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EMBO Mol Med 2023 May 08;155:e17078. doi: 10.15252/emmm.202217078.
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RAF1 deficiency causes a lethal syndrome that underscores RTK signaling during embryogenesis.

Wong S , Tan YX , Loh AYT , Tan KY , Lee H , Aziz Z , Nelson SF , Özkan E , Kayserili H , Escande-Beillard N , Reversade B .

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.

PubMed ID: 37066513
PMC ID: PMC10165362
Article link: EMBO Mol Med

Species referenced: Xenopus laevis
Genes referenced: abl1 egf map3k5 mapk1 pam raf1 tbxt tubb2b
GO keywords: MAPK cascade [+]

Disease Ontology terms: acrocardiofacial syndrome [+]
Phenotypes: Xla Wt + Hsa.RAF1 (Fig. 2 D r1c2) [+]

Article Images: [+] show captions
References [+] :
Aoki, Recent advances in RASopathies. 2016, Pubmed