Translating the Role of mTOR- and RAS-Associated Signalopathies in Autism Spectrum Disorder: Models, Mechanisms and Treatment
Mutations affecting mTOR or RAS signaling underlie defined syndromes (the so-called mTORopathies and RASopathies) with high risk for Autism Spectrum Disorder (ASD). These syndromes show a broad variety of somatic phenotypes including cancers, skin abnormalities, heart disease and facial dysmorphisms...
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oai:doaj.org-article:a1e112a6b0604051859be71f92fc7c752021-11-25T17:41:28ZTranslating the Role of mTOR- and RAS-Associated Signalopathies in Autism Spectrum Disorder: Models, Mechanisms and Treatment10.3390/genes121117462073-4425https://doaj.org/article/a1e112a6b0604051859be71f92fc7c752021-10-01T00:00:00Zhttps://www.mdpi.com/2073-4425/12/11/1746https://doaj.org/toc/2073-4425Mutations affecting mTOR or RAS signaling underlie defined syndromes (the so-called mTORopathies and RASopathies) with high risk for Autism Spectrum Disorder (ASD). These syndromes show a broad variety of somatic phenotypes including cancers, skin abnormalities, heart disease and facial dysmorphisms. Less well studied are the neuropsychiatric symptoms such as ASD. Here, we assess the relevance of these signalopathies in ASD reviewing genetic, human cell model, rodent studies and clinical trials. We conclude that signalopathies have an increased liability for ASD and that, in particular, ASD individuals with dysmorphic features and intellectual disability (ID) have a higher chance for disruptive mutations in RAS- and mTOR-related genes. Studies on rodent and human cell models confirm aberrant neuronal development as the underlying pathology. Human studies further suggest that multiple hits are necessary to induce the respective phenotypes. Recent clinical trials do only report improvements for comorbid conditions such as epilepsy or cancer but not for behavioral aspects. Animal models show that treatment during early development can rescue behavioral phenotypes. Taken together, we suggest investigating the differential roles of mTOR and RAS signaling in both human and rodent models, and to test drug treatment both during and after neuronal development in the available model systems.Verica VasicMattson S. O. JonesDenise HaslingerLisa S. KnausMichael J. SchmeisserGaia NovarinoAndreas G. ChiocchettiMDPI AGarticleAutism Spectrum DisordermTORRASintellectual disabilityGeneticsQH426-470ENGenes, Vol 12, Iss 1746, p 1746 (2021) |
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Autism Spectrum Disorder mTOR RAS intellectual disability Genetics QH426-470 |
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Autism Spectrum Disorder mTOR RAS intellectual disability Genetics QH426-470 Verica Vasic Mattson S. O. Jones Denise Haslinger Lisa S. Knaus Michael J. Schmeisser Gaia Novarino Andreas G. Chiocchetti Translating the Role of mTOR- and RAS-Associated Signalopathies in Autism Spectrum Disorder: Models, Mechanisms and Treatment |
description |
Mutations affecting mTOR or RAS signaling underlie defined syndromes (the so-called mTORopathies and RASopathies) with high risk for Autism Spectrum Disorder (ASD). These syndromes show a broad variety of somatic phenotypes including cancers, skin abnormalities, heart disease and facial dysmorphisms. Less well studied are the neuropsychiatric symptoms such as ASD. Here, we assess the relevance of these signalopathies in ASD reviewing genetic, human cell model, rodent studies and clinical trials. We conclude that signalopathies have an increased liability for ASD and that, in particular, ASD individuals with dysmorphic features and intellectual disability (ID) have a higher chance for disruptive mutations in RAS- and mTOR-related genes. Studies on rodent and human cell models confirm aberrant neuronal development as the underlying pathology. Human studies further suggest that multiple hits are necessary to induce the respective phenotypes. Recent clinical trials do only report improvements for comorbid conditions such as epilepsy or cancer but not for behavioral aspects. Animal models show that treatment during early development can rescue behavioral phenotypes. Taken together, we suggest investigating the differential roles of mTOR and RAS signaling in both human and rodent models, and to test drug treatment both during and after neuronal development in the available model systems. |
format |
article |
author |
Verica Vasic Mattson S. O. Jones Denise Haslinger Lisa S. Knaus Michael J. Schmeisser Gaia Novarino Andreas G. Chiocchetti |
author_facet |
Verica Vasic Mattson S. O. Jones Denise Haslinger Lisa S. Knaus Michael J. Schmeisser Gaia Novarino Andreas G. Chiocchetti |
author_sort |
Verica Vasic |
title |
Translating the Role of mTOR- and RAS-Associated Signalopathies in Autism Spectrum Disorder: Models, Mechanisms and Treatment |
title_short |
Translating the Role of mTOR- and RAS-Associated Signalopathies in Autism Spectrum Disorder: Models, Mechanisms and Treatment |
title_full |
Translating the Role of mTOR- and RAS-Associated Signalopathies in Autism Spectrum Disorder: Models, Mechanisms and Treatment |
title_fullStr |
Translating the Role of mTOR- and RAS-Associated Signalopathies in Autism Spectrum Disorder: Models, Mechanisms and Treatment |
title_full_unstemmed |
Translating the Role of mTOR- and RAS-Associated Signalopathies in Autism Spectrum Disorder: Models, Mechanisms and Treatment |
title_sort |
translating the role of mtor- and ras-associated signalopathies in autism spectrum disorder: models, mechanisms and treatment |
publisher |
MDPI AG |
publishDate |
2021 |
url |
https://doaj.org/article/a1e112a6b0604051859be71f92fc7c75 |
work_keys_str_mv |
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1718412120780963840 |