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Classically, AIS is explained by hemizygous mutations in the X-chromosomal androgen receptor (<jats:italic>AR<\/jats:italic>) gene. Nevertheless, the majority of individuals with clinically diagnosed AIS do not carry an <jats:italic>AR<\/jats:italic> gene mutation. Here, we present a patient with a 46,XY karyotype, born with undervirilized genitalia, age-appropriate testosterone levels and no uterus, characteristic for AIS. Diagnostic whole exome sequencing (WES) showed a maternally inherited LINE1 (L1) retrotransposon insertion in the 5\u2032 untranslated region (5\u2032UTR) of the <jats:italic>AR<\/jats:italic> gene. Long-read nanopore sequencing confirmed this as an insertion of a truncated L1 element of \u2248\u20092.7\u00a0kb and showed\u00a0an increased DNA methylation at the L1 insertion site in patient-derived genital skin fibroblasts (GSFs) compared to healthy controls. The insertion coincided with reduced AR transcript and protein levels in patient-derived GSFs confirming the clinical diagnosis AIS. Our results underline the relevance of retrotransposons in human disease, and expand the growing list of human diseases associated with them.<\/jats:p>","DOI":"10.1038\/s41598-024-65439-w","type":"journal-article","created":{"date-parts":[[2024,7,15]],"date-time":"2024-07-15T17:01:58Z","timestamp":1721062918000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":9,"title":["LINE1-mediated epigenetic repression of androgen receptor transcription causes androgen insensitivity syndrome"],"prefix":"10.1038","volume":"14","author":[{"given":"Jelena","family":"Pozojevic","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Radhika","family":"Sivaprasad","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joshua","family":"La\u00df","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Franziska","family":"Haarich","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joanne","family":"Trinh","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Naseebullah","family":"Kakar","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kristin","family":"Schulz","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kristian","family":"H\u00e4ndler","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Annemarie A.","family":"Verrijn Stuart","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jacques C.","family":"Giltay","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Koen L.","family":"van Gassen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Almuth","family":"Caliebe","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paul-Martin","family":"Holterhus","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Malte","family":"Spielmann","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nadine C.","family":"Hornig","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2024,7,15]]},"reference":[{"key":"65439_CR1","doi-asserted-by":"publisher","DOI":"10.1016\/j.mce.2020.111146","volume":"523","author":"NC Hornig","year":"2021","unstructured":"Hornig, N. 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PLoS\u00a0One 11, e0154158 (2016).","journal-title":"PLoS\u00a0One"},{"key":"65439_CR4","doi-asserted-by":"publisher","first-page":"2976","DOI":"10.3390\/ijms24032976","volume":"24","author":"N Ryczek","year":"2023","unstructured":"Ryczek, N., \u0141y\u015b, A. & Maka\u0142owska, I. The functional meaning of 5\u2019UTR in protein-coding genes. Int. J. Mol. Sci. 24, 2976 (2023).","journal-title":"Int. J. Mol. Sci."},{"key":"65439_CR5","doi-asserted-by":"publisher","first-page":"4217","DOI":"10.1038\/s41467-021-24445-6","volume":"12","author":"Y Lim","year":"2021","unstructured":"Lim, Y. et al. Multiplexed functional genomic analysis of 5\u2032 untranslated region mutations across the spectrum of prostate cancer. Nat. Commun. 12, 4217 (2021).","journal-title":"Nat. Commun."},{"key":"65439_CR6","doi-asserted-by":"publisher","first-page":"860","DOI":"10.1038\/35057062","volume":"409","author":"ES Lander","year":"2001","unstructured":"Lander, E. S. et al. 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