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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: Besterman, Aaron D., Althoff, Thorsten, Elfferich, Peter, Gutierrez-Mejia, Irma, Sadik, Joshua, Bernstein, Jonathan A., van Ierland, Yvette, Kattentidt-Mouravieva, Anja A., Nellist, Mark, Abramson, Jeff, Martinez-Agosto, Julian A.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8279410/
https://www.ncbi.nlm.nih.gov/pubmed/34197453
http://dx.doi.org/10.1371/journal.pgen.1009651
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author Besterman, Aaron D.
Althoff, Thorsten
Elfferich, Peter
Gutierrez-Mejia, Irma
Sadik, Joshua
Bernstein, Jonathan A.
van Ierland, Yvette
Kattentidt-Mouravieva, Anja A.
Nellist, Mark
Abramson, Jeff
Martinez-Agosto, Julian A.
author_facet Besterman, Aaron D.
Althoff, Thorsten
Elfferich, Peter
Gutierrez-Mejia, Irma
Sadik, Joshua
Bernstein, Jonathan A.
van Ierland, Yvette
Kattentidt-Mouravieva, Anja A.
Nellist, Mark
Abramson, Jeff
Martinez-Agosto, Julian A.
author_sort Besterman, Aaron D.
collection PubMed
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.
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spelling pubmed-82794102021-07-26 Functional and structural analyses of novel Smith-Kingsmore Syndrome-Associated MTOR variants reveal potential new mechanisms and predictors of pathogenicity Besterman, Aaron D. Althoff, Thorsten Elfferich, Peter Gutierrez-Mejia, Irma Sadik, Joshua Bernstein, Jonathan A. van Ierland, Yvette Kattentidt-Mouravieva, Anja A. Nellist, Mark Abramson, Jeff Martinez-Agosto, Julian A. PLoS Genet Research Article 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. Public Library of Science 2021-07-01 /pmc/articles/PMC8279410/ /pubmed/34197453 http://dx.doi.org/10.1371/journal.pgen.1009651 Text en © 2021 Besterman et al https://creativecommons.org/licenses/by/4.0/This is an open access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
spellingShingle Research Article
Besterman, Aaron D.
Althoff, Thorsten
Elfferich, Peter
Gutierrez-Mejia, Irma
Sadik, Joshua
Bernstein, Jonathan A.
van Ierland, Yvette
Kattentidt-Mouravieva, Anja A.
Nellist, Mark
Abramson, Jeff
Martinez-Agosto, Julian A.
Functional and structural analyses of novel Smith-Kingsmore Syndrome-Associated MTOR variants reveal potential new mechanisms and predictors of pathogenicity
title 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_short 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
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8279410/
https://www.ncbi.nlm.nih.gov/pubmed/34197453
http://dx.doi.org/10.1371/journal.pgen.1009651
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