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RDEB is caused by loss-of-function mutations in <jats:italic>COL7A1<\/jats:italic> encoding type VII collagen (C7), the main component of anchoring fibrils which form attachment structures stabilizing the cutaneous basement membrane zone. Most of the previously reported <jats:italic>COL7A1<\/jats:italic> mutations are located in the coding or intronic regions. We describe 6 patients with localized or intermediate RDEB for whom one recessive pathogenic variant in the coding region and a second variant in the <jats:italic>COL7A1<\/jats:italic> promoter were identified. These substitutions, three of which are novel, are localized in two Sp1 binding sites of the promoter region. DNA pull-down assay showed a drastic reduction of Sp1 binding consistent with a dramatic decrease in <jats:italic>COL7A1<\/jats:italic> transcript and almost undetectable C7 protein levels. Our results reveal that mutations in the <jats:italic>COL7A1<\/jats:italic> promoter on the background of a null allele can underlie localized or intermediate RDEB. They further emphasize the functional importance of Sp1 motifs in the proximal <jats:italic>COL7A1<\/jats:italic> promoter which should be carefully investigated for regulatory mutations in the case of RDEB with only one pathogenic variant identified in the coding or intronic regions.<\/jats:p>","DOI":"10.1038\/s41431-024-01717-5","type":"journal-article","created":{"date-parts":[[2024,12,5]],"date-time":"2024-12-05T12:18:26Z","timestamp":1733401106000},"page":"344-350","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Novel variants impairing Sp1 transcription factor binding in the COL7A1 promoter cause mild cases of recessive dystrophic epidermolysis bullosa"],"prefix":"10.1038","volume":"33","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2070-7604","authenticated-orcid":false,"given":"Nathalie","family":"Pironon","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Artyom","family":"Gasparyan","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mar\u00eda Joao","family":"Yubero","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sabine","family":"Duchatelet","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0001-4502-0502","authenticated-orcid":false,"given":"Kristina","family":"Hovhannesyan","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Stephanie","family":"Leclerc-Mercier","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Natella","family":"Kostandyan","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Francis","family":"Palisson","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tamara","family":"Sarkisian","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7386-2769","authenticated-orcid":false,"given":"Matthias","family":"Titeux","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8987-1317","authenticated-orcid":false,"given":"Ignacia","family":"Fuentes","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3412-7512","authenticated-orcid":false,"given":"Alain","family":"Hovnanian","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"297","published-online":{"date-parts":[[2024,12,5]]},"reference":[{"key":"1717_CR1","doi-asserted-by":"publisher","first-page":"614","DOI":"10.1111\/bjd.18921","volume":"183","author":"C Has","year":"2020","unstructured":"Has C, Bauer JW, Bodemer C, Bolling MC, Bruckner\u2010Tuderman L, Diem A, et al. 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Informed consents were obtained from the individuals and\/or legal guardians, including permission for the publication of clinical photographs and details.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethical approval and consent to participate"}}]}}