@article{cab57c44678d4c78ba64277f69afc146,
title = "Enhanced MAPK1 Function Causes a Neurodevelopmental Disorder within the RASopathy Clinical Spectrum",
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, Carcinogenesis, Child, Preschool, ERK2, Female, Humans, MAP Kinase Signaling System, MAPK cascade, MKP3, Male, Mitogen-Activated Protein Kinase 1, Mutation, Missense, Neurodevelopmental Disorders, Noonan Syndrome, Noonan syndrome, Phenotype, Protein Tyrosine Phosphatase, Non-Receptor Type 11, RAS signaling, RASopathies, RSK, Signal Transduction, Whole Exome Sequencing, exome sequencing, intracellular signaling, ras Proteins, C. elegans, Carcinogenesis, Child, Preschool, ERK2, Female, Humans, MAP Kinase Signaling System, MAPK cascade, MKP3, Male, Mitogen-Activated Protein Kinase 1, Mutation, Missense, Neurodevelopmental Disorders, Noonan Syndrome, Noonan syndrome, Phenotype, Protein Tyrosine Phosphatase, Non-Receptor Type 11, RAS signaling, RASopathies, RSK, Signal Transduction, Whole Exome Sequencing, exome sequencing, intracellular signaling, ras Proteins",
author = "Giuseppe Zampino and Marialetizia Motta and Luca Pannone and Francesca Pantaleoni and Gianfranco Bocchinfuso and Radio, {Francesca Clementina} and Serena Cecchetti and Andrea Ciolfi and {Di Rocco}, Martina and Elting, {Mariet W.} and Brilstra, {Eva H.} and Stefania Boni and Laura Mazzanti and Federica Tamburrino and Larry Walsh and Katelyn Payne and Alberto Fern{\'a}ndez-Ja{\'e}n and Mythily Ganapathi and Chung, {Wendy K.} and Grange, {Dorothy K.} and Ashita Dave-Wala and Reshmi, {Shalini C.} and Bartholomew, {Dennis W.} and Danielle Mouhlas and Giovanna Carpentieri and Alessandro Bruselles and Simone Pizzi and Emanuele Bellacchio and Francesca Piceci-Sparascio and Christina Li{\ss}ewski and Julia Brinkmann and Waclaw, {Ronald R.} and Quinten Waisfisz and {Van Gassen}, Koen and Wentzensen, {Ingrid M.} and Morrow, {Michelle M.} and Sara {\'A}lvarez and M{\'o}nica Mart{\'i}nez-Garc{\'i}a and {De Luca}, Alessandro and Luigi Memo and Cesare Rossi and Marco Seri and Gelb, {Bruce D.} and Martin Zenker and Bruno Dallapiccola and Lorenzo Stella and Prada, {Carlos E.} and Simone Martinelli and Elisabetta Flex and Marco Tartaglia",
year = "2020",
doi = "10.1016/j.ajhg.2020.06.018",
language = "English",
volume = "107",
pages = "499--513",
journal = "American Journal of Human Genetics",
issn = "0002-9297",
publisher = "University of Chicago Press:PO Box 37005, Journals Division:Chicago, IL 60637:(877)705-1878, (877)705-1878, (773)753-2247, EMAIL: subscriptions@press.uchicago.edu, INTERNET: http://www.press.uchicago.edu, Fax: (877)705-1879, (773)753-0811",
}