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Microcephaly Modeling of Kinetochore Mutation Reveals a Brain-Specific Phenotype
Most genes mutated in microcephaly patients are expressed ubiquitously, and yet the brain is the only major organ compromised in most patients. Why the phenotype remains brain specific is poorly understood. In this study, we used in vitro differentiation of human embryonic stem cells to monitor the...
Autores principales: | , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
2018
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6392048/ https://www.ncbi.nlm.nih.gov/pubmed/30304678 http://dx.doi.org/10.1016/j.celrep.2018.09.032 |
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author | Javed, Attya Omer Li, Yun Muffat, Julien Su, Kuan-Chung Cohen, Malkiel A. Lungjangwa, Tenzin Aubourg, Patrick Cheeseman, Iain M. Jaenisch, Rudolf |
author_facet | Javed, Attya Omer Li, Yun Muffat, Julien Su, Kuan-Chung Cohen, Malkiel A. Lungjangwa, Tenzin Aubourg, Patrick Cheeseman, Iain M. Jaenisch, Rudolf |
author_sort | Javed, Attya Omer |
collection | PubMed |
description | Most genes mutated in microcephaly patients are expressed ubiquitously, and yet the brain is the only major organ compromised in most patients. Why the phenotype remains brain specific is poorly understood. In this study, we used in vitro differentiation of human embryonic stem cells to monitor the effect of a point mutation in kinetochore null protein 1 (KNL1;CASC5), identified in microcephaly patients, during in vitro brain development. We found that neural progenitors bearing a patient mutation showed reduced KNL1 levels, aneuploidy, and an abrogated spindle assembly checkpoint. By contrast, no reduction of KNL1 levels or abnormalities was observed in fibroblasts and neural crest cells. We established that the KNL1 patient mutation generates an exonic splicing silencer site, which mainly affects neural progenitors because of their higher levels of splicing proteins. Our results provide insight into the brain-specific phenomenon, consistent with microcephaly being the only major phenotype of patients bearing KNL1 mutation. |
format | Online Article Text |
id | pubmed-6392048 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2018 |
record_format | MEDLINE/PubMed |
spelling | pubmed-63920482019-02-27 Microcephaly Modeling of Kinetochore Mutation Reveals a Brain-Specific Phenotype Javed, Attya Omer Li, Yun Muffat, Julien Su, Kuan-Chung Cohen, Malkiel A. Lungjangwa, Tenzin Aubourg, Patrick Cheeseman, Iain M. Jaenisch, Rudolf Cell Rep Article Most genes mutated in microcephaly patients are expressed ubiquitously, and yet the brain is the only major organ compromised in most patients. Why the phenotype remains brain specific is poorly understood. In this study, we used in vitro differentiation of human embryonic stem cells to monitor the effect of a point mutation in kinetochore null protein 1 (KNL1;CASC5), identified in microcephaly patients, during in vitro brain development. We found that neural progenitors bearing a patient mutation showed reduced KNL1 levels, aneuploidy, and an abrogated spindle assembly checkpoint. By contrast, no reduction of KNL1 levels or abnormalities was observed in fibroblasts and neural crest cells. We established that the KNL1 patient mutation generates an exonic splicing silencer site, which mainly affects neural progenitors because of their higher levels of splicing proteins. Our results provide insight into the brain-specific phenomenon, consistent with microcephaly being the only major phenotype of patients bearing KNL1 mutation. 2018-10-09 /pmc/articles/PMC6392048/ /pubmed/30304678 http://dx.doi.org/10.1016/j.celrep.2018.09.032 Text en This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). |
spellingShingle | Article Javed, Attya Omer Li, Yun Muffat, Julien Su, Kuan-Chung Cohen, Malkiel A. Lungjangwa, Tenzin Aubourg, Patrick Cheeseman, Iain M. Jaenisch, Rudolf Microcephaly Modeling of Kinetochore Mutation Reveals a Brain-Specific Phenotype |
title | Microcephaly Modeling of Kinetochore Mutation Reveals a Brain-Specific Phenotype |
title_full | Microcephaly Modeling of Kinetochore Mutation Reveals a Brain-Specific Phenotype |
title_fullStr | Microcephaly Modeling of Kinetochore Mutation Reveals a Brain-Specific Phenotype |
title_full_unstemmed | Microcephaly Modeling of Kinetochore Mutation Reveals a Brain-Specific Phenotype |
title_short | Microcephaly Modeling of Kinetochore Mutation Reveals a Brain-Specific Phenotype |
title_sort | microcephaly modeling of kinetochore mutation reveals a brain-specific phenotype |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6392048/ https://www.ncbi.nlm.nih.gov/pubmed/30304678 http://dx.doi.org/10.1016/j.celrep.2018.09.032 |
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