{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,10]],"date-time":"2026-06-10T16:03:05Z","timestamp":1781107385894,"version":"3.54.1"},"reference-count":60,"publisher":"National Academy of Sciences","issue":"27","license":[{"start":{"date-parts":[[2023,6,26]],"date-time":"2023-06-26T00:00:00Z","timestamp":1687737600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100009619","name":"Japan Agency for Medical Research and Development","doi-asserted-by":"publisher","award":["JP20ek0109488"],"award-info":[{"award-number":["JP20ek0109488"]}],"id":[{"id":"10.13039\/100009619","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100009619","name":"Japan Agency for Medical Research and Development","doi-asserted-by":"publisher","award":["JP21ek0109549"],"award-info":[{"award-number":["JP21ek0109549"]}],"id":[{"id":"10.13039\/100009619","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001691","name":"MEXT | Japan Society for the Promotion of Science","doi-asserted-by":"publisher","award":["JP20H00629"],"award-info":[{"award-number":["JP20H00629"]}],"id":[{"id":"10.13039\/501100001691","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":[[2023,7,4]]},"abstract":"<jats:p>\n                    Xeroderma pigmentosum (XP) is a genodermatosis defined by cutaneous photosensitivity with an increased risk of skin tumors because of DNA repair deficiency. The worldwide prevalence of XP is ~1 to 4 in million, with higher incidence in some countries and regions including Japan (1 in 22,000) and North Africa due to founder mutations and a high degree of consanguinity. Among XP, the complementation group F (XP-F), is a rare form (1% of worldwide XP); however, this is underdiagnosed, because the\n                    <jats:italic>ERCC4<\/jats:italic>\n                    \/\n                    <jats:italic>XPF<\/jats:italic>\n                    gene is essential for fetal development and most of previously reported\n                    <jats:italic>ERCC4<\/jats:italic>\n                    \/\n                    <jats:italic>XPF<\/jats:italic>\n                    pathogenic variants are hypomorphs causing relatively mild phenotypes. From the largest Japanese XP cohort study, we report 17 XP-F cases bearing two pathogenic variants, both identified in deep intronic regions of the\n                    <jats:italic>ERCC4<\/jats:italic>\n                    \/\n                    <jats:italic>XPF<\/jats:italic>\n                    gene. The first variant, located in intron 1, is a Japanese founder mutation, which additionally accounts for ~10% of the entire Japanese XP cases (MAF = 0.00196), causing an aberrant pre-mRNA splicing due to a miss-binding of U1snRNA. The second mutation located in intron eight induces an alternative polyadenylation. Both mutations cause a reduction of the\n                    <jats:italic>ERCC4<\/jats:italic>\n                    \/\n                    <jats:italic>XPF<\/jats:italic>\n                    gene expression, resulting in XP clinical manifestations. Most cases developed early-onset skin cancers, indicating that these variants need critical attention. We further demonstrate that antisense oligonucleotides designed for the mutations can restore the XPF protein expression and DNA repair capacity in the patients\u2019 cells. Collectively, these pathogenic variants can be potential therapeutic targets for XP.\n                  <\/jats:p>","DOI":"10.1073\/pnas.2217423120","type":"journal-article","created":{"date-parts":[[2023,6,26]],"date-time":"2023-06-26T15:09:49Z","timestamp":1687792189000},"update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":12,"title":["Deep intronic founder mutations identified in the\n                    <i>ERCC4<\/i>\n                    \/\n                    <i>XPF<\/i>\n                    gene are potential therapeutic targets for a high-frequency form of xeroderma pigmentosum"],"prefix":"10.1073","volume":"120","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-1083-0847","authenticated-orcid":false,"given":"Chikako","family":"Senju","sequence":"first","affiliation":[{"name":"Department of Genetics, Research Institute of Environmental Medicine, Nagoya University, Nagoya 464-8601, Japan"},{"name":"Department of Human Genetics and Molecular Biology, Graduate School of Medicine, Nagoya University, Nagoya 464-8601, Japan"},{"name":"Department of Genome Repair, Atomic Bomb Disease Institute, Nagasaki University, Nagasaki 852-8523, Japan"},{"name":"Department of Radiation Medical Sciences, Atomic Bomb Disease Institute, Nagasaki University, Nagasaki 852-8523, Japan"},{"name":"Department of Hematology, Atomic Bomb Disease Institute, Nagasaki University, Nagasaki 852-8523, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3835-3093","authenticated-orcid":false,"given":"Yuka","family":"Nakazawa","sequence":"additional","affiliation":[{"name":"Department of Genetics, Research Institute of Environmental Medicine, Nagoya University, Nagoya 464-8601, Japan"},{"name":"Department of Human Genetics and Molecular Biology, Graduate School of Medicine, Nagoya University, Nagoya 464-8601, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8288-7829","authenticated-orcid":false,"given":"Taichi","family":"Oso","sequence":"additional","affiliation":[{"name":"Department of Genetics, Research Institute of Environmental Medicine, Nagoya University, Nagoya 464-8601, Japan"},{"name":"Department of Human Genetics and Molecular Biology, Graduate School of Medicine, Nagoya University, Nagoya 464-8601, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0007-8286-6121","authenticated-orcid":false,"given":"Mayuko","family":"Shimada","sequence":"additional","affiliation":[{"name":"Department of Genetics, Research Institute of Environmental Medicine, Nagoya University, Nagoya 464-8601, Japan"},{"name":"Department of Human Genetics and Molecular Biology, Graduate School of Medicine, Nagoya University, Nagoya 464-8601, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kana","family":"Kato","sequence":"additional","affiliation":[{"name":"Department of Genetics, Research Institute of Environmental Medicine, Nagoya University, Nagoya 464-8601, Japan"},{"name":"Department of Human Genetics and Molecular Biology, Graduate School of Medicine, Nagoya University, Nagoya 464-8601, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6178-3342","authenticated-orcid":false,"given":"Michiko","family":"Matsuse","sequence":"additional","affiliation":[{"name":"Department of Radiation Medical Sciences, Atomic Bomb Disease Institute, Nagasaki University, Nagasaki 852-8523, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6541-5221","authenticated-orcid":false,"given":"Mariko","family":"Tsujimoto","sequence":"additional","affiliation":[{"name":"Division of Dermatology, Department of Internal Related, Kobe University Graduate School of Medicine, Kobe 650-0017, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Taro","family":"Masaki","sequence":"additional","affiliation":[{"name":"Division of Dermatology, Department of Internal Related, Kobe University Graduate School of Medicine, Kobe 650-0017, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3683-7147","authenticated-orcid":false,"given":"Yasushi","family":"Miyazaki","sequence":"additional","affiliation":[{"name":"Department of Hematology, Atomic Bomb Disease Institute, Nagasaki University, Nagasaki 852-8523, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0622-7682","authenticated-orcid":false,"given":"Satoshi","family":"Fukushima","sequence":"additional","affiliation":[{"name":"Department of Dermatology and Plastic Surgery, Faculty of Life Sciences, Kumamoto University, Kumamoto 860-8556, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Satoshi","family":"Tateishi","sequence":"additional","affiliation":[{"name":"Department of Cell Maintenance, Institute of Molecular Embryology and Genetics, Kumamoto University, Kumamoto 860-0811, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Atsushi","family":"Utani","sequence":"additional","affiliation":[{"name":"Department of Dermatology, Graduate School of Biomedical Sciences, Nagasaki University, Nagasaki 852-8501, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hiroyuki","family":"Murota","sequence":"additional","affiliation":[{"name":"Department of Dermatology, Graduate School of Biomedical Sciences, Nagasaki University, Nagasaki 852-8501, Japan"},{"name":"Leading Medical Research Core Unit, Life-Science Innovation, Graduate School of Biomedical Sciences, Nagasaki University, Nagasaki 852-8501, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Katsumi","family":"Tanaka","sequence":"additional","affiliation":[{"name":"Department of Plastic and Reconstructive Surgery, Graduate School of Biomedical Sciences, Nagasaki University, Nagasaki 852-8501, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2744-8046","authenticated-orcid":false,"given":"Norisato","family":"Mitsutake","sequence":"additional","affiliation":[{"name":"Department of Radiation Medical Sciences, Atomic Bomb Disease Institute, Nagasaki University, Nagasaki 852-8523, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0803-9455","authenticated-orcid":false,"given":"Shinichi","family":"Moriwaki","sequence":"additional","affiliation":[{"name":"Department of Dermatology, Osaka Medical and Pharmaceutical University, Takatsuki 569-8686, 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