{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,27]],"date-time":"2026-10-27T18:41:39Z","timestamp":1793126499497,"version":"4.5.0"},"reference-count":36,"publisher":"Public Library of Science (PLoS)","issue":"10","license":[{"start":{"date-parts":[[2023,10,5]],"date-time":"2023-10-05T00:00:00Z","timestamp":1696464000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100011960","name":"Debra International","doi-asserted-by":"publisher","award":["Roopenian-2"],"award-info":[{"award-number":["Roopenian-2"]}],"id":[{"id":"10.13039\/501100011960","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100019725","name":"DEBRA Austria","doi-asserted-by":"publisher","award":["Roopenian-1"],"award-info":[{"award-number":["Roopenian-1"]}],"id":[{"id":"10.13039\/501100019725","id-type":"DOI","asserted-by":"publisher"}]},{"name":"National Institute of Health","award":["OD011190"],"award-info":[{"award-number":["OD011190"]}]},{"name":"National Institute of Health","award":["DP1 GM105378"],"award-info":[{"award-number":["DP1 GM105378"]}]},{"name":"National Institute of Health","award":["R01 GM088040"],"award-info":[{"award-number":["R01 GM088040"]}]},{"name":"Jim and Ann Orr MGH Research Scholar Award"},{"DOI":"10.13039\/100005946","name":"Jackson Laboratory","doi-asserted-by":"publisher","award":["DCR DRAF"],"award-info":[{"award-number":["DCR DRAF"]}],"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>Previous work strongly implicated Collagen 17a1 (<jats:italic>Col17a1<\/jats:italic>) as a potent genetic modifier of junctional epidermolysis bullosa (JEB) caused by a hypomorphic mutation (<jats:italic>Lamc2<\/jats:italic><jats:sup><jats:italic>jeb<\/jats:italic><\/jats:sup>) in mice. The importance of the noncollagenous domain (NC4) of COLXVII was suggested by use of a congenic reduction approach that restricted the modifier effect to 2\u20133 neighboring amino acid changes in that domain. The current study utilizes TALEN and CRISPR\/Cas9 induced amino acid replacements and in-frame indels nested to NC4 to further investigate the role of this and adjoining COLXVII domains both as modifiers and primary risk effectors. We confirm the importance of COLXVI AA 1275 S\/G and 1277 N\/S substitutions and utilize small nested indels to show that subtle changes in this microdomain attenuate JEB. We further show that large in-frame indels removing up to 1482 bp and 169 AA of NC6 through NC1 domains are surprisingly disease free on their own but can be very potent modifiers of <jats:italic>Lamc2<\/jats:italic><jats:sup><jats:italic>jeb\/jeb<\/jats:italic><\/jats:sup> JEB. Together these studies exploiting gene editing to functionally dissect the <jats:italic>Col17a1<\/jats:italic> modifier demonstrate the importance of epistatic interactions between a primary disease-causing mutation in one gene and innocuous \u2018healthy\u2019 alleles in other genes.<\/jats:p>","DOI":"10.1371\/journal.pone.0292456","type":"journal-article","created":{"date-parts":[[2023,10,5]],"date-time":"2023-10-05T17:27:30Z","timestamp":1696526850000},"page":"e0292456","update-policy":"https:\/\/doi.org\/10.1371\/journal.pone.corrections_policy","source":"Crossref","is-referenced-by-count":7,"title":["Functional analysis of Collagen 17a1: A genetic modifier of 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":"Robert Y.","family":"Wilpan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0350-4602","authenticated-orcid":true,"given":"Benjamin E.","family":"Low","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kathleen A.","family":"Silva","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Deepak","family":"Reyon","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"J. 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