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

Marialetizia Motta, Luca Pannone, Francesca Pantaleoni, Gianfranco Bocchinfuso, Francesca Clementina Radio, Serena Cecchetti, Andrea Ciolfi, Martina Di Rocco, Mariet W. Elting, Eva H. Brilstra, Stefania Boni, Laura Mazzanti, Federica Tamburrino, Larry Walsh, Katelyn Payne, Alberto Fernández-Jaén, Mythily Ganapathi, Wendy K. Chung, Dorothy K. Grange, Ashita Dave-WalaShalini C. Reshmi, Dennis W. Bartholomew, Danielle Mouhlas, Giovanna Carpentieri, Alessandro Bruselles, Simone Pizzi, Emanuele Bellacchio, Francesca Piceci-Sparascio, Christina Lißewski, Julia Brinkmann, Ronald R. Waclaw, Quinten Waisfisz, Koen van Gassen, Ingrid M. Wentzensen, Michelle M. Morrow, Sara Álvarez, Mónica Martínez-García, Alessandro De Luca, Luigi Memo, Giuseppe Zampino, Cesare Rossi, Marco Seri, Bruce D. Gelb, Martin Zenker, Bruno Dallapiccola, Lorenzo Stella, Carlos E. Prada, Simone Martinelli, Elisabetta Flex, Marco Tartaglia

Research output: Contribution to journalArticlepeer-review

51 Scopus citations


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.

Original languageEnglish
Pages (from-to)499-513
Number of pages15
JournalAmerican journal of human genetics
Issue number3
StatePublished - Sep 3 2020


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


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