2. Academic Validation
  3. Enhanced MAPK1 Function Causes a Neurodevelopmental Disorder within the RASopathy Clinical Spectrum

Enhanced MAPK1 Function Causes a Neurodevelopmental Disorder within the RASopathy Clinical Spectrum

  • Am J Hum Genet. 2020 Sep 3;107(3):499-513. doi: 10.1016/j.ajhg.2020.06.018.
Marialetizia Motta 1,  Luca Pannone 2,  Francesca Pantaleoni 1,  Gianfranco Bocchinfuso 3,  Francesca Clementina Radio 1,  Serena Cecchetti 4,  Andrea Ciolfi 1,  Martina Di Rocco 5,  Mariet W Elting 6,  Eva H Brilstra 7,  Stefania Boni 8,  Laura Mazzanti 9,  Federica Tamburrino 9,  Larry Walsh 10,  Katelyn Payne 10,  Alberto Fernández-Jaén 11,  Mythily Ganapathi 12,  Wendy K Chung 13,  Dorothy K Grange 14,  Ashita Dave-Wala 15,  Shalini C Reshmi 16,  Dennis W Bartholomew 15,  Danielle Mouhlas 15,  Giovanna Carpentieri 2,  Alessandro Bruselles 17,  Simone Pizzi 1,  Emanuele Bellacchio 1,  Francesca Piceci-Sparascio 18,  Christina Lißewski 19,  Julia Brinkmann 19,  Ronald R Waclaw 20,  Quinten Waisfisz 6,  Koen van Gassen 7,  Ingrid M Wentzensen 21,  Michelle M Morrow 21,  Sara Álvarez 22,  Mónica Martínez-García 22,  Alessandro De Luca 18,  Luigi Memo 23,  Giuseppe Zampino 24,  Cesare Rossi 25,  Marco Seri 25,  Bruce D Gelb 26,  Martin Zenker 19,  Bruno Dallapiccola 1,  Lorenzo Stella 3,  Carlos E Prada 27,  Simone Martinelli 17,  Elisabetta Flex 17,  Marco Tartaglia 28
Affiliations

Affiliations

  • 1 Genetics and Rare Diseases Research Division, Ospedale Pediatrico Bambino Gesù, IRCCS, 00146 Rome, Italy.
  • 2 Genetics and Rare Diseases Research Division, Ospedale Pediatrico Bambino Gesù, IRCCS, 00146 Rome, Italy; Department of Oncology and Molecular Medicine, Istituto Superiore di Sanità, 00161 Rome, Italy.
  • 3 Department of Chemical Science and Technologies, University of Rome Tor Vergata, 00133, Rome, Italy.
  • 4 Microscopy Area, Core Facilities, Istituto Superiore di Sanità, 00161 Rome, Italy.
  • 5 Department of Oncology and Molecular Medicine, Istituto Superiore di Sanità, 00161 Rome, Italy; Department of Biochemical Science "A. Rossi Fanelli," Sapienza University of Rome, 00185 Rome, Italy.
  • 6 Department of Clinical Genetics, Amsterdam UMC, Vrije Universiteit, 1117 Amsterdam, the Netherlands.
  • 7 Department of Genetics, University Medical Center Utrecht, 3584 CX Utrecht, the Netherlands.
  • 8 Medical Genetics Unit, S. Martino Hospital, 32100 Belluno, Italy.
  • 9 Department of Medical and Surgical Sciences, Policlinico S. Orsola-Malpighi Hospital, University of Bologna, 40138 Bologna, Italy.
  • 10 Indiana University Health at Riley Hospital for Children, Indianapolis, IN 46202, USA.
  • 11 Department of Pediatrics Neurology, Hospital Universitario Quirón de Madrid, Universidad Europea de Madrid, 28223 Madrid, Spain.
  • 12 Department of Pathology and Cell Biology, Columbia University Medical Center, New York, NY 10032, USA.
  • 13 Departments of Pediatrics and Medicine, Columbia University Medical Center, New York, NY 10032, USA.
  • 14 Department of Pediatrics, Division of Genetics and Genomic Medicine, Washington University School of Medicine, St. Louis, MO 63110, USA.
  • 15 Institute for Genomic Medicine, Nationwide Children's Hospital, Columbus, OH 43215, USA.
  • 16 Institute for Genomic Medicine, Nationwide Children's Hospital, Columbus, OH 43215, USA; Department of Pediatrics, Nationwide Children's Hospital, Columbus, OH 43215, USA.
  • 17 Department of Oncology and Molecular Medicine, Istituto Superiore di Sanità, 00161 Rome, Italy.
  • 18 Medical Genetics Division, Fondazione IRCCS Casa Sollievo della Sofferenza, 71013 San Giovanni Rotondo, Italy.
  • 19 Institute of Human Genetics, University Hospital Magdeburg, 39120 Magdeburg, Germany.
  • 20 Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH 45229, USA.
  • 21 GeneDx, Gaithersburg, 20877 MD, USA.
  • 22 Medical Department, NimGenetics, 28049 Madrid, Spain.
  • 23 Ambulatorio Genetica Clinica, Ospedale San Bortolo, 36100 Vicenza, Italy.
  • 24 Center for Rare Disease and Congenital Defects, Fondazione Policlinico Universitario Gemelli, Università Cattolica del Sacro Cuore, 00168 Rome, Italy.
  • 25 Medical Genetics Unit, Policlinico S. Orsola-Malpighi, University of Bologna, 40138 Bologna, Italy.
  • 26 Mindich Child Health and Development Institute and Department of Pediatrics, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
  • 27 Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH 45229, USA; Division of Human Genetics, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA.
  • 28 Genetics and Rare Diseases Research Division, Ospedale Pediatrico Bambino Gesù, IRCCS, 00146 Rome, Italy. Electronic address: marco.tartaglia@opbg.net.
PMID: 32721402 DOI: 10.1016/j.ajhg.2020.06.018
Abstract

Signal transduction through the RAF-MEK-ERK pathway, the first described mitogen-associated protein kinase (MAPK) cascade, mediates multiple cellular processes and participates in early and late developmental programs. Aberrant signaling through this cascade contributes to oncogenesis and underlies the RASopathies, a family of cancer-prone disorders. Here, we report that de novo missense variants in MAPK1, encoding the mitogen-activated protein kinase 1 (i.e., extracellular signal-regulated protein kinase 2, ERK2), cause a neurodevelopmental disease within the RASopathy phenotypic spectrum, reminiscent of Noonan syndrome in some subjects. Pathogenic variants promote increased phosphorylation of the kinase, which enhances translocation to the nucleus and boosts MAPK signaling in vitro and in vivo. Two variant classes are identified, one of which directly disrupts binding to MKP3, a dual-specificity protein Phosphatase negatively regulating ERK function. Importantly, signal dysregulation driven by pathogenic MAPK1 variants is stimulus reliant and retains dependence on MEK activity. Our data support a model in which the identified pathogenic variants operate with counteracting effects on MAPK1 function by differentially impacting the ability of the kinase to interact with regulators and substrates, which likely explains the minor role of these variants as driver events contributing to oncogenesis. After nearly 20 years from the discovery of the first gene implicated in Noonan syndrome, PTPN11, the last tier of the MAPK cascade joins the group of genes mutated in RASopathies.

Keywords

C. elegans; ERK2; MAPK cascade; MKP3; Noonan syndrome; RAS signaling; RASopathies; RSK; exome sequencing; intracellular signaling.

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