1 Ocak 2023 Dergi makalesi Açık Erişim

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

Citation Style Language JSON

{
  "DOI": "10.15252/emmm.202217078", 
  "abstract": "<p>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.</p>", 
  "author": [
    {
      "family": "Wong", 
      "given": " Samantha"
    }, 
    {
      "family": "Tan", 
      "given": " Yu Xuan"
    }, 
    {
      "family": "Loh", 
      "given": " Abigail Yi Ting"
    }, 
    {
      "family": "Tan", 
      "given": " Kiat Yi"
    }, 
    {
      "family": "Lee", 
      "given": " Hane"
    }, 
    {
      "family": "Aziz", 
      "given": " Zainab"
    }, 
    {
      "family": "Nelson", 
      "given": " Stanley F."
    }, 
    {
      "family": "Ozkan", 
      "given": " Engin"
    }, 
    {
      "family": "Kayserili", 
      "given": " H\u00fclya"
    }, 
    {
      "family": "Escande-Beillard", 
      "given": " Nathalie"
    }, 
    {
      "family": "Reversade", 
      "given": " Bruno"
    }
  ], 
  "container_title": "EMBO MOLECULAR MEDICINE", 
  "id": "270832", 
  "issue": "5", 
  "issued": {
    "date-parts": [
      [
        2023, 
        1, 
        1
      ]
    ]
  }, 
  "page": "15", 
  "title": "RAF1 deficiency causes a lethal syndrome that underscores RTK signaling during embryogenesis", 
  "type": "article-journal", 
  "volume": "15"
}