Annual Review of Genomics and Human Genetics Cognitive Dysfunctions in Intellectual Disabilities: The Contributions of the Ras-MAPK and PI3K-AKT-mTOR Pathways Sarah C. Borrie, 1 Hilde Brems, 1 Eric Legius, 1 and Claudia Bagni 1,2,3 1 Department of Human Genetics, KU Leuven, 3000 Leuven, Belgium 2 Department of Fundamental Neuroscience, University of Lausanne, 1005 Lausanne, Switzerland; email: [email protected] 3 Department of Biomedicine and Prevention, University of Rome Tor Vergata, 00173 Rome, Italy Annu. Rev. Genom. Hum. Genet. 2017. 18:115–42 The Annual Review of Genomics and Human Genetics is online at genom.annualreviews.org https://doi.org/10.1146/annurev-genom-091416- 035332 Copyright c 2017 by Annual Reviews. All rights reserved Keywords synaptic plasticity, FXS, Rasopathy, mTOR, autism, learning disabilities Abstract The Ras-MAPK and PI3K-AKT-mTOR signaling cascades were originally identified as cancer regulatory pathways but have now been demonstrated to be critical for synaptic plasticity and behavior. Neurodevelopmental dis- orders arising from mutations in these pathways exhibit related neurolog- ical phenotypes, including cognitive dysfunction, autism, and intellectual disability. The downstream targets of these pathways include regulation of transcription and protein synthesis. Other disorders that affect protein trans- lation include fragile X syndrome (an important cause of syndromal autism), and other translational regulators are now also linked to autism. Here, we review how mechanisms of synaptic plasticity have been revealed by stud- ies of mouse models for Ras-MAPK, PI3K-AKT-mTOR, and translation regulatory pathway disorders. We discuss the face validity of these mouse models and review current progress in clinical trials directed at ameliorating cognitive and behavioral symptoms. 115 Click here to view this article's online features: • Download figures as PPT slides • Navigate linked references • Download citations • Explore related articles • Search keywords ANNUAL REVIEWS Further Annu. Rev. Genom. Hum. Genet. 2017.18:115-142. Downloaded from www.annualreviews.org Access provided by 171.243.67.90 on 05/30/23. For personal use only.
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