Academic Journal
Enhanced MAPK1 Function Causes a Neurodevelopmental Disorder within the RASopathy Clinical Spectrum
| العنوان: | Enhanced MAPK1 Function Causes a Neurodevelopmental Disorder within the RASopathy Clinical Spectrum |
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| المؤلفون: | Motta M., Pannone L., Pantaleoni F., Bocchinfuso G., Radio F. C., Cecchetti S., Ciolfi A., Di Rocco M., Elting M. W., Brilstra E. H., Boni S., Mazzanti L., Tamburrino F., Walsh L., Payne K., Fernandez-Jaen A., Ganapathi M., Chung W. K., Grange D. K., Dave-Wala A., Reshmi S. C., Bartholomew D. W., Mouhlas D., Carpentieri G., Bruselles A., Pizzi S., Bellacchio E., Piceci-Sparascio F., Lissewski C., Brinkmann J., Waclaw R. R., Waisfisz Q., van Gassen K., Wentzensen I. M., Morrow M. M., Alvarez S., Martinez-Garcia M., De Luca A., Memo L., Zampino G., Rossi C., Seri M., Gelb B. D., Zenker M., Dallapiccola B., Stella L., Prada C. E., Martinelli S., Flex E., Tartaglia M. |
| المساهمون: | Motta, M., Pannone, L., Pantaleoni, F., Bocchinfuso, G., Radio, F. C., Cecchetti, S., Ciolfi, A., Di Rocco, M., Elting, M. W., Brilstra, E. H., Boni, S., Mazzanti, L., Tamburrino, F., Walsh, L., Payne, K., Fernandez-Jaen, A., Ganapathi, M., Chung, W. K., Grange, D. K., Dave-Wala, A., Reshmi, S. C., Bartholomew, D. W., Mouhlas, D., Carpentieri, G., Bruselles, A., Pizzi, S., Bellacchio, E., Piceci-Sparascio, F., Lissewski, C., Brinkmann, J., Waclaw, R. R., Waisfisz, Q., van Gassen, K., Wentzensen, I. M., Morrow, M. M., Alvarez, S., Martinez-Garcia, M., De Luca, A., Memo, L., Zampino, G., Rossi, C., Seri, M., Gelb, B. D., Zenker, M., Dallapiccola, B., Stella, L., Prada, C. E., Martinelli, S., Flex, E., Tartaglia, M. |
| بيانات النشر: | Cell Press 50 HAMPSHIRE ST, FLOOR 5, CAMBRIDGE, MA 02139 USA |
| سنة النشر: | 2020 |
| المجموعة: | Sapienza Università di Roma: CINECA IRIS |
| مصطلحات موضوعية: | C. elegan, ERK2, exome sequencing, intracellular signaling, MAPK cascade, MKP3, Noonan syndrome, RAS signaling, RASopathie, RSK, Carcinogenesi, Child, Preschool, Female, Human, MAP Kinase Signaling System, Male, Mitogen-Activated Protein Kinase 1, Mutation, Missense, Neurodevelopmental Disorder, Phenotype, Protein Tyrosine Phosphatase, Non-Receptor Type 11, Signal Transduction, Whole Exome Sequencing, ras Proteins |
| الوصف: | 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. |
| نوع الوثيقة: | article in journal/newspaper |
| اللغة: | English |
| Relation: | info:eu-repo/semantics/altIdentifier/pmid/32721402; info:eu-repo/semantics/altIdentifier/wos/WOS:000565899700010; volume:107; issue:3; firstpage:499; lastpage:513; numberofpages:15; journal:AMERICAN JOURNAL OF HUMAN GENETICS; http://hdl.handle.net/11573/1554965; info:eu-repo/semantics/altIdentifier/scopus/2-s2.0-85089385871 |
| DOI: | 10.1016/j.ajhg.2020.06.018 |
| الاتاحة: | http://hdl.handle.net/11573/1554965 https://doi.org/10.1016/j.ajhg.2020.06.018 |
| رقم الانضمام: | edsbas.FC222232 |
| قاعدة البيانات: | BASE |
| DOI: | 10.1016/j.ajhg.2020.06.018 |
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