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Cohen Syndrome Patient iPSC-Derived Neurospheres and Forebrain-Like Glutamatergic Neurons Reveal Reduced Proliferation of Neural Progenitor Cells and Altered Expression of Synapse Genes
Cohen syndrome (CS), a rare autosomal recessive disorder, has been associated with genetic mutations in the VPS13B gene, which regulates vesicle-mediated protein sorting and transport. However, the cellular mechanism underlying CS pathogenesis in patient-derived human neurons remains unknown. We ide...
Autores principales: | , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
MDPI
2020
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7356975/ https://www.ncbi.nlm.nih.gov/pubmed/32560273 http://dx.doi.org/10.3390/jcm9061886 |
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author | Lee, You-Kyung Hwang, Su-Kyeong Lee, Soo-Kyung Yang, Jung-eun Kwak, Ji-Hye Seo, Hyunhyo Ahn, Hyunjun Lee, Yong-Seok Kim, Janghwan Lim, Chae-Seok Kaang, Bong-Kiun Lee, Jae-Hyung Lee, Jin-A Lee, Kyungmin |
author_facet | Lee, You-Kyung Hwang, Su-Kyeong Lee, Soo-Kyung Yang, Jung-eun Kwak, Ji-Hye Seo, Hyunhyo Ahn, Hyunjun Lee, Yong-Seok Kim, Janghwan Lim, Chae-Seok Kaang, Bong-Kiun Lee, Jae-Hyung Lee, Jin-A Lee, Kyungmin |
author_sort | Lee, You-Kyung |
collection | PubMed |
description | Cohen syndrome (CS), a rare autosomal recessive disorder, has been associated with genetic mutations in the VPS13B gene, which regulates vesicle-mediated protein sorting and transport. However, the cellular mechanism underlying CS pathogenesis in patient-derived human neurons remains unknown. We identified a novel compound heterozygous mutation, due to homozygous variation of biparental origin and heterozygous variation inherited from the father, in the VPS13B gene in a 20-month-old female patient. To understand the cellular pathogenic mechanisms, we generated induced pluripotent stem cells (iPSCs) from the fibroblasts of the CS patient. The iPSCs were differentiated into forebrain-like functional glutamatergic neurons or neurospheres. Functional annotation from transcriptomic analysis using CS iPSC-derived neurons revealed that synapse-related functions were enriched among the upregulated and downregulated genes in the CS neurons, whereas processes associated with neurodevelopment were enriched in the downregulated genes. The developing CS neurospheres were small in size compared to control neurospheres, likely due to the reduced proliferation of SOX2-positive neural stem cells. Moreover, the number of SV2B-positive puncta and spine-like structures was significantly reduced in the CS neurons, suggesting synaptic dysfunction. Taking these findings together, for the first time, we report a potential cellular pathogenic mechanism which reveals the alteration of neurodevelopment-related genes and the dysregulation of synaptic function in the human induced neurons differentiated from iPSCs and neurospheres of a CS patient. |
format | Online Article Text |
id | pubmed-7356975 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2020 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
spelling | pubmed-73569752020-07-23 Cohen Syndrome Patient iPSC-Derived Neurospheres and Forebrain-Like Glutamatergic Neurons Reveal Reduced Proliferation of Neural Progenitor Cells and Altered Expression of Synapse Genes Lee, You-Kyung Hwang, Su-Kyeong Lee, Soo-Kyung Yang, Jung-eun Kwak, Ji-Hye Seo, Hyunhyo Ahn, Hyunjun Lee, Yong-Seok Kim, Janghwan Lim, Chae-Seok Kaang, Bong-Kiun Lee, Jae-Hyung Lee, Jin-A Lee, Kyungmin J Clin Med Article Cohen syndrome (CS), a rare autosomal recessive disorder, has been associated with genetic mutations in the VPS13B gene, which regulates vesicle-mediated protein sorting and transport. However, the cellular mechanism underlying CS pathogenesis in patient-derived human neurons remains unknown. We identified a novel compound heterozygous mutation, due to homozygous variation of biparental origin and heterozygous variation inherited from the father, in the VPS13B gene in a 20-month-old female patient. To understand the cellular pathogenic mechanisms, we generated induced pluripotent stem cells (iPSCs) from the fibroblasts of the CS patient. The iPSCs were differentiated into forebrain-like functional glutamatergic neurons or neurospheres. Functional annotation from transcriptomic analysis using CS iPSC-derived neurons revealed that synapse-related functions were enriched among the upregulated and downregulated genes in the CS neurons, whereas processes associated with neurodevelopment were enriched in the downregulated genes. The developing CS neurospheres were small in size compared to control neurospheres, likely due to the reduced proliferation of SOX2-positive neural stem cells. Moreover, the number of SV2B-positive puncta and spine-like structures was significantly reduced in the CS neurons, suggesting synaptic dysfunction. Taking these findings together, for the first time, we report a potential cellular pathogenic mechanism which reveals the alteration of neurodevelopment-related genes and the dysregulation of synaptic function in the human induced neurons differentiated from iPSCs and neurospheres of a CS patient. MDPI 2020-06-16 /pmc/articles/PMC7356975/ /pubmed/32560273 http://dx.doi.org/10.3390/jcm9061886 Text en © 2020 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/). |
spellingShingle | Article Lee, You-Kyung Hwang, Su-Kyeong Lee, Soo-Kyung Yang, Jung-eun Kwak, Ji-Hye Seo, Hyunhyo Ahn, Hyunjun Lee, Yong-Seok Kim, Janghwan Lim, Chae-Seok Kaang, Bong-Kiun Lee, Jae-Hyung Lee, Jin-A Lee, Kyungmin Cohen Syndrome Patient iPSC-Derived Neurospheres and Forebrain-Like Glutamatergic Neurons Reveal Reduced Proliferation of Neural Progenitor Cells and Altered Expression of Synapse Genes |
title | Cohen Syndrome Patient iPSC-Derived Neurospheres and Forebrain-Like Glutamatergic Neurons Reveal Reduced Proliferation of Neural Progenitor Cells and Altered Expression of Synapse Genes |
title_full | Cohen Syndrome Patient iPSC-Derived Neurospheres and Forebrain-Like Glutamatergic Neurons Reveal Reduced Proliferation of Neural Progenitor Cells and Altered Expression of Synapse Genes |
title_fullStr | Cohen Syndrome Patient iPSC-Derived Neurospheres and Forebrain-Like Glutamatergic Neurons Reveal Reduced Proliferation of Neural Progenitor Cells and Altered Expression of Synapse Genes |
title_full_unstemmed | Cohen Syndrome Patient iPSC-Derived Neurospheres and Forebrain-Like Glutamatergic Neurons Reveal Reduced Proliferation of Neural Progenitor Cells and Altered Expression of Synapse Genes |
title_short | Cohen Syndrome Patient iPSC-Derived Neurospheres and Forebrain-Like Glutamatergic Neurons Reveal Reduced Proliferation of Neural Progenitor Cells and Altered Expression of Synapse Genes |
title_sort | cohen syndrome patient ipsc-derived neurospheres and forebrain-like glutamatergic neurons reveal reduced proliferation of neural progenitor cells and altered expression of synapse genes |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7356975/ https://www.ncbi.nlm.nih.gov/pubmed/32560273 http://dx.doi.org/10.3390/jcm9061886 |
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