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

Abstract

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 RAF1 T543M 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.

Modelling human genetic disorders in Xenopus tropicalis

“…In addition to VUS classifications, Xenopus is an excellent platform for modelling diseases with known causal genetic variants but unknown molecular mechanisms of disease ( Mascibroda et al, 2022 ; Wong et al, 2023 ; Marquez et al, 2021 ; Colleluori and Khokha, 2023 ; Sempou et al, 2022 ; Willsey et al, 2021 ; Rosenthal et al, 2021 ; Grand et al, 2023 ; Getwan et al, 2021 ; Kulkarni and Khokha, 2018 ; Boskovski et al, 2013 ). In this case, specific variants can be studied, and molecular mechanisms identified in vivo .…”

Noonan syndrome: rhGH treatment and PTPN11 mutation

“…Delayed puberty may also be observed in some children. Mutations in 16 genes, including PTPN11 (50%), SOS1 (20%) and RAF1 (5%–15%), have been linked to the development of Noonan syndrome (Kessler et al, 2021; Pagnamenta et al, 2019; Tartaglia et al, 2011; Wong et al, 2023). As the RAS‐MAPK pathway is present in most cells, it regulates important cellular processes like growth factors and hormone secretion, making it a key factor in the syndrome development (Tafazoli et al, 2017).…”