Cargando…

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...

Descripción completa

Detalles Bibliográficos
Autores principales: Javed, Attya Omer, Li, Yun, Muffat, Julien, Su, Kuan-Chung, Cohen, Malkiel A., Lungjangwa, Tenzin, Aubourg, Patrick, Cheeseman, Iain M., Jaenisch, Rudolf
Formato: Online Artículo Texto
Lenguaje:English
Publicado: 2018
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
_version_ 1783398406550454272
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
work_keys_str_mv AT javedattyaomer microcephalymodelingofkinetochoremutationrevealsabrainspecificphenotype
AT liyun microcephalymodelingofkinetochoremutationrevealsabrainspecificphenotype
AT muffatjulien microcephalymodelingofkinetochoremutationrevealsabrainspecificphenotype
AT sukuanchung microcephalymodelingofkinetochoremutationrevealsabrainspecificphenotype
AT cohenmalkiela microcephalymodelingofkinetochoremutationrevealsabrainspecificphenotype
AT lungjangwatenzin microcephalymodelingofkinetochoremutationrevealsabrainspecificphenotype
AT aubourgpatrick microcephalymodelingofkinetochoremutationrevealsabrainspecificphenotype
AT cheesemaniainm microcephalymodelingofkinetochoremutationrevealsabrainspecificphenotype
AT jaenischrudolf microcephalymodelingofkinetochoremutationrevealsabrainspecificphenotype