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...

Descripción completa

Guardado en:
Detalles Bibliográficos
Autores principales: Verica Vasic, Mattson S. O. Jones, Denise Haslinger, Lisa S. Knaus, Michael J. Schmeisser, Gaia Novarino, Andreas G. Chiocchetti
Formato: article
Lenguaje:EN
Publicado: MDPI AG 2021
Materias:
RAS
Acceso en línea:https://doaj.org/article/a1e112a6b0604051859be71f92fc7c75
Etiquetas: Agregar Etiqueta
Sin Etiquetas, Sea el primero en etiquetar este registro!
id oai:doaj.org-article:a1e112a6b0604051859be71f92fc7c75
record_format dspace
spelling 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)
institution DOAJ
collection DOAJ
language EN
topic Autism Spectrum Disorder
mTOR
RAS
intellectual disability
Genetics
QH426-470
spellingShingle 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 AT vericavasic translatingtheroleofmtorandrasassociatedsignalopathiesinautismspectrumdisordermodelsmechanismsandtreatment
AT mattsonsojones translatingtheroleofmtorandrasassociatedsignalopathiesinautismspectrumdisordermodelsmechanismsandtreatment
AT denisehaslinger translatingtheroleofmtorandrasassociatedsignalopathiesinautismspectrumdisordermodelsmechanismsandtreatment
AT lisasknaus translatingtheroleofmtorandrasassociatedsignalopathiesinautismspectrumdisordermodelsmechanismsandtreatment
AT michaeljschmeisser translatingtheroleofmtorandrasassociatedsignalopathiesinautismspectrumdisordermodelsmechanismsandtreatment
AT gaianovarino translatingtheroleofmtorandrasassociatedsignalopathiesinautismspectrumdisordermodelsmechanismsandtreatment
AT andreasgchiocchetti translatingtheroleofmtorandrasassociatedsignalopathiesinautismspectrumdisordermodelsmechanismsandtreatment
_version_ 1718412120780963840