{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,26]],"date-time":"2026-02-26T20:09:02Z","timestamp":1772136542695,"version":"3.50.1"},"reference-count":30,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2025,7,18]],"date-time":"2025-07-18T00:00:00Z","timestamp":1752796800000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2025,7,18]],"date-time":"2025-07-18T00:00:00Z","timestamp":1752796800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"DOI":"10.13039\/501100001665","name":"Agence Nationale de la Recherche","doi-asserted-by":"publisher","award":["French National Research Agency (ANR) ANR-23-CE17-0042-01"],"award-info":[{"award-number":["French National Research Agency (ANR) ANR-23-CE17-0042-01"]}],"id":[{"id":"10.13039\/501100001665","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001665","name":"Agence Nationale de la Recherche","doi-asserted-by":"publisher","award":["ANR-23-IAHU-0001"],"award-info":[{"award-number":["ANR-23-IAHU-0001"]}],"id":[{"id":"10.13039\/501100001665","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100007354","name":"Fondation Lefoulon Delalande","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100007354","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Inserm gold cross-cutting program"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Commun Biol"],"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>\n                    Hereditary Hemorrhagic Telangiectasia (HHT) is a rare vascular disease mainly caused by pathogenic mutations in\n                    <jats:italic>ACVRL1<\/jats:italic>\n                    and\n                    <jats:italic>ENG<\/jats:italic>\n                    genes. Despite advances in HHT diagnosis, the molecular origin of some cases remains unclear. Recently, we observed a high prevalence of HHT-causing 5\u2019UTR variants in\n                    <jats:italic>ENG<\/jats:italic>\n                    . These variants commonly introduce upstream AUG codons (uAUGs) at the origin of upstream open reading frames (upORFs) overlapping the coding sequence, all terminating at the same stop codon located at position c.125 (uAUG-c.125). Here, we analyzed all 5\u2019UTR\n                    <jats:italic>ENG<\/jats:italic>\n                    single nucleotide variants that could alter upORFs in silico. Interestingly, we found that 85% of uAUG-c.125 variants alter the protein levels. Furthermore, we identified 2 variants creating uAUG-c.125 and uCUG-c.125 in HHT patients and experimentally demonstrated their association with reduced endoglin levels\n                  <\/jats:p>\n                  <jats:p>\n                    This study provides new elements for the interpretation of upORF-altering variants in the 5\u2019UTR of\n                    <jats:italic>ENG<\/jats:italic>\n                    with new insights for the molecular diagnosis of HHT.\n                  <\/jats:p>","DOI":"10.1038\/s42003-025-08461-6","type":"journal-article","created":{"date-parts":[[2025,7,18]],"date-time":"2025-07-18T18:31:58Z","timestamp":1752863518000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Overlapping upstream ORFs ending at c.125 lead to reduced Endoglin, contributing to Hereditary Hemorrhagic Telangiectasia"],"prefix":"10.1038","volume":"8","author":[{"given":"Carole","family":"Proust","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Cl\u00e9mence","family":"Deiber","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Caroline","family":"Meguerditchian","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Maud","family":"Tusseau","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Alexandre","family":"Guilhem","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Shirine","family":"Mohamed","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3938-1165","authenticated-orcid":false,"given":"Aur\u00e9lie","family":"Goyenvalle","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"B\u00e9atrice","family":"Jaspard-Vinassa","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sophie","family":"Dupuis-Girod","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9084-7800","authenticated-orcid":false,"given":"David-Alexandre","family":"Tr\u00e9gou\u00ebt","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4923-4353","authenticated-orcid":false,"given":"Omar","family":"Soukarieh","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"297","published-online":{"date-parts":[[2025,7,18]]},"reference":[{"key":"8461_CR1","doi-asserted-by":"publisher","first-page":"1907","DOI":"10.1182\/blood.2019004560","volume":"136","author":"CL Shovlin","year":"2020","unstructured":"Shovlin, C. L. et al. Mutational and phenotypic characterization of hereditary hemorrhagic telangiectasia. Blood 136, 1907\u20131918 (2020).","journal-title":"Blood"},{"key":"8461_CR2","doi-asserted-by":"crossref","unstructured":"Cerd\u00e0, P. et al. New genetic drivers in hemorrhagic hereditary telangiectasia. Eur. J. Intern. Med. 119, 99\u2013108 (2024).","DOI":"10.1016\/j.ejim.2023.08.024"},{"key":"8461_CR3","doi-asserted-by":"publisher","first-page":"989","DOI":"10.7326\/M20-1443","volume":"173","author":"ME Faughnan","year":"2020","unstructured":"Faughnan, M. E. et al. Second international guidelines for the diagnosis and management of hereditary hemorrhagic telangiectasia. Ann. Intern. Med. 173, 989\u20131001 (2020).","journal-title":"Ann. Intern. Med."},{"key":"8461_CR4","doi-asserted-by":"publisher","first-page":"2314","DOI":"10.1182\/blood.2023021777","volume":"143","author":"ME Bernab\u00e9u-Herrero","year":"2024","unstructured":"Bernab\u00e9u-Herrero, M. E. et al. Mutations causing premature termination codons discriminate and generate cellular and clinical variability in HHT. Blood 143, 2314\u20132331 (2024).","journal-title":"Blood"},{"key":"8461_CR5","doi-asserted-by":"publisher","first-page":"1142","DOI":"10.1093\/hmg\/ddu531","volume":"24","author":"C Mallet","year":"2015","unstructured":"Mallet, C. et al. Functional analysis of endoglin mutations from hereditary hemorrhagic telangiectasia type 1 patients reveals different mechanisms for endoglin loss of function. Hum. Mol. Genet. 24, 1142\u20131154 (2015).","journal-title":"Hum. Mol. Genet."},{"key":"8461_CR6","doi-asserted-by":"publisher","first-page":"1903","DOI":"10.1016\/j.ajhg.2023.09.005","volume":"110","author":"S Xiao","year":"2023","unstructured":"Xiao, S. et al. Functional filter for whole-genome sequencing data identifies HHT and stress-associated non-coding SMAD4 polyadenylation site variants >5 kb from coding DNA. Am. J. Hum. Genet. 110, 1903\u20131918 (2023).","journal-title":"J. Hum. Genet."},{"key":"8461_CR7","doi-asserted-by":"publisher","DOI":"10.1016\/j.ejmg.2024.104919","volume":"68","author":"M Tusseau","year":"2024","unstructured":"Tusseau, M. et al. Genome sequencing identify chromosome 9 inversions disrupting ENG in 2 unrelated HHT families. Eur. J. Med. Genet. 68, 104919 (2024).","journal-title":"Eur. J. Med. Genet."},{"key":"8461_CR8","doi-asserted-by":"publisher","first-page":"667","DOI":"10.1002\/humu.20342","volume":"27","author":"AD Bossler","year":"2006","unstructured":"Bossler, A. D., Richards, J., George, C., Godmilow, L. & Ganguly, A. Novel mutations in ENG and ACVRL1 identified in a series of 200 individuals undergoing clinical genetic testing for hereditary hemorrhagic telangiectasia (HHT): correlation of genotype with phenotype. Hum. Mutat. 27, 667\u2013675 (2006).","journal-title":"Hum. Mutat."},{"key":"8461_CR9","doi-asserted-by":"publisher","DOI":"10.1186\/1750-1172-6-85","volume":"6","author":"K Damjanovich","year":"2011","unstructured":"Damjanovich, K. et al. 5\u2019UTR mutations of ENG cause hereditary hemorrhagic telangiectasia. Orphanet J. Rare Dis. 6, 85 (2011).","journal-title":"Orphanet J. Rare Dis."},{"key":"8461_CR10","doi-asserted-by":"publisher","DOI":"10.1186\/1471-2350-12-130","volume":"12","author":"M-J Kim","year":"2011","unstructured":"Kim, M.-J. et al. Clinical and genetic analyses of three Korean families with hereditary hemorrhagic telangiectasia. BMC Med. Genet. 12, 130 (2011).","journal-title":"BMC Med. Genet."},{"key":"8461_CR11","doi-asserted-by":"publisher","DOI":"10.1186\/s12881-017-0380-0","volume":"18","author":"V Albi\u00f1ana","year":"2017","unstructured":"Albi\u00f1ana, V. et al. Mutation affecting the proximal promoter of Endoglin as the origin of hereditary hemorrhagic telangiectasia type 1. BMC Med. Genet. 18, 20 (2017).","journal-title":"BMC Med. Genet."},{"key":"8461_CR12","doi-asserted-by":"publisher","first-page":"333","DOI":"10.1038\/s10038-019-0564-x","volume":"64","author":"L Ruiz-Llorente","year":"2019","unstructured":"Ruiz-Llorente, L. et al. Characterization of a family mutation in the 5\u2019 untranslated region of the endoglin gene causative of hereditary hemorrhagic telangiectasia. J. Hum. Genet. 64, 333\u2013339 (2019).","journal-title":"J. Hum. Genet."},{"key":"8461_CR13","doi-asserted-by":"publisher","first-page":"32","DOI":"10.1038\/s41525-023-00378-5","volume":"8","author":"O Soukarieh","year":"2023","unstructured":"Soukarieh, O. et al. uAUG creating variants in the 5\u2019UTR of ENG causing hereditary hemorrhagic telangiectasia. NPJ Genom. Med 8, 32 (2023).","journal-title":"NPJ Genom. 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Endoglin requirement for BMP9 signaling in endothelial cells reveals new mechanism of action for selective anti-endoglin antibodies. PLoS One 7, e50920 (2012).","journal-title":"PLoS One"},{"key":"8461_CR17","doi-asserted-by":"publisher","first-page":"4018","DOI":"10.1038\/sj.emboj.7600386","volume":"23","author":"F Lebrin","year":"2004","unstructured":"Lebrin, F. et al. Endoglin promotes endothelial cell proliferation and TGF-beta\/ALK1 signal transduction. EMBO J. 23, 4018\u20134028 (2004).","journal-title":"EMBO J."},{"key":"8461_CR18","doi-asserted-by":"publisher","first-page":"1917","DOI":"10.1016\/j.celrep.2017.05.011","volume":"19","author":"T Saito","year":"2017","unstructured":"Saito, T. et al. Structural Basis of the Human Endoglin-BMP9 Interaction: Insights into BMP Signaling and HHT1. Cell Rep. 19, 1917\u20131928 (2017).","journal-title":"Cell Rep."},{"key":"8461_CR19","doi-asserted-by":"publisher","first-page":"1717","DOI":"10.1101\/gad.305250.117","volume":"31","author":"MG Kearse","year":"2017","unstructured":"Kearse, M. G. & Wilusz, J. E. Non-AUG translation: a new start for protein synthesis in eukaryotes. Genes Dev. 31, 1717\u20131731 (2017).","journal-title":"Genes Dev."},{"key":"8461_CR20","doi-asserted-by":"publisher","first-page":"587","DOI":"10.1038\/s42003-022-03534-2","volume":"5","author":"I Basu","year":"2022","unstructured":"Basu, I., Gorai, B., Chandran, T., Maiti, P. K. & Hussain, T. Selection of start codon during mRNA scanning in eukaryotic translation initiation. Commun. Biol. 5, 587 (2022).","journal-title":"Commun. Biol."},{"key":"8461_CR21","doi-asserted-by":"publisher","first-page":"494","DOI":"10.1038\/nature21036","volume":"541","author":"A Sendoel","year":"2017","unstructured":"Sendoel, A. et al. Translation from unconventional 5\u2019 start sites drives tumour initiation. Nature 541, 494\u2013499 (2017).","journal-title":"Nature"},{"key":"8461_CR22","doi-asserted-by":"publisher","first-page":"387","DOI":"10.1016\/j.ebiom.2019.05.058","volume":"44","author":"K Sato","year":"2019","unstructured":"Sato, K. et al. Novel oncogene 5MP1 reprograms c-Myc translation initiation to drive malignant phenotypes in colorectal cancer. EBioMedicine 44, 387\u2013402 (2019).","journal-title":"EBioMedicine"},{"key":"8461_CR23","doi-asserted-by":"publisher","first-page":"lqaf017","DOI":"10.1093\/nargab\/lqaf017","volume":"7","author":"C Meguerditchian","year":"2025","unstructured":"Meguerditchian, C. et al. Enhancing the annotation of small ORF-altering variants using MORFEE: introducing MORFEEdb, a comprehensive catalog of SNVs affecting upstream ORFs in human 5\u2019UTRs. NAR Genom. Bioinform. 7, lqaf017 (2025).","journal-title":"NAR Genom. 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PLoS Genet. 12, e1005756 (2016).","journal-title":"PLoS Genet."},{"key":"8461_CR29","doi-asserted-by":"publisher","first-page":"e0256411","DOI":"10.1371\/journal.pone.0256411","volume":"17","author":"AC Gleason","year":"2022","unstructured":"Gleason, A. C., Ghadge, G., Chen, J., Sonobe, Y. & Roos, R. P. Machine learning predicts translation initiation sites in neurologic diseases with nucleotide repeat expansions. PLoS One 17, e0256411 (2022).","journal-title":"PLoS One"},{"key":"8461_CR30","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pcbi.1005170","volume":"12","author":"K Reuter","year":"2016","unstructured":"Reuter, K., Biehl, A., Koch, L. & Helms, V. PreTIS: a tool to predict non-canonical 5\u2019 UTR translational initiation sites in human and mouse. PLoS Comput. Biol. 12, e1005170 (2016).","journal-title":"PLoS Comput. Biol."}],"container-title":["Communications Biology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/s42003-025-08461-6.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s42003-025-08461-6","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s42003-025-08461-6.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,9,7]],"date-time":"2025-09-07T14:43:15Z","timestamp":1757256195000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/s42003-025-08461-6"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,7,18]]},"references-count":30,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2025,12]]}},"alternative-id":["8461"],"URL":"https:\/\/doi.org\/10.1038\/s42003-025-08461-6","relation":{"has-preprint":[{"id-type":"doi","id":"10.21203\/rs.3.rs-4808835\/v1","asserted-by":"object"}]},"ISSN":["2399-3642"],"issn-type":[{"value":"2399-3642","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,7,18]]},"assertion":[{"value":"23 April 2025","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"30 June 2025","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"18 July 2025","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"The authors declare that they have no known competing financial or non-financial interests or personal relationships that could have appeared to influence the work reported in this paper.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"1072"}}