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16p13.11 deletion variants associated with neuropsychiatric disorders cause morphological and synaptic changes in induced pluripotent stem cell-derived neurons
16p13.11 copy number variants (CNVs) have been associated with autism, schizophrenia, psychosis, intellectual disability, and epilepsy. The majority of 16p13.11 deletions or duplications occur within three well-defined intervals, and despite growing knowledge of the functions of individual genes wit...
Autores principales: | , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Frontiers Media S.A.
2022
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9669751/ https://www.ncbi.nlm.nih.gov/pubmed/36405918 http://dx.doi.org/10.3389/fpsyt.2022.924956 |
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author | Buttermore, Elizabeth D. Anderson, Nickesha C. Chen, Pin-Fang Makhortova, Nina R. Kim, Kristina H. Wafa, Syed M. A. Dwyer, Sean Micozzi, John M. Winden, Kellen D. Zhang, Bo Han, Min-Joon Kleiman, Robin J. Brownstein, Catherine A. Sahin, Mustafa Gonzalez-Heydrich, Joseph |
author_facet | Buttermore, Elizabeth D. Anderson, Nickesha C. Chen, Pin-Fang Makhortova, Nina R. Kim, Kristina H. Wafa, Syed M. A. Dwyer, Sean Micozzi, John M. Winden, Kellen D. Zhang, Bo Han, Min-Joon Kleiman, Robin J. Brownstein, Catherine A. Sahin, Mustafa Gonzalez-Heydrich, Joseph |
author_sort | Buttermore, Elizabeth D. |
collection | PubMed |
description | 16p13.11 copy number variants (CNVs) have been associated with autism, schizophrenia, psychosis, intellectual disability, and epilepsy. The majority of 16p13.11 deletions or duplications occur within three well-defined intervals, and despite growing knowledge of the functions of individual genes within these intervals, the molecular mechanisms that underlie commonly observed clinical phenotypes remain largely unknown. Patient-derived, induced pluripotent stem cells (iPSCs) provide a platform for investigating the morphological, electrophysiological, and gene-expression changes that result from 16p13.11 CNVs in human-derived neurons. Patient derived iPSCs with varying sizes of 16p13.11 deletions and familial controls were differentiated into cortical neurons for phenotypic analysis. High-content imaging and morphological analysis of patient-derived neurons demonstrated an increase in neurite branching in patients compared with controls. Whole-transcriptome sequencing revealed expression level changes in neuron development and synaptic-related gene families, suggesting a defect in synapse formation. Subsequent quantification of synapse number demonstrated increased numbers of synapses on neurons derived from early-onset patients compared to controls. The identification of common phenotypes among neurons derived from patients with overlapping 16p13.11 deletions will further assist in ascertaining common pathways and targets that could be utilized for screening drug candidates. These studies can help to improve future treatment options and clinical outcomes for 16p13.11 deletion patients. |
format | Online Article Text |
id | pubmed-9669751 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | Frontiers Media S.A. |
record_format | MEDLINE/PubMed |
spelling | pubmed-96697512022-11-18 16p13.11 deletion variants associated with neuropsychiatric disorders cause morphological and synaptic changes in induced pluripotent stem cell-derived neurons Buttermore, Elizabeth D. Anderson, Nickesha C. Chen, Pin-Fang Makhortova, Nina R. Kim, Kristina H. Wafa, Syed M. A. Dwyer, Sean Micozzi, John M. Winden, Kellen D. Zhang, Bo Han, Min-Joon Kleiman, Robin J. Brownstein, Catherine A. Sahin, Mustafa Gonzalez-Heydrich, Joseph Front Psychiatry Psychiatry 16p13.11 copy number variants (CNVs) have been associated with autism, schizophrenia, psychosis, intellectual disability, and epilepsy. The majority of 16p13.11 deletions or duplications occur within three well-defined intervals, and despite growing knowledge of the functions of individual genes within these intervals, the molecular mechanisms that underlie commonly observed clinical phenotypes remain largely unknown. Patient-derived, induced pluripotent stem cells (iPSCs) provide a platform for investigating the morphological, electrophysiological, and gene-expression changes that result from 16p13.11 CNVs in human-derived neurons. Patient derived iPSCs with varying sizes of 16p13.11 deletions and familial controls were differentiated into cortical neurons for phenotypic analysis. High-content imaging and morphological analysis of patient-derived neurons demonstrated an increase in neurite branching in patients compared with controls. Whole-transcriptome sequencing revealed expression level changes in neuron development and synaptic-related gene families, suggesting a defect in synapse formation. Subsequent quantification of synapse number demonstrated increased numbers of synapses on neurons derived from early-onset patients compared to controls. The identification of common phenotypes among neurons derived from patients with overlapping 16p13.11 deletions will further assist in ascertaining common pathways and targets that could be utilized for screening drug candidates. These studies can help to improve future treatment options and clinical outcomes for 16p13.11 deletion patients. Frontiers Media S.A. 2022-11-03 /pmc/articles/PMC9669751/ /pubmed/36405918 http://dx.doi.org/10.3389/fpsyt.2022.924956 Text en Copyright © 2022 Buttermore, Anderson, Chen, Makhortova, Kim, Wafa, Dwyer, Micozzi, Winden, Zhang, Han, Kleiman, Brownstein, Sahin and Gonzalez-Heydrich. https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms. |
spellingShingle | Psychiatry Buttermore, Elizabeth D. Anderson, Nickesha C. Chen, Pin-Fang Makhortova, Nina R. Kim, Kristina H. Wafa, Syed M. A. Dwyer, Sean Micozzi, John M. Winden, Kellen D. Zhang, Bo Han, Min-Joon Kleiman, Robin J. Brownstein, Catherine A. Sahin, Mustafa Gonzalez-Heydrich, Joseph 16p13.11 deletion variants associated with neuropsychiatric disorders cause morphological and synaptic changes in induced pluripotent stem cell-derived neurons |
title | 16p13.11 deletion variants associated with neuropsychiatric disorders cause morphological and synaptic changes in induced pluripotent stem cell-derived neurons |
title_full | 16p13.11 deletion variants associated with neuropsychiatric disorders cause morphological and synaptic changes in induced pluripotent stem cell-derived neurons |
title_fullStr | 16p13.11 deletion variants associated with neuropsychiatric disorders cause morphological and synaptic changes in induced pluripotent stem cell-derived neurons |
title_full_unstemmed | 16p13.11 deletion variants associated with neuropsychiatric disorders cause morphological and synaptic changes in induced pluripotent stem cell-derived neurons |
title_short | 16p13.11 deletion variants associated with neuropsychiatric disorders cause morphological and synaptic changes in induced pluripotent stem cell-derived neurons |
title_sort | 16p13.11 deletion variants associated with neuropsychiatric disorders cause morphological and synaptic changes in induced pluripotent stem cell-derived neurons |
topic | Psychiatry |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9669751/ https://www.ncbi.nlm.nih.gov/pubmed/36405918 http://dx.doi.org/10.3389/fpsyt.2022.924956 |
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