TY - JOUR
T1 - Enhanced MAPK1 Function Causes a Neurodevelopmental Disorder within the RASopathy Clinical Spectrum
AU - Motta, Marialetizia
AU - Pannone, Luca
AU - Pantaleoni, Francesca
AU - Bocchinfuso, Gianfranco
AU - Radio, Francesca Clementina
AU - Cecchetti, Serena
AU - Ciolfi, Andrea
AU - Di Rocco, Martina
AU - Elting, Mariet W.
AU - Brilstra, Eva H.
AU - Boni, Stefania
AU - Mazzanti, Laura
AU - Tamburrino, Federica
AU - Walsh, Larry
AU - Payne, Katelyn
AU - Fernández-Jaén, Alberto
AU - Ganapathi, Mythily
AU - Chung, Wendy K.
AU - Grange, Dorothy K.
AU - Dave-Wala, Ashita
AU - Reshmi, Shalini C.
AU - Bartholomew, Dennis W.
AU - Mouhlas, Danielle
AU - Carpentieri, Giovanna
AU - Bruselles, Alessandro
AU - Pizzi, Simone
AU - Bellacchio, Emanuele
AU - Piceci-Sparascio, Francesca
AU - Lißewski, Christina
AU - Brinkmann, Julia
AU - Waclaw, Ronald R.
AU - Waisfisz, Quinten
AU - Van Gassen, Koen
AU - Wentzensen, Ingrid M.
AU - Morrow, Michelle M.
AU - Álvarez, Sara
AU - Martínez-García, Mónica
AU - De Luca, Alessandro
AU - Memo, Luigi
AU - Zampino, Giuseppe
AU - Rossi, Cesare
AU - Seri, Marco
AU - Gelb, Bruce D.
AU - Zenker, Martin
AU - Dallapiccola, Bruno
AU - Stella, Lorenzo
AU - Prada, Carlos E.
AU - Martinelli, Simone
AU - Flex, Elisabetta
AU - Tartaglia, Marco
PY - 2020
Y1 - 2020
N2 - 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.
AB - 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.
KW - C. elegans
KW - Carcinogenesis
KW - Child, Preschool
KW - ERK2
KW - Female
KW - Humans
KW - MAP Kinase Signaling System
KW - MAPK cascade
KW - MKP3
KW - Male
KW - Mitogen-Activated Protein Kinase 1
KW - Mutation, Missense
KW - Neurodevelopmental Disorders
KW - Noonan Syndrome
KW - Noonan syndrome
KW - Phenotype
KW - Protein Tyrosine Phosphatase, Non-Receptor Type 11
KW - RAS signaling
KW - RASopathies
KW - RSK
KW - Signal Transduction
KW - Whole Exome Sequencing
KW - exome sequencing
KW - intracellular signaling
KW - ras Proteins
KW - C. elegans
KW - Carcinogenesis
KW - Child, Preschool
KW - ERK2
KW - Female
KW - Humans
KW - MAP Kinase Signaling System
KW - MAPK cascade
KW - MKP3
KW - Male
KW - Mitogen-Activated Protein Kinase 1
KW - Mutation, Missense
KW - Neurodevelopmental Disorders
KW - Noonan Syndrome
KW - Noonan syndrome
KW - Phenotype
KW - Protein Tyrosine Phosphatase, Non-Receptor Type 11
KW - RAS signaling
KW - RASopathies
KW - RSK
KW - Signal Transduction
KW - Whole Exome Sequencing
KW - exome sequencing
KW - intracellular signaling
KW - ras Proteins
UR - http://hdl.handle.net/10807/166663
U2 - 10.1016/j.ajhg.2020.06.018
DO - 10.1016/j.ajhg.2020.06.018
M3 - Article
SN - 0002-9297
VL - 107
SP - 499
EP - 513
JO - American Journal of Human Genetics
JF - American Journal of Human Genetics
ER -