{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,25]],"date-time":"2026-09-25T22:54:06Z","timestamp":1790376846142,"version":"4.1.0"},"update-to":[{"DOI":"10.1371\/journal.pgen.1009651","type":"new_version","label":"New version","source":"publisher","updated":{"date-parts":[[2021,7,14]],"date-time":"2021-07-14T00:00:00Z","timestamp":1626220800000}}],"reference-count":59,"publisher":"Public Library of Science (PLoS)","issue":"7","license":[{"start":{"date-parts":[[2021,7,1]],"date-time":"2021-07-01T00:00:00Z","timestamp":1625097600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000057","name":"National Institute of General Medical Sciences","doi-asserted-by":"publisher","award":["2T32GM008243\u20103"],"award-info":[{"award-number":["2T32GM008243\u20103"]}],"id":[{"id":"10.13039\/100000057","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100005337","name":"American Academy of Child and Adolescent Psychiatry","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100005337","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000057","name":"National Institute of General Medical Sciences","doi-asserted-by":"publisher","award":["1R35GM135175-01"],"award-info":[{"award-number":["1R35GM135175-01"]}],"id":[{"id":"10.13039\/100000057","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000057","name":"National Institute of General Medical Sciences","doi-asserted-by":"publisher","award":["1R35GM135175-01"],"award-info":[{"award-number":["1R35GM135175-01"]}],"id":[{"id":"10.13039\/100000057","id-type":"DOI","asserted-by":"publisher"}]},{"name":"UCLA Medical Student Summer Research Fellowship Program in Psychiatry and Biobehavioral Sciences"}],"content-domain":{"domain":["www.plosgenetics.org"],"crossmark-restriction":false},"short-container-title":["PLoS Genet"],"abstract":"<jats:p>Smith-Kingsmore syndrome (SKS) is a rare neurodevelopmental disorder characterized by macrocephaly\/megalencephaly, developmental delay, intellectual disability, hypotonia, and seizures. It is caused by dominant missense mutations in <jats:italic>MTOR<\/jats:italic>. The pathogenicity of novel variants in <jats:italic>MTOR<\/jats:italic> in patients with neurodevelopmental disorders can be difficult to determine and the mechanism by which variants cause disease remains poorly understood. We report 7 patients with SKS with 4 novel <jats:italic>MTOR<\/jats:italic> variants and describe their phenotypes. We perform <jats:italic>in vitro<\/jats:italic> functional analyses to confirm <jats:italic>MTOR<\/jats:italic> activation and interrogate disease mechanisms. We complete structural analyses to understand the 3D properties of pathogenic variants. We examine the accuracy of relative accessible surface area, a quantitative measure of amino acid side-chain accessibility, as a predictor of <jats:italic>MTOR<\/jats:italic> variant pathogenicity.<\/jats:p>\n<jats:p>We describe novel clinical features of patients with SKS. We confirm MTOR Complex 1 activation and identify MTOR Complex 2 activation as a new potential mechanism of disease in SKS. We find that pathogenic <jats:italic>MTOR<\/jats:italic> variants disproportionately cluster in hotspots in the core of the protein, where they disrupt alpha helix packing due to the insertion of bulky amino acid side chains. We find that relative accessible surface area is significantly lower for SKS-associated variants compared to benign variants. We expand the phenotype of SKS and demonstrate that additional pathways of activation may contribute to disease. Incorporating 3D properties of <jats:italic>MTOR<\/jats:italic> variants may help in pathogenicity classification. We hope these findings may contribute to improving the precision of care and therapeutic development for individuals with SKS.<\/jats:p>","DOI":"10.1371\/journal.pgen.1009651","type":"journal-article","created":{"date-parts":[[2021,7,1]],"date-time":"2021-07-01T18:49:06Z","timestamp":1625165346000},"page":"e1009651","update-policy":"https:\/\/doi.org\/10.1371\/journal.pgen.corrections_policy","source":"Crossref","is-referenced-by-count":24,"title":["Functional and structural analyses of novel Smith-Kingsmore Syndrome-Associated MTOR variants reveal potential new mechanisms and predictors of pathogenicity"],"prefix":"10.1371","volume":"17","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-8671-1203","authenticated-orcid":true,"given":"Aaron D.","family":"Besterman","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5688-5328","authenticated-orcid":true,"given":"Thorsten","family":"Althoff","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6684-7114","authenticated-orcid":true,"given":"Peter","family":"Elfferich","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3590-3202","authenticated-orcid":true,"given":"Irma","family":"Gutierrez-Mejia","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9371-893X","authenticated-orcid":true,"given":"Joshua","family":"Sadik","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5369-346X","authenticated-orcid":true,"given":"Jonathan A.","family":"Bernstein","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1055-9855","authenticated-orcid":true,"given":"Yvette","family":"van Ierland","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anja A.","family":"Kattentidt-Mouravieva","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mark","family":"Nellist","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jeff","family":"Abramson","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6776-6949","authenticated-orcid":true,"given":"Julian A.","family":"Martinez-Agosto","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"340","published-online":{"date-parts":[[2021,7,1]]},"reference":[{"key":"pgen.1009651.ref001","doi-asserted-by":"crossref","first-page":"582","DOI":"10.1002\/ajmg.c.31736","article-title":"Megalencephaly syndromes associated with mutations of core components of the PI3K-AKT\u2013MTOR pathway: PIK3CA, PIK3R2, AKT3, and MTOR","author":"WB Dobyns","year":"2019","journal-title":"American Journal of Medical Genetics, Part C: Seminars in Medical Genetics"},{"key":"pgen.1009651.ref002","doi-asserted-by":"crossref","first-page":"402","DOI":"10.1002\/ajmg.c.31531","article-title":"Somatic overgrowth disorders of the PI3K\/AKT\/mTOR pathway & therapeutic strategies","volume":"172","author":"KM Keppler-Noreuil","year":"2016","journal-title":"Am J Med Genet Part C Semin Med Genet"},{"key":"pgen.1009651.ref003","first-page":"762","article-title":"mTOR mutations in Smith-Kingsmore syndrome: Four additional patients and a review","volume":"93","author":"G Gordo","year":"2018","journal-title":"Clin Genet. 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