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...
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| Format: | Article |
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Elsevier
2018
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| Online Access: | http://hdl.handle.net/1721.1/118648 https://orcid.org/0000-0002-3829-5612 |
| _version_ | 1811072553005875200 |
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| author | Omer Javed, Attya Muffat, Julien Su, Kuan-Chung Lungjangwa, Tenzin Aubourg, Patrick Li, Yun Cohen, Malkiel A Cheeseman, Iain M Jaenisch, Rudolf |
| author2 | Massachusetts Institute of Technology. Department of Biology |
| author_facet | Massachusetts Institute of Technology. Department of Biology Omer Javed, Attya Muffat, Julien Su, Kuan-Chung Lungjangwa, Tenzin Aubourg, Patrick Li, Yun Cohen, Malkiel A Cheeseman, Iain M Jaenisch, Rudolf |
| author_sort | Omer Javed, Attya |
| collection | MIT |
| 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. |
| first_indexed | 2024-09-23T09:07:45Z |
| format | Article |
| id | mit-1721.1/118648 |
| institution | Massachusetts Institute of Technology |
| last_indexed | 2024-09-23T09:07:45Z |
| publishDate | 2018 |
| publisher | Elsevier |
| record_format | dspace |
| spelling | mit-1721.1/1186482022-09-30T13:38:22Z Microcephaly Modeling of Kinetochore Mutation Reveals a Brain-Specific Phenotype Omer Javed, Attya Muffat, Julien Su, Kuan-Chung Lungjangwa, Tenzin Aubourg, Patrick Li, Yun Cohen, Malkiel A Cheeseman, Iain M Jaenisch, Rudolf Massachusetts Institute of Technology. Department of Biology Picower Institute for Learning and Memory Li, Yun Cohen, Malkiel A Cheeseman, Iain M Jaenisch, Rudolf 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. Simons Foundation. Postdoctoral Fellowship International Rett Syndrome Foundation (Postdoctoral Fellowship) Brain & Behavior Research Foundation (Young Investigator Grant) National Institutes of Health (U.S.) (grant HD 045022) National Institutes of Health (U.S.) (grant R37-CA084198) National Institutes of Health (U.S.) (grant 1U19AI131135-01) 2018-10-22T16:28:56Z 2018-10-22T16:28:56Z 2018-10 2018-08 2018-10-22T15:55:31Z Article http://purl.org/eprint/type/JournalArticle 22111247 http://hdl.handle.net/1721.1/118648 Omer Javed, Attya, Yun Li, Julien Muffat, Kuan-Chung Su, Malkiel A. Cohen, Tenzin Lungjangwa, Patrick Aubourg, Iain M. Cheeseman, and Rudolf Jaenisch. “Microcephaly Modeling of Kinetochore Mutation Reveals a Brain-Specific Phenotype.” Cell Reports 25, no. 2 (October 2018): 368–382.e5. https://orcid.org/0000-0002-3829-5612 http://dx.doi.org/10.1016/j.celrep.2018.09.032 Cell Reports Creative Commons Attribution-NonCommercial-NoDerivs License http://creativecommons.org/licenses/by-nc-nd/4.0/ application/pdf Elsevier Elsevier |
| spellingShingle | Omer Javed, Attya Muffat, Julien Su, Kuan-Chung Lungjangwa, Tenzin Aubourg, Patrick Li, Yun Cohen, Malkiel A 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 |
| url | http://hdl.handle.net/1721.1/118648 https://orcid.org/0000-0002-3829-5612 |
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