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Impaired expression of the COSMOC/MOCOS gene unit in ASD patient stem cells

Autism spectrum disorders (ASD) are complex neurodevelopmental disorders with a very large number of risk loci detected in the genome. However, at best, each of them explains rare cases, the majority being idiopathic. Genomic data on ASD derive mostly from post-mortem brain analyses or cell lines de...

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Autores principales: Rontani, Pauline, Perche, Olivier, Greetham, Louise, Jullien, Nicolas, Gepner, Bruno, Féron, François, Nivet, Emmanuel, Erard-Garcia, Madeleine
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8159765/
https://www.ncbi.nlm.nih.gov/pubmed/32327736
http://dx.doi.org/10.1038/s41380-020-0728-2
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author Rontani, Pauline
Perche, Olivier
Greetham, Louise
Jullien, Nicolas
Gepner, Bruno
Féron, François
Nivet, Emmanuel
Erard-Garcia, Madeleine
author_facet Rontani, Pauline
Perche, Olivier
Greetham, Louise
Jullien, Nicolas
Gepner, Bruno
Féron, François
Nivet, Emmanuel
Erard-Garcia, Madeleine
author_sort Rontani, Pauline
collection PubMed
description Autism spectrum disorders (ASD) are complex neurodevelopmental disorders with a very large number of risk loci detected in the genome. However, at best, each of them explains rare cases, the majority being idiopathic. Genomic data on ASD derive mostly from post-mortem brain analyses or cell lines derived from blood or patient-specific induced pluripotent stem cells (iPSCS). Therefore, the transcriptional and regulatory architecture of the nervous system, particularly during early developmental periods, remains highly incomplete. To access the critical disturbances that may have occurred during pregnancy or early childhood, we recently isolated stem cells from the nasal cavity of anesthetized patients diagnosed for ASD and compared them to stem cells from gender-matched control individuals without neuropsychiatric disorders. This allowed us to discover MOCOS, a non-mutated molybdenum cofactor sulfurase-coding gene that was under-expressed in the stem cells of most ASD patients of our cohort, disturbing redox homeostasis and synaptogenesis. We now report that a divergent transcription upstream of MOCOS generates an antisense long noncoding RNA, to which we coined the name COSMOC. Surprisingly, COSMOC is strongly under-expressed in all ASD patients of our cohort with the exception of a patient affected by Asperger syndrome. Knockdown studies indicate that loss of COSMOC reduces MOCOS expression, destabilizes lipid and energy metabolisms of stem cells, but also affects neuronal maturation and splicing of synaptic genes. Impaired expression of the COSMOC/MOCOS bidirectional unit might shed new lights on the origins of ASD that could be of importance for future translational studies.
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spelling pubmed-81597652021-06-17 Impaired expression of the COSMOC/MOCOS gene unit in ASD patient stem cells Rontani, Pauline Perche, Olivier Greetham, Louise Jullien, Nicolas Gepner, Bruno Féron, François Nivet, Emmanuel Erard-Garcia, Madeleine Mol Psychiatry Article Autism spectrum disorders (ASD) are complex neurodevelopmental disorders with a very large number of risk loci detected in the genome. However, at best, each of them explains rare cases, the majority being idiopathic. Genomic data on ASD derive mostly from post-mortem brain analyses or cell lines derived from blood or patient-specific induced pluripotent stem cells (iPSCS). Therefore, the transcriptional and regulatory architecture of the nervous system, particularly during early developmental periods, remains highly incomplete. To access the critical disturbances that may have occurred during pregnancy or early childhood, we recently isolated stem cells from the nasal cavity of anesthetized patients diagnosed for ASD and compared them to stem cells from gender-matched control individuals without neuropsychiatric disorders. This allowed us to discover MOCOS, a non-mutated molybdenum cofactor sulfurase-coding gene that was under-expressed in the stem cells of most ASD patients of our cohort, disturbing redox homeostasis and synaptogenesis. We now report that a divergent transcription upstream of MOCOS generates an antisense long noncoding RNA, to which we coined the name COSMOC. Surprisingly, COSMOC is strongly under-expressed in all ASD patients of our cohort with the exception of a patient affected by Asperger syndrome. Knockdown studies indicate that loss of COSMOC reduces MOCOS expression, destabilizes lipid and energy metabolisms of stem cells, but also affects neuronal maturation and splicing of synaptic genes. Impaired expression of the COSMOC/MOCOS bidirectional unit might shed new lights on the origins of ASD that could be of importance for future translational studies. Nature Publishing Group UK 2020-04-23 2021 /pmc/articles/PMC8159765/ /pubmed/32327736 http://dx.doi.org/10.1038/s41380-020-0728-2 Text en © The Author(s) 2020 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
Rontani, Pauline
Perche, Olivier
Greetham, Louise
Jullien, Nicolas
Gepner, Bruno
Féron, François
Nivet, Emmanuel
Erard-Garcia, Madeleine
Impaired expression of the COSMOC/MOCOS gene unit in ASD patient stem cells
title Impaired expression of the COSMOC/MOCOS gene unit in ASD patient stem cells
title_full Impaired expression of the COSMOC/MOCOS gene unit in ASD patient stem cells
title_fullStr Impaired expression of the COSMOC/MOCOS gene unit in ASD patient stem cells
title_full_unstemmed Impaired expression of the COSMOC/MOCOS gene unit in ASD patient stem cells
title_short Impaired expression of the COSMOC/MOCOS gene unit in ASD patient stem cells
title_sort impaired expression of the cosmoc/mocos gene unit in asd patient stem cells
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8159765/
https://www.ncbi.nlm.nih.gov/pubmed/32327736
http://dx.doi.org/10.1038/s41380-020-0728-2
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