Microcephaly Modeling of Kinetochore Mutation Reveals a Brain-Specific Phenotype
Author(s)Omer Javed, Attya; Muffat, Julien; Su, Kuan-Chung; Lungjangwa, Tenzin; Aubourg, Patrick; Li, Yun; Cohen, Malkiel A; Cheeseman, Iain M; Jaenisch, Rudolf; ... Show more Show less
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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.
DepartmentMassachusetts Institute of Technology. Department of Biology; Picower Institute for Learning and Memory
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.
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