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...
| Main Authors: | , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Springer Nature
2023-04-01
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| Series: | EMBO Molecular Medicine |
| Subjects: | |
| Online Access: | https://doi.org/10.15252/emmm.202217078 |
| _version_ | 1826983420061810688 |
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| author | Samantha Wong Yu Xuan Tan Abigail Yi Ting Loh Kiat Yi Tan Hane Lee Zainab Aziz Stanley F Nelson Engin Özkan Hülya Kayserili Nathalie Escande‐Beillard Bruno Reversade |
| author_facet | Samantha Wong Yu Xuan Tan Abigail Yi Ting Loh Kiat Yi Tan Hane Lee Zainab Aziz Stanley F Nelson Engin Özkan Hülya Kayserili Nathalie Escande‐Beillard Bruno Reversade |
| author_sort | Samantha Wong |
| collection | DOAJ |
| description | 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 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. |
| first_indexed | 2024-03-07T16:55:38Z |
| format | Article |
| id | doaj.art-12fc7fb5e634482b982be6cd3b0c8a2c |
| institution | Directory Open Access Journal |
| issn | 1757-4676 1757-4684 |
| language | English |
| last_indexed | 2025-02-18T06:36:44Z |
| publishDate | 2023-04-01 |
| publisher | Springer Nature |
| record_format | Article |
| series | EMBO Molecular Medicine |
| spelling | doaj.art-12fc7fb5e634482b982be6cd3b0c8a2c2024-11-10T12:37:39ZengSpringer NatureEMBO Molecular Medicine1757-46761757-46842023-04-0115511510.15252/emmm.202217078RAF1 deficiency causes a lethal syndrome that underscores RTK signaling during embryogenesisSamantha Wong0Yu Xuan Tan1Abigail Yi Ting Loh2Kiat Yi Tan3Hane Lee4Zainab Aziz5Stanley F Nelson6Engin Özkan7Hülya Kayserili8Nathalie Escande‐Beillard9Bruno Reversade10Institute of Molecular and Cellular Biology, A*STARInstitute of Molecular and Cellular Biology, A*STARInstitute of Molecular and Cellular Biology, A*STARInstitute of Molecular and Cellular Biology, A*STARDepartment of Pathology and Laboratory Medicine, David Geffen School of Medicine, University of California Los AngelesDepartment of Biochemistry and Molecular Biology, The University of ChicagoDepartment of Pathology and Laboratory Medicine, David Geffen School of Medicine, University of California Los AngelesDepartment of Biochemistry and Molecular Biology, The University of ChicagoDepartment of Medical Genetics, Koç University, School of MedicineInstitute of Molecular and Cellular Biology, A*STARInstitute of Molecular and Cellular Biology, A*STARAbstract 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.https://doi.org/10.15252/emmm.202217078ASK1ERKRAF1RASopathyXenopus |
| spellingShingle | Samantha Wong Yu Xuan Tan Abigail Yi Ting Loh Kiat Yi Tan Hane Lee Zainab Aziz Stanley F Nelson Engin Özkan Hülya Kayserili Nathalie Escande‐Beillard Bruno Reversade RAF1 deficiency causes a lethal syndrome that underscores RTK signaling during embryogenesis EMBO Molecular Medicine ASK1 ERK RAF1 RASopathy Xenopus |
| title | RAF1 deficiency causes a lethal syndrome that underscores RTK signaling during embryogenesis |
| title_full | RAF1 deficiency causes a lethal syndrome that underscores RTK signaling during embryogenesis |
| title_fullStr | RAF1 deficiency causes a lethal syndrome that underscores RTK signaling during embryogenesis |
| title_full_unstemmed | RAF1 deficiency causes a lethal syndrome that underscores RTK signaling during embryogenesis |
| title_short | RAF1 deficiency causes a lethal syndrome that underscores RTK signaling during embryogenesis |
| title_sort | raf1 deficiency causes a lethal syndrome that underscores rtk signaling during embryogenesis |
| topic | ASK1 ERK RAF1 RASopathy Xenopus |
| url | https://doi.org/10.15252/emmm.202217078 |
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