{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,25]],"date-time":"2026-02-25T01:43:25Z","timestamp":1771983805411,"version":"3.50.1"},"reference-count":194,"publisher":"MDPI AG","issue":"11","license":[{"start":{"date-parts":[[2021,10,30]],"date-time":"2021-10-30T00:00:00Z","timestamp":1635552000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100002347","name":"Federal Ministry of Education and Research","doi-asserted-by":"publisher","award":["779282"],"award-info":[{"award-number":["779282"]}],"id":[{"id":"10.13039\/501100002347","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100002347","name":"Federal Ministry of Education and Research","doi-asserted-by":"publisher","award":["GeNeRARe 01GM1519A"],"award-info":[{"award-number":["GeNeRARe 01GM1519A"]}],"id":[{"id":"10.13039\/501100002347","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100002428","name":"FWF Austrian Science Fund","doi-asserted-by":"publisher","award":["DK W1232-B24"],"award-info":[{"award-number":["DK W1232-B24"]}],"id":[{"id":"10.13039\/501100002428","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000780","name":"European Commission","doi-asserted-by":"publisher","award":["Aims-2 Trials 777394"],"award-info":[{"award-number":["Aims-2 Trials 777394"]}],"id":[{"id":"10.13039\/501100000780","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100010663","name":"European Research Council","doi-asserted-by":"publisher","award":["715508 (REVERSEAUTISM)"],"award-info":[{"award-number":["715508 (REVERSEAUTISM)"]}],"id":[{"id":"10.13039\/100010663","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001659","name":"Deutsche Forschungsgemeinschaft","doi-asserted-by":"publisher","award":["CRC 1080, project B10"],"award-info":[{"award-number":["CRC 1080, project B10"]}],"id":[{"id":"10.13039\/501100001659","id-type":"DOI","asserted-by":"publisher"}]},{"name":"State of Hesse Ministry for Science and Arts","award":["LOEWE-Grant to the CePTER-Consortium (www. uni-frankfurt.de\/67689811)"],"award-info":[{"award-number":["LOEWE-Grant to the CePTER-Consortium (www. uni-frankfurt.de\/67689811)"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Genes"],"abstract":"<jats:p>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.<\/jats:p>","DOI":"10.3390\/genes12111746","type":"journal-article","created":{"date-parts":[[2021,11,1]],"date-time":"2021-11-01T22:21:08Z","timestamp":1635805268000},"page":"1746","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":15,"title":["Translating the Role of mTOR- and RAS-Associated Signalopathies in Autism Spectrum Disorder: Models, Mechanisms and Treatment"],"prefix":"10.3390","volume":"12","author":[{"given":"Verica","family":"Vasic","sequence":"first","affiliation":[{"name":"Institute for Microscopic Anatomy and Neurobiology, University Medical Center of the Johannes Gutenberg-University, 55131 Mainz, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mattson S. O.","family":"Jones","sequence":"additional","affiliation":[{"name":"Autism Therapy and Research Center of Excellence, Department of Child and Adolescent Psychiatry, Psychosomatics and Psychotherapy, University Hospital Frankfurt, 60528 Frankfurt am Main, Germany"},{"name":"Center for Personalized Translational Epilepsy Research (CePTER), Goethe University Frankfurt, 60528 Frankfurt am Main, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Denise","family":"Haslinger","sequence":"additional","affiliation":[{"name":"Autism Therapy and Research Center of Excellence, Department of Child and Adolescent Psychiatry, Psychosomatics and Psychotherapy, University Hospital Frankfurt, 60528 Frankfurt am Main, Germany"},{"name":"Institute of Science and Technology (IST) Austria, 3400 Klosterneuburg, Austria"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lisa S.","family":"Knaus","sequence":"additional","affiliation":[{"name":"Institute of Science and Technology (IST) Austria, 3400 Klosterneuburg, Austria"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Michael J.","family":"Schmeisser","sequence":"additional","affiliation":[{"name":"Institute for Microscopic Anatomy and Neurobiology, University Medical Center of the Johannes Gutenberg-University, 55131 Mainz, Germany"},{"name":"Focus Program Translational Neurosciences (FTN), University Medical Center of the Johannes Gutenberg-University, 55131 Mainz, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Gaia","family":"Novarino","sequence":"additional","affiliation":[{"name":"Institute of Science and Technology (IST) Austria, 3400 Klosterneuburg, Austria"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7329-9985","authenticated-orcid":false,"given":"Andreas G.","family":"Chiocchetti","sequence":"additional","affiliation":[{"name":"Autism Therapy and Research Center of Excellence, Department of Child and Adolescent Psychiatry, Psychosomatics and Psychotherapy, University Hospital Frankfurt, 60528 Frankfurt am Main, Germany"},{"name":"Center for Personalized Translational Epilepsy Research (CePTER), Goethe University Frankfurt, 60528 Frankfurt am Main, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2021,10,30]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1182","DOI":"10.1001\/jama.2017.12141","article-title":"The Heritability of Autism Spectrum Disorder","volume":"318","author":"Sandin","year":"2017","journal-title":"JAMA"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"183","DOI":"10.1038\/s41580-019-0199-y","article-title":"mTOR at the nexus of nutrition, growth, ageing and disease","volume":"21","author":"Liu","year":"2020","journal-title":"Nat. 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