RAF1 deficiency causes a lethal syndrome that underscores RTK signaling during embryogenesis

Samantha Wong, Yu Xuan Tan, Abigail Yi Ting Loh, Kiat Yi Tan, Hane Lee, Zainab Aziz, Stanley F Nelson, Engin Özkan, Hulya Kayserili, Nathalie Escande-Beillard, Bruno Reversade

Research output: Contribution to journalArticlepeer-review

1 Scopus citations


Somatic and germline gain-of-function point mutations in RAF, one of the first oncogenes to be discovered in humans, delineate a group of tumor-prone syndromes known as the RASopathies. In this study, we document the first human phenotype resulting from the germline loss-of-function of the proto-oncogene RAF1 (a.k.a. CRAF). 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-based prediction and functional tests using human knock-in 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-induced apoptosis mediated by ASK1. In Xenopus embryos, mutant RAF1T543M failed to phenocopy the effects of normal and overactive 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.
Original languageEnglish (US)
JournalEMBO Molecular Medicine
StatePublished - Apr 17 2023

ASJC Scopus subject areas

  • Molecular Medicine


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