italic><jats:sup><jats:italic>jeb<\/jats:italic><\/jats:sup>. This work identifies six additional Quantitative Trait Loci (QTL) that modify disease in <jats:italic>Lamc2<\/jats:italic><jats:sup><jats:italic>jeb\/jeb<\/jats:italic><\/jats:sup> mice. Three QTL include other known \u2018EB related genes\u2019, with the strongest modifier effect mapping to a region including the epidermal hemi-desmosomal structural gene dystonin (<jats:italic>Dst-e\/Bpag1-e<\/jats:italic>). Three other QTL map to intervals devoid of known EB-associated genes. Of these, one contains the nuclear receptor coactivator <jats:italic>Ppargc1a<\/jats:italic> as its primary candidate and the others contain related genes <jats:italic>Pparg<\/jats:italic> and <jats:italic>Igf1<\/jats:italic>, 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.<\/jats:p>","DOI":"10.1371\/journal.pone.0288263","type":"journal-article","created":{"date-parts":[[2023,7,12]],"date-time":"2023-07-12T18:04:29Z","timestamp":1689185069000},"page":"e0288263","update-policy":"https:\/\/doi.org\/10.1371\/journal.pone.corrections_policy","source":"Crossref","is-referenced-by-count":7,"title":["Seven naturally variant loci serve as genetic modifiers of Lamc2jeb induced non-Herlitz junctional Epidermolysis Bullosa in mice"],"prefix":"10.1371","volume":"18","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-7937-232X","authenticated-orcid":true,"given":"Thomas J.","family":"Sproule","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vivek M.","family":"Philip","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nabig A.","family":"Chaudhry","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Derry C.","family":"Roopenian","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1523-5430","authenticated-orcid":true,"given":"John P.","family":"Sundberg","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"340","published-online":{"date-parts":[[2023,7,12]]},"reference":[{"issue":"6","key":"pone.0288263.ref001","doi-asserted-by":"crossref","first-page":"1211","DOI":"10.1016\/j.jid.2017.02.011","article-title":"The \"Kelch\" surprise: KLHL24, a new player in the pathogenesis of skin fragility","volume":"137","author":"C Has","year":"2017","journal-title":"J Invest Dermatol"},{"key":"pone.0288263.ref002","doi-asserted-by":"crossref","first-page":"313","DOI":"10.1016\/j.matbio.2018.04.001","article-title":"Epidermolysis bullosa: Molecular pathology of connective tissue components in the cutaneous basement membrane zone","volume":"71\u201372","author":"C Has","year":"2018","journal-title":"Matrix biology: journal of the International Society for Matrix Biology"},{"key":"pone.0288263.ref003","doi-asserted-by":"crossref","first-page":"245","DOI":"10.1146\/annurev-genom-090413-025540","article-title":"The genetics of skin fragility","volume":"15","author":"C Has","year":"2014","journal-title":"Annu Rev Genomics Hum Genet"},{"key":"pone.0288263.ref004","doi-asserted-by":"crossref","first-page":"22","DOI":"10.1016\/j.matbio.2017.11.003","article-title":"Recessive mutation in tetraspanin CD151 causes Kindler syndrome-like epidermolysis bullosa with multi-systemic manifestations including nephropathy","volume":"66","author":"H Vahidnezhad","year":"2018","journal-title":"Matrix biology: journal of the International Society for Matrix Biology"},{"issue":"7","key":"pone.0288263.ref005","doi-asserted-by":"crossref","first-page":"450","DOI":"10.1136\/jmg.2010.086751","article-title":"Molecular mechanisms of phenotypic variability in junctional epidermolysis bullosa","volume":"48","author":"D Kiritsi","year":"2011","journal-title":"Journal of medical genetics"},{"issue":"2","key":"pone.0288263.ref006","doi-asserted-by":"crossref","first-page":"273","DOI":"10.1046\/j.1523-1747.2003.12325.x","article-title":"Skin expression of metalloproteinases and tissue inhibitor of metalloproteinases in sibling patients with recessive dystrophic epidermolysis and intrafamilial phenotypic variation","volume":"121","author":"C Bodemer","year":"2003","journal-title":"J Invest Dermatol"},{"issue":"1","key":"pone.0288263.ref007","doi-asserted-by":"crossref","first-page":"10","DOI":"10.1159\/000322619","article-title":"COL7A1 Recessive mutations in two siblings with distinct subtypes of dystrophic epidermolysis bullosa: pruriginosa versus nails only","volume":"222","author":"S Pruneddu","year":"2011","journal-title":"Dermatology"},{"issue":"4","key":"pone.0288263.ref008","doi-asserted-by":"crossref","first-page":"614","DOI":"10.1111\/bjd.18921","article-title":"Consensus reclassification of inherited epidermolysis bullosa and other disorders with skin fragility","volume":"183","author":"C Has","year":"2020","journal-title":"The British journal of dermatology"},{"issue":"8","key":"pone.0288263.ref009","doi-asserted-by":"crossref","first-page":"641","DOI":"10.1136\/jmg.2005.039685","article-title":"Epidermolysis bullosa. 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