Functional and structural analyses of novel Smith-Kingsmore Syndrome-Associated MTOR variants reveal potential new mechanisms and predictors of pathogenicity.

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 MTOR. The pathogenicity of novel variants in MTOR in patients with...

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Autores principales:	Aaron D Besterman, Thorsten Althoff, Peter Elfferich, Irma Gutierrez-Mejia, Joshua Sadik, Jonathan A Bernstein, Yvette van Ierland, Anja A Kattentidt-Mouravieva, Mark Nellist, Jeff Abramson, Julian A Martinez-Agosto
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2021
Materias:	Genetics QH426-470
Acceso en línea:	https://doaj.org/article/f757fb86f4094e309faddeac52736bbc
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spelling	oai:doaj.org-article:f757fb86f4094e309faddeac52736bbc2021-12-02T20:02:58ZFunctional and structural analyses of novel Smith-Kingsmore Syndrome-Associated MTOR variants reveal potential new mechanisms and predictors of pathogenicity.1553-73901553-740410.1371/journal.pgen.1009651https://doaj.org/article/f757fb86f4094e309faddeac52736bbc2021-07-01T00:00:00Zhttps://doi.org/10.1371/journal.pgen.1009651https://doaj.org/toc/1553-7390https://doaj.org/toc/1553-7404Smith-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 MTOR. The pathogenicity of novel variants in MTOR 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 MTOR variants and describe their phenotypes. We perform in vitro functional analyses to confirm MTOR 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 MTOR variant pathogenicity. 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 MTOR 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 MTOR 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.Aaron D BestermanThorsten AlthoffPeter ElfferichIrma Gutierrez-MejiaJoshua SadikJonathan A BernsteinYvette van IerlandAnja A Kattentidt-MouravievaMark NellistJeff AbramsonJulian A Martinez-AgostoPublic Library of Science (PLoS)articleGeneticsQH426-470ENPLoS Genetics, Vol 17, Iss 7, p e1009651 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Genetics QH426-470
spellingShingle	Genetics QH426-470 Aaron D Besterman Thorsten Althoff Peter Elfferich Irma Gutierrez-Mejia Joshua Sadik Jonathan A Bernstein Yvette van Ierland Anja A Kattentidt-Mouravieva Mark Nellist Jeff Abramson Julian A Martinez-Agosto Functional and structural analyses of novel Smith-Kingsmore Syndrome-Associated MTOR variants reveal potential new mechanisms and predictors of pathogenicity.
description	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 MTOR. The pathogenicity of novel variants in MTOR 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 MTOR variants and describe their phenotypes. We perform in vitro functional analyses to confirm MTOR 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 MTOR variant pathogenicity. 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 MTOR 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 MTOR 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.
format	article
author	Aaron D Besterman Thorsten Althoff Peter Elfferich Irma Gutierrez-Mejia Joshua Sadik Jonathan A Bernstein Yvette van Ierland Anja A Kattentidt-Mouravieva Mark Nellist Jeff Abramson Julian A Martinez-Agosto
author_facet	Aaron D Besterman Thorsten Althoff Peter Elfferich Irma Gutierrez-Mejia Joshua Sadik Jonathan A Bernstein Yvette van Ierland Anja A Kattentidt-Mouravieva Mark Nellist Jeff Abramson Julian A Martinez-Agosto
author_sort	Aaron D Besterman
title	Functional and structural analyses of novel Smith-Kingsmore Syndrome-Associated MTOR variants reveal potential new mechanisms and predictors of pathogenicity.
title_short	Functional and structural analyses of novel Smith-Kingsmore Syndrome-Associated MTOR variants reveal potential new mechanisms and predictors of pathogenicity.
title_full	Functional and structural analyses of novel Smith-Kingsmore Syndrome-Associated MTOR variants reveal potential new mechanisms and predictors of pathogenicity.
title_fullStr	Functional and structural analyses of novel Smith-Kingsmore Syndrome-Associated MTOR variants reveal potential new mechanisms and predictors of pathogenicity.
title_full_unstemmed	Functional and structural analyses of novel Smith-Kingsmore Syndrome-Associated MTOR variants reveal potential new mechanisms and predictors of pathogenicity.
title_sort	functional and structural analyses of novel smith-kingsmore syndrome-associated mtor variants reveal potential new mechanisms and predictors of pathogenicity.
publisher	Public Library of Science (PLoS)
publishDate	2021
url	https://doaj.org/article/f757fb86f4094e309faddeac52736bbc
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Functional and structural analyses of novel Smith-Kingsmore Syndrome-Associated MTOR variants reveal potential new mechanisms and predictors of pathogenicity.

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