{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,8]],"date-time":"2026-07-08T07:28:11Z","timestamp":1783495691599,"version":"3.55.0"},"reference-count":50,"publisher":"National Academy of Sciences","issue":"35","license":[{"start":{"date-parts":[[2024,8,19]],"date-time":"2024-08-19T00:00:00Z","timestamp":1724025600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"funder":[{"DOI":"10.13039\/100008081","name":"Dystrophic Epidermolysis Bullosa Research Association","doi-asserted-by":"publisher","award":["DEBRA-France-2020"],"award-info":[{"award-number":["DEBRA-France-2020"]}],"id":[{"id":"10.13039\/100008081","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["www.pnas.org"],"crossmark-restriction":true},"short-container-title":["Proc. Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2024,8,27]]},"abstract":"<jats:p>\n                    Recessive dystrophic epidermolysis bullosa (RDEB) is a rare and most often severe genetic disease characterized by recurrent blistering and erosions of the skin and mucous membranes after minor trauma, leading to major local and systemic complications. The disease is caused by loss-of-function variants in\n                    <jats:italic>COL7A1<\/jats:italic>\n                    encoding type VII collagen (C7), the main component of anchoring fibrils, which form attachment structures stabilizing the cutaneous basement membrane zone. Alterations in C7 protein structure and\/or expression lead to abnormal, rare or absent anchoring fibrils resulting in loss of dermal-epidermal adherence and skin blistering. To date, more than 1,200 distinct\n                    <jats:italic>COL7A1<\/jats:italic>\n                    deleterious variants have been reported and 19% are splice variants. Here, we describe two RDEB patients for whom we identified two pathogenic deep intronic pathogenic variants in\n                    <jats:italic>COL7A1<\/jats:italic>\n                    . One of these variants (c.7795-97C &gt; G) promotes the inclusion of a pseudoexon between exons 104 and 105 in the\n                    <jats:italic>COL7A1<\/jats:italic>\n                    transcript, while the other causes partial or complete retention of intron 51. We used antisense oligonucleotide (ASO) mediated exon skipping to correct these aberrant splicing events in vitro. This led to increased normal mRNA splicing above 94% and restoration of C7 protein expression at a level (up to 56%) that should be sufficient to reverse the phenotype. This first report of exon skipping applied to counteract deep intronic variants in\n                    <jats:italic>COL7A1<\/jats:italic>\n                    represents a promising therapeutic strategy for personalized medicine directed at patients with intronic variants at a distance of consensus splice sites.\n                  <\/jats:p>","DOI":"10.1073\/pnas.2401781121","type":"journal-article","created":{"date-parts":[[2024,8,19]],"date-time":"2024-08-19T15:06:21Z","timestamp":1724079981000},"update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":11,"title":["Splice modulation strategy applied to deep intronic variants in\n                    <i>COL7A1<\/i>\n                    causing recessive dystrophic epidermolysis bullosa"],"prefix":"10.1073","volume":"121","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2070-7604","authenticated-orcid":false,"given":"Nathalie","family":"Pironon","sequence":"first","affiliation":[{"name":"Universit\u00e9 Paris Cit\u00e9, Inserm, UMR 1163, Institut Imagine, Laboratory of Genetic Skin Diseases, Paris F-75015, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5375-738X","authenticated-orcid":false,"given":"Emmanuelle","family":"Bourrat","sequence":"additional","affiliation":[{"name":"Department of Dermatology, Assistance Publique des H\u00f4pitaux de Paris (AP-HP), H\u00f4pital Saint Louis, Paris, France"},{"name":"Centre de r\u00e9f\u00e9rence des Maladies G\u00e9n\u00e9tiques \u00e0 Expression Cutan\u00e9e (MAGEC Nord Site Saint Louis), H\u00f4pital Saint Louis F-75010, Paris, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Catherine","family":"Prost","sequence":"additional","affiliation":[{"name":"H\u00f4pital Avicenne, Assistance Publique des H\u00f4pitaux de Paris, Bobigny F-93000, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mei","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Dermatology, The Keck School of Medicine, University of Southern California, LA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David T.","family":"Woodley","sequence":"additional","affiliation":[{"name":"Department of Dermatology, The Keck School of Medicine, University of Southern California, LA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7386-2769","authenticated-orcid":false,"given":"Matthias","family":"Titeux","sequence":"additional","affiliation":[{"name":"Universit\u00e9 Paris Cit\u00e9, Inserm, UMR 1163, Institut Imagine, Laboratory of Genetic Skin Diseases, Paris F-75015, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alain","family":"Hovnanian","sequence":"additional","affiliation":[{"name":"Universit\u00e9 Paris Cit\u00e9, Inserm, UMR 1163, Institut Imagine, Laboratory of Genetic Skin Diseases, Paris F-75015, France"},{"name":"Department of Genomic Medicine of Rare Diseases, Assistance Publique des H\u00f4pitaux de Paris (AP-HP), H\u00f4pital Necker-Enfants Malades, F-75015 Paris, France"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"341","published-online":{"date-parts":[[2024,8,19]]},"reference":[{"key":"e_1_3_4_1_2","doi-asserted-by":"publisher","DOI":"10.1007\/s00439-017-1779-6"},{"key":"e_1_3_4_2_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.jid.2020.08.018"},{"key":"e_1_3_4_3_2","doi-asserted-by":"publisher","DOI":"10.1038\/mtna.2016.87"},{"key":"e_1_3_4_4_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.jid.2016.07.029"},{"key":"e_1_3_4_5_2","doi-asserted-by":"publisher","DOI":"10.1111\/jdv.17671"},{"key":"e_1_3_4_6_2","doi-asserted-by":"publisher","DOI":"10.1159\/000212504"},{"key":"e_1_3_4_7_2","doi-asserted-by":"publisher","DOI":"10.1126\/scitranslmed.aal5209"},{"key":"e_1_3_4_8_2","doi-asserted-by":"publisher","DOI":"10.1111\/bjd.13858"},{"key":"e_1_3_4_9_2","doi-asserted-by":"publisher","DOI":"10.1111\/bjd.14312"},{"key":"e_1_3_4_10_2","doi-asserted-by":"publisher","DOI":"10.1007\/s00439-017-1809-4"},{"key":"e_1_3_4_11_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.80.5.1184"},{"key":"e_1_3_4_12_2","doi-asserted-by":"publisher","DOI":"10.1007\/s00439-017-1820-9"},{"key":"e_1_3_4_13_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.jcf.2021.06.003"},{"key":"e_1_3_4_14_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.jid.2020.02.032"},{"key":"e_1_3_4_15_2","doi-asserted-by":"publisher","DOI":"10.1093\/clinchem\/hvab042"},{"key":"e_1_3_4_16_2","doi-asserted-by":"publisher","DOI":"10.1172\/JCI34292"},{"key":"e_1_3_4_17_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.jid.2016.03.005"},{"key":"e_1_3_4_18_2","doi-asserted-by":"publisher","DOI":"10.1089\/nat.2022.0060"},{"key":"e_1_3_4_19_2","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkg616"},{"key":"e_1_3_4_20_2","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkp215"},{"key":"e_1_3_4_21_2","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkab442"},{"key":"e_1_3_4_22_2","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkad067"},{"key":"e_1_3_4_23_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.nmd.2019.09.007"},{"key":"e_1_3_4_24_2","doi-asserted-by":"publisher","DOI":"10.1002\/mus.27853"},{"key":"e_1_3_4_25_2","doi-asserted-by":"publisher","DOI":"10.1002\/acn3.51235"},{"key":"e_1_3_4_26_2","doi-asserted-by":"publisher","DOI":"10.1089\/nat.2021.0043"},{"key":"e_1_3_4_27_2","doi-asserted-by":"publisher","DOI":"10.1212\/WNL.0000000000005680"},{"key":"e_1_3_4_28_2","doi-asserted-by":"publisher","DOI":"10.1001\/jamanetworkopen.2023.53094"},{"key":"e_1_3_4_29_2","doi-asserted-by":"publisher","DOI":"10.1126\/scitranslmed.aan0713"},{"key":"e_1_3_4_30_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.nmd.2023.03.008"},{"key":"e_1_3_4_31_2","doi-asserted-by":"publisher","DOI":"10.1002\/mus.27347"},{"key":"e_1_3_4_32_2","doi-asserted-by":"publisher","DOI":"10.1007\/s40261-023-01320-4"},{"key":"e_1_3_4_33_2","doi-asserted-by":"publisher","DOI":"10.3390\/ijms22073326"},{"key":"e_1_3_4_34_2","doi-asserted-by":"publisher","DOI":"10.3390\/ijms222212222"},{"key":"e_1_3_4_35_2","doi-asserted-by":"publisher","DOI":"10.1089\/nat.2023.0015"},{"key":"e_1_3_4_36_2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1813279"},{"key":"e_1_3_4_37_2","doi-asserted-by":"publisher","DOI":"10.3389\/fphar.2022.1006304"},{"key":"e_1_3_4_38_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41587-023-02078-y"},{"key":"e_1_3_4_39_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41591-018-0326-x"},{"key":"e_1_3_4_40_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-023-06277-0"},{"key":"e_1_3_4_41_2","doi-asserted-by":"publisher","DOI":"10.1038\/d41573-020-00027-x"},{"key":"e_1_3_4_42_2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa2206663"},{"key":"e_1_3_4_43_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41591-022-01737-y"},{"key":"e_1_3_4_44_2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa2301244"},{"key":"e_1_3_4_45_2","doi-asserted-by":"publisher","DOI":"10.1038\/mtna.2014.62"},{"key":"e_1_3_4_46_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.jid.2016.02.002"},{"key":"e_1_3_4_47_2","doi-asserted-by":"publisher","DOI":"10.1034\/j.1600-0625.2000.009003165.x"},{"key":"e_1_3_4_48_2","doi-asserted-by":"publisher","DOI":"10.1038\/265421a0"},{"key":"e_1_3_4_49_2","doi-asserted-by":"publisher","DOI":"10.1007\/978-1-4939-8651-4_35"},{"key":"e_1_3_4_50_2","unstructured":"N. Pironon Sequencing data of Patient 1 and Patient 2 of the manuscript entitled \u201cSplice modulation strategy applied to deep intronic variants in COL7A1 causing recessive dystrophic epidermolysis bullosa\u201d. NCBI BioProject. https:\/\/www.ncbi.nlm.nih.gov\/bioproject\/1144368. Deposited 5 August 2024."}],"container-title":["Proceedings of the National Academy of Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/pnas.org\/doi\/pdf\/10.1073\/pnas.2401781121","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,8,19]],"date-time":"2024-08-19T15:06:43Z","timestamp":1724080003000},"score":1,"resource":{"primary":{"URL":"https:\/\/pnas.org\/doi\/10.1073\/pnas.2401781121"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,8,19]]},"references-count":50,"journal-issue":{"issue":"35","published-print":{"date-parts":[[2024,8,27]]}},"alternative-id":["10.1073\/pnas.2401781121"],"URL":"https:\/\/doi.org\/10.1073\/pnas.2401781121","relation":{},"ISSN":["0027-8424","1091-6490"],"issn-type":[{"value":"0027-8424","type":"print"},{"value":"1091-6490","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,8,19]]},"assertion":[{"value":"2024-01-26","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2024-07-09","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2024-08-19","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"e2401781121"}}