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In this study, we document the first human phenotype resulting from the germline loss\u2010of\u2010function of the proto\u2010oncogene\n                    <jats:italic>RAF1<\/jats:italic>\n                    (a.k.a.\n                    <jats:italic>CRAF<\/jats:italic>\n                    ). In a consanguineous family, we uncovered a homozygous p.Thr543Met variant segregating with a neonatal lethal syndrome with cutaneous, craniofacial, cardiac, and limb anomalies. Structure\u2010based prediction and functional tests using human knock\u2010in cells showed that threonine 543 is essential to: (i) ensure RAF1's stability and phosphorylation, (ii) maintain its kinase activity toward substrates of the MAPK pathway, and (iii) protect from stress\u2010induced apoptosis mediated by ASK1. In\n                    <jats:italic>Xenopus<\/jats:italic>\n                    embryos, mutant RAF1\n                    <jats:sup>T543M<\/jats:sup>\n                    failed to phenocopy the effects of normal and\u00a0overactive FGF\/MAPK signaling, confirming its hypomorphic activity. Collectively, our data disclose the genetic and molecular etiology of a novel lethal syndrome with progeroid features, highlighting the importance of RTK signaling for human development and homeostasis.\n                  <\/jats:p>","DOI":"10.15252\/emmm.202217078","type":"journal-article","created":{"date-parts":[[2023,4,17]],"date-time":"2023-04-17T03:37:44Z","timestamp":1681702664000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["RAF1 deficiency causes a lethal syndrome that underscores RTK signaling during embryogenesis"],"prefix":"10.1038","volume":"15","author":[{"given":"Samantha","family":"Wong","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yu Xuan","family":"Tan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0038-4510","authenticated-orcid":false,"given":"Abigail Yi Ting","family":"Loh","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2139-3304","authenticated-orcid":false,"given":"Kiat Yi","family":"Tan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hane","family":"Lee","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zainab","family":"Aziz","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2082-3114","authenticated-orcid":false,"given":"Stanley F","family":"Nelson","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0263-6729","authenticated-orcid":false,"given":"Engin","family":"\u00d6zkan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0376-499X","authenticated-orcid":false,"given":"H\u00fclya","family":"Kayserili","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7706-1608","authenticated-orcid":false,"given":"Nathalie","family":"Escande\u2010Beillard","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4070-7997","authenticated-orcid":false,"given":"Bruno","family":"Reversade","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2023,4,17]]},"reference":[{"key":"BFEMMM202217078_CR1","doi-asserted-by":"crossref","first-page":"33","DOI":"10.1038\/jhg.2015.114","volume":"61","author":"Y Aoki","year":"2016","unstructured":"Aoki Y, Niihori T, Inoue S\u2010I, Matsubara Y (2016) Recent advances in RASopathies. 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