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Novel effects of Ras-MAPK pathogenic variants on the developing human brain and their link to gene expression and inhibition abilities
The RASopathies are genetic syndromes associated with pathogenic variants causing dysregulation of the Ras/mitogen-activated protein kinase (Ras-MAPK) pathway, essential for brain development, and increased risk for neurodevelopmental disorders. Yet, the effects of most pathogenic variants on the hu...
Autores principales: | , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
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Nature Publishing Group UK
2023
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10322993/ https://www.ncbi.nlm.nih.gov/pubmed/37407569 http://dx.doi.org/10.1038/s41398-023-02504-4 |
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author | Rai, Bhavana Naylor, Paige E. Siqueiros-Sanchez, Monica Wintermark, Max Raman, Mira M. Jo, Booil Reiss, Allan L. Green, Tamar |
author_facet | Rai, Bhavana Naylor, Paige E. Siqueiros-Sanchez, Monica Wintermark, Max Raman, Mira M. Jo, Booil Reiss, Allan L. Green, Tamar |
author_sort | Rai, Bhavana |
collection | PubMed |
description | The RASopathies are genetic syndromes associated with pathogenic variants causing dysregulation of the Ras/mitogen-activated protein kinase (Ras-MAPK) pathway, essential for brain development, and increased risk for neurodevelopmental disorders. Yet, the effects of most pathogenic variants on the human brain are unknown. We examined: (1) How Ras-MAPK activating variants of PTPN11/SOS1 protein-coding genes affect brain anatomy. (2) The relationship between PTPN11 gene expression levels and brain anatomy, and (3) The relevance of subcortical anatomy to attention and memory skills affected in the RASopathies. We collected structural brain MRI and cognitive-behavioral data from 40 pre-pubertal children with Noonan syndrome (NS), caused by PTPN11 (n = 30) or SOS1 (n = 10) variants (age 8.53 ± 2.15, 25 females), and compared them to 40 age- and sex-matched typically developing controls (9.24 ± 1.62, 27 females). We identified widespread effects of NS on cortical and subcortical volumes and on determinants of cortical gray matter volume, surface area (SA), and cortical thickness (CT). In NS, we observed smaller volumes of bilateral striatum, precentral gyri, and primary visual area (d’s < −0.8), and extensive effects on SA (d’s > |0.8|) and CT (d’s > |0.5|) relative to controls. Further, SA effects were associated with increasing PTPN11 gene expression, most prominently in the temporal lobe. Lastly, PTPN11 variants disrupted normative relationships between the striatum and inhibition functioning. We provide evidence for the effects of Ras-MAPK pathogenic variants on striatal and cortical anatomy as well as links between PTPN11 gene expression and cortical SA increases, and striatal volume and inhibition skills. These findings provide essential translational information on the Ras-MAPK pathway’s effect on human brain development and function. |
format | Online Article Text |
id | pubmed-10322993 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
publisher | Nature Publishing Group UK |
record_format | MEDLINE/PubMed |
spelling | pubmed-103229932023-07-07 Novel effects of Ras-MAPK pathogenic variants on the developing human brain and their link to gene expression and inhibition abilities Rai, Bhavana Naylor, Paige E. Siqueiros-Sanchez, Monica Wintermark, Max Raman, Mira M. Jo, Booil Reiss, Allan L. Green, Tamar Transl Psychiatry Article The RASopathies are genetic syndromes associated with pathogenic variants causing dysregulation of the Ras/mitogen-activated protein kinase (Ras-MAPK) pathway, essential for brain development, and increased risk for neurodevelopmental disorders. Yet, the effects of most pathogenic variants on the human brain are unknown. We examined: (1) How Ras-MAPK activating variants of PTPN11/SOS1 protein-coding genes affect brain anatomy. (2) The relationship between PTPN11 gene expression levels and brain anatomy, and (3) The relevance of subcortical anatomy to attention and memory skills affected in the RASopathies. We collected structural brain MRI and cognitive-behavioral data from 40 pre-pubertal children with Noonan syndrome (NS), caused by PTPN11 (n = 30) or SOS1 (n = 10) variants (age 8.53 ± 2.15, 25 females), and compared them to 40 age- and sex-matched typically developing controls (9.24 ± 1.62, 27 females). We identified widespread effects of NS on cortical and subcortical volumes and on determinants of cortical gray matter volume, surface area (SA), and cortical thickness (CT). In NS, we observed smaller volumes of bilateral striatum, precentral gyri, and primary visual area (d’s < −0.8), and extensive effects on SA (d’s > |0.8|) and CT (d’s > |0.5|) relative to controls. Further, SA effects were associated with increasing PTPN11 gene expression, most prominently in the temporal lobe. Lastly, PTPN11 variants disrupted normative relationships between the striatum and inhibition functioning. We provide evidence for the effects of Ras-MAPK pathogenic variants on striatal and cortical anatomy as well as links between PTPN11 gene expression and cortical SA increases, and striatal volume and inhibition skills. These findings provide essential translational information on the Ras-MAPK pathway’s effect on human brain development and function. Nature Publishing Group UK 2023-07-06 /pmc/articles/PMC10322993/ /pubmed/37407569 http://dx.doi.org/10.1038/s41398-023-02504-4 Text en © The Author(s) 2023 https://creativecommons.org/licenses/by/4.0/Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) . |
spellingShingle | Article Rai, Bhavana Naylor, Paige E. Siqueiros-Sanchez, Monica Wintermark, Max Raman, Mira M. Jo, Booil Reiss, Allan L. Green, Tamar Novel effects of Ras-MAPK pathogenic variants on the developing human brain and their link to gene expression and inhibition abilities |
title | Novel effects of Ras-MAPK pathogenic variants on the developing human brain and their link to gene expression and inhibition abilities |
title_full | Novel effects of Ras-MAPK pathogenic variants on the developing human brain and their link to gene expression and inhibition abilities |
title_fullStr | Novel effects of Ras-MAPK pathogenic variants on the developing human brain and their link to gene expression and inhibition abilities |
title_full_unstemmed | Novel effects of Ras-MAPK pathogenic variants on the developing human brain and their link to gene expression and inhibition abilities |
title_short | Novel effects of Ras-MAPK pathogenic variants on the developing human brain and their link to gene expression and inhibition abilities |
title_sort | novel effects of ras-mapk pathogenic variants on the developing human brain and their link to gene expression and inhibition abilities |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10322993/ https://www.ncbi.nlm.nih.gov/pubmed/37407569 http://dx.doi.org/10.1038/s41398-023-02504-4 |
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