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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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American Journal Experts
2023
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9980214/ https://www.ncbi.nlm.nih.gov/pubmed/36865206 http://dx.doi.org/10.21203/rs.3.rs-2580911/v1 |
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author | Rai, Bhavana Naylor, Paige Sanchez, Monica Siqueiros Wintermark, Max Raman, Mira Jo, Booil Reiss, Allan Green, Tamar |
author_facet | Rai, Bhavana Naylor, Paige Sanchez, Monica Siqueiros Wintermark, Max Raman, Mira Jo, Booil Reiss, Allan 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 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-9980214 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
publisher | American Journal Experts |
record_format | MEDLINE/PubMed |
spelling | pubmed-99802142023-03-03 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 Sanchez, Monica Siqueiros Wintermark, Max Raman, Mira Jo, Booil Reiss, Allan Green, Tamar Res Sq 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 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. American Journal Experts 2023-02-21 /pmc/articles/PMC9980214/ /pubmed/36865206 http://dx.doi.org/10.21203/rs.3.rs-2580911/v1 Text en https://creativecommons.org/licenses/by/4.0/This work is licensed under a Creative Commons Attribution 4.0 International License (https://creativecommons.org/licenses/by/4.0/) , which allows reusers to distribute, remix, adapt, and build upon the material in any medium or format, so long as attribution is given to the creator. The license allows for commercial use. https://creativecommons.org/licenses/by/4.0/License: This work is licensed under a Creative Commons Attribution 4.0 International License. Read Full License (https://creativecommons.org/licenses/by/4.0/) |
spellingShingle | Article Rai, Bhavana Naylor, Paige Sanchez, Monica Siqueiros Wintermark, Max Raman, Mira Jo, Booil Reiss, Allan 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/PMC9980214/ https://www.ncbi.nlm.nih.gov/pubmed/36865206 http://dx.doi.org/10.21203/rs.3.rs-2580911/v1 |
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