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Regulation of human cerebral cortical development by EXOC7 and EXOC8, components of the exocyst complex, and roles in neural progenitor cell proliferation and survival

PURPOSE: The exocyst complex is a conserved protein complex that mediates fusion of intracellular vesicles to the plasma membrane and is implicated in processes including cell polarity, cell migration, ciliogenesis, cytokinesis, autophagy, and fusion of secretory vesicles. The essential role of thes...

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Autores principales: Coulter, Michael E., Musaev, Damir, DeGennaro, Ellen M., Zhang, Xiaochang, Henke, Katrin, James, Kiely N., Smith, Richard S., Hill, R. Sean, Partlow, Jennifer N., Muna Al-Saffar, Kamumbu, A. Stacy, Hatem, Nicole, Barkovich, A. James, Aziza, Jacqueline, Chassaing, Nicolas, Zaki, Maha S., Sultan, Tipu, Burglen, Lydie, Rajab, Anna, Al-Gazali, Lihadh, Mochida, Ganeshwaran H., Harris, Matthew P., Gleeson, Joseph G., Walsh, Christopher A.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group US 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7272323/
https://www.ncbi.nlm.nih.gov/pubmed/32103185
http://dx.doi.org/10.1038/s41436-020-0758-9
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author Coulter, Michael E.
Musaev, Damir
DeGennaro, Ellen M.
Zhang, Xiaochang
Henke, Katrin
James, Kiely N.
Smith, Richard S.
Hill, R. Sean
Partlow, Jennifer N.
Muna Al-Saffar
Kamumbu, A. Stacy
Hatem, Nicole
Barkovich, A. James
Aziza, Jacqueline
Chassaing, Nicolas
Zaki, Maha S.
Sultan, Tipu
Burglen, Lydie
Rajab, Anna
Al-Gazali, Lihadh
Mochida, Ganeshwaran H.
Harris, Matthew P.
Gleeson, Joseph G.
Walsh, Christopher A.
author_facet Coulter, Michael E.
Musaev, Damir
DeGennaro, Ellen M.
Zhang, Xiaochang
Henke, Katrin
James, Kiely N.
Smith, Richard S.
Hill, R. Sean
Partlow, Jennifer N.
Muna Al-Saffar
Kamumbu, A. Stacy
Hatem, Nicole
Barkovich, A. James
Aziza, Jacqueline
Chassaing, Nicolas
Zaki, Maha S.
Sultan, Tipu
Burglen, Lydie
Rajab, Anna
Al-Gazali, Lihadh
Mochida, Ganeshwaran H.
Harris, Matthew P.
Gleeson, Joseph G.
Walsh, Christopher A.
author_sort Coulter, Michael E.
collection PubMed
description PURPOSE: The exocyst complex is a conserved protein complex that mediates fusion of intracellular vesicles to the plasma membrane and is implicated in processes including cell polarity, cell migration, ciliogenesis, cytokinesis, autophagy, and fusion of secretory vesicles. The essential role of these genes in human genetic disorders, however, is unknown. METHODS: We performed homozygosity mapping and exome sequencing of consanguineous families with recessively inherited brain development disorders. We modeled an EXOC7 splice variant in vitro and examined EXOC7 messenger RNA (mRNA) expression in developing mouse and human cortex. We modeled exoc7 loss-of-function in a zebrafish knockout. RESULTS: We report variants in exocyst complex members, EXOC7 and EXOC8, in a novel disorder of cerebral cortex development. In EXOC7, we identified four independent partial loss-of-function (LOF) variants in a recessively inherited disorder characterized by brain atrophy, seizures, and developmental delay, and in severe cases, microcephaly and infantile death. In EXOC8, we found a homozygous truncating variant in a family with a similar clinical disorder. We modeled exoc7 deficiency in zebrafish and found the absence of exoc7 causes microcephaly. CONCLUSION: Our results highlight the essential role of the exocyst pathway in normal cortical development and how its perturbation causes complex brain disorders.
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spelling pubmed-72723232020-06-15 Regulation of human cerebral cortical development by EXOC7 and EXOC8, components of the exocyst complex, and roles in neural progenitor cell proliferation and survival Coulter, Michael E. Musaev, Damir DeGennaro, Ellen M. Zhang, Xiaochang Henke, Katrin James, Kiely N. Smith, Richard S. Hill, R. Sean Partlow, Jennifer N. Muna Al-Saffar Kamumbu, A. Stacy Hatem, Nicole Barkovich, A. James Aziza, Jacqueline Chassaing, Nicolas Zaki, Maha S. Sultan, Tipu Burglen, Lydie Rajab, Anna Al-Gazali, Lihadh Mochida, Ganeshwaran H. Harris, Matthew P. Gleeson, Joseph G. Walsh, Christopher A. Genet Med Article PURPOSE: The exocyst complex is a conserved protein complex that mediates fusion of intracellular vesicles to the plasma membrane and is implicated in processes including cell polarity, cell migration, ciliogenesis, cytokinesis, autophagy, and fusion of secretory vesicles. The essential role of these genes in human genetic disorders, however, is unknown. METHODS: We performed homozygosity mapping and exome sequencing of consanguineous families with recessively inherited brain development disorders. We modeled an EXOC7 splice variant in vitro and examined EXOC7 messenger RNA (mRNA) expression in developing mouse and human cortex. We modeled exoc7 loss-of-function in a zebrafish knockout. RESULTS: We report variants in exocyst complex members, EXOC7 and EXOC8, in a novel disorder of cerebral cortex development. In EXOC7, we identified four independent partial loss-of-function (LOF) variants in a recessively inherited disorder characterized by brain atrophy, seizures, and developmental delay, and in severe cases, microcephaly and infantile death. In EXOC8, we found a homozygous truncating variant in a family with a similar clinical disorder. We modeled exoc7 deficiency in zebrafish and found the absence of exoc7 causes microcephaly. CONCLUSION: Our results highlight the essential role of the exocyst pathway in normal cortical development and how its perturbation causes complex brain disorders. Nature Publishing Group US 2020-02-27 2020 /pmc/articles/PMC7272323/ /pubmed/32103185 http://dx.doi.org/10.1038/s41436-020-0758-9 Text en © The Author(s) 2020 Open Access This article is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License, which permits any non-commercial use, sharing, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, and provide a link to the Creative Commons license. You do not have permission under this license to share adapted material derived from this article or parts of it. 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-nc-nd/4.0/.
spellingShingle Article
Coulter, Michael E.
Musaev, Damir
DeGennaro, Ellen M.
Zhang, Xiaochang
Henke, Katrin
James, Kiely N.
Smith, Richard S.
Hill, R. Sean
Partlow, Jennifer N.
Muna Al-Saffar
Kamumbu, A. Stacy
Hatem, Nicole
Barkovich, A. James
Aziza, Jacqueline
Chassaing, Nicolas
Zaki, Maha S.
Sultan, Tipu
Burglen, Lydie
Rajab, Anna
Al-Gazali, Lihadh
Mochida, Ganeshwaran H.
Harris, Matthew P.
Gleeson, Joseph G.
Walsh, Christopher A.
Regulation of human cerebral cortical development by EXOC7 and EXOC8, components of the exocyst complex, and roles in neural progenitor cell proliferation and survival
title Regulation of human cerebral cortical development by EXOC7 and EXOC8, components of the exocyst complex, and roles in neural progenitor cell proliferation and survival
title_full Regulation of human cerebral cortical development by EXOC7 and EXOC8, components of the exocyst complex, and roles in neural progenitor cell proliferation and survival
title_fullStr Regulation of human cerebral cortical development by EXOC7 and EXOC8, components of the exocyst complex, and roles in neural progenitor cell proliferation and survival
title_full_unstemmed Regulation of human cerebral cortical development by EXOC7 and EXOC8, components of the exocyst complex, and roles in neural progenitor cell proliferation and survival
title_short Regulation of human cerebral cortical development by EXOC7 and EXOC8, components of the exocyst complex, and roles in neural progenitor cell proliferation and survival
title_sort regulation of human cerebral cortical development by exoc7 and exoc8, components of the exocyst complex, and roles in neural progenitor cell proliferation and survival
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7272323/
https://www.ncbi.nlm.nih.gov/pubmed/32103185
http://dx.doi.org/10.1038/s41436-020-0758-9
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