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Biallelic BUB1 mutations cause microcephaly, developmental delay, and variable effects on cohesion and chromosome segregation

Budding uninhibited by benzimidazoles (BUB1) contributes to multiple mitotic processes. Here, we describe the first two patients with biallelic BUB1 germline mutations, who both display microcephaly, intellectual disability, and several patient-specific features. The identified mutations cause varia...

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Autores principales: Carvalhal, Sara, Bader, Ingrid, Rooimans, Martin A., Oostra, Anneke B., Balk, Jesper A., Feichtinger, René G., Beichler, Christine, Speicher, Michael R., van Hagen, Johanna M., Waisfisz, Quinten, van Haelst, Mieke, Bruijn, Martijn, Tavares, Alexandra, Mayr, Johannes A., Wolthuis, Rob M. F., Oliveira, Raquel A., de Lange, Job
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Association for the Advancement of Science 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8769543/
https://www.ncbi.nlm.nih.gov/pubmed/35044816
http://dx.doi.org/10.1126/sciadv.abk0114
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author Carvalhal, Sara
Bader, Ingrid
Rooimans, Martin A.
Oostra, Anneke B.
Balk, Jesper A.
Feichtinger, René G.
Beichler, Christine
Speicher, Michael R.
van Hagen, Johanna M.
Waisfisz, Quinten
van Haelst, Mieke
Bruijn, Martijn
Tavares, Alexandra
Mayr, Johannes A.
Wolthuis, Rob M. F.
Oliveira, Raquel A.
de Lange, Job
author_facet Carvalhal, Sara
Bader, Ingrid
Rooimans, Martin A.
Oostra, Anneke B.
Balk, Jesper A.
Feichtinger, René G.
Beichler, Christine
Speicher, Michael R.
van Hagen, Johanna M.
Waisfisz, Quinten
van Haelst, Mieke
Bruijn, Martijn
Tavares, Alexandra
Mayr, Johannes A.
Wolthuis, Rob M. F.
Oliveira, Raquel A.
de Lange, Job
author_sort Carvalhal, Sara
collection PubMed
description Budding uninhibited by benzimidazoles (BUB1) contributes to multiple mitotic processes. Here, we describe the first two patients with biallelic BUB1 germline mutations, who both display microcephaly, intellectual disability, and several patient-specific features. The identified mutations cause variable degrees of reduced total protein level and kinase activity, leading to distinct mitotic defects. Both patients’ cells show prolonged mitosis duration, chromosome segregation errors, and an overall functional spindle assembly checkpoint. However, while BUB1 levels mostly affect BUBR1 kinetochore recruitment, impaired kinase activity prohibits centromeric recruitment of Aurora B, SGO1, and TOP2A, correlating with anaphase bridges, aneuploidy, and defective sister chromatid cohesion. We do not observe accelerated cohesion fatigue. We hypothesize that unresolved DNA catenanes increase cohesion strength, with concomitant increase in anaphase bridges. In conclusion, BUB1 mutations cause a neurodevelopmental disorder, with clinical and cellular phenotypes that partially resemble previously described syndromes, including autosomal recessive primary microcephaly, mosaic variegated aneuploidy, and cohesinopathies.
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spelling pubmed-87695432022-02-01 Biallelic BUB1 mutations cause microcephaly, developmental delay, and variable effects on cohesion and chromosome segregation Carvalhal, Sara Bader, Ingrid Rooimans, Martin A. Oostra, Anneke B. Balk, Jesper A. Feichtinger, René G. Beichler, Christine Speicher, Michael R. van Hagen, Johanna M. Waisfisz, Quinten van Haelst, Mieke Bruijn, Martijn Tavares, Alexandra Mayr, Johannes A. Wolthuis, Rob M. F. Oliveira, Raquel A. de Lange, Job Sci Adv Biomedicine and Life Sciences Budding uninhibited by benzimidazoles (BUB1) contributes to multiple mitotic processes. Here, we describe the first two patients with biallelic BUB1 germline mutations, who both display microcephaly, intellectual disability, and several patient-specific features. The identified mutations cause variable degrees of reduced total protein level and kinase activity, leading to distinct mitotic defects. Both patients’ cells show prolonged mitosis duration, chromosome segregation errors, and an overall functional spindle assembly checkpoint. However, while BUB1 levels mostly affect BUBR1 kinetochore recruitment, impaired kinase activity prohibits centromeric recruitment of Aurora B, SGO1, and TOP2A, correlating with anaphase bridges, aneuploidy, and defective sister chromatid cohesion. We do not observe accelerated cohesion fatigue. We hypothesize that unresolved DNA catenanes increase cohesion strength, with concomitant increase in anaphase bridges. In conclusion, BUB1 mutations cause a neurodevelopmental disorder, with clinical and cellular phenotypes that partially resemble previously described syndromes, including autosomal recessive primary microcephaly, mosaic variegated aneuploidy, and cohesinopathies. American Association for the Advancement of Science 2022-01-19 /pmc/articles/PMC8769543/ /pubmed/35044816 http://dx.doi.org/10.1126/sciadv.abk0114 Text en Copyright © 2022 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works. Distributed under a Creative Commons Attribution License 4.0 (CC BY). https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution license (https://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
spellingShingle Biomedicine and Life Sciences
Carvalhal, Sara
Bader, Ingrid
Rooimans, Martin A.
Oostra, Anneke B.
Balk, Jesper A.
Feichtinger, René G.
Beichler, Christine
Speicher, Michael R.
van Hagen, Johanna M.
Waisfisz, Quinten
van Haelst, Mieke
Bruijn, Martijn
Tavares, Alexandra
Mayr, Johannes A.
Wolthuis, Rob M. F.
Oliveira, Raquel A.
de Lange, Job
Biallelic BUB1 mutations cause microcephaly, developmental delay, and variable effects on cohesion and chromosome segregation
title Biallelic BUB1 mutations cause microcephaly, developmental delay, and variable effects on cohesion and chromosome segregation
title_full Biallelic BUB1 mutations cause microcephaly, developmental delay, and variable effects on cohesion and chromosome segregation
title_fullStr Biallelic BUB1 mutations cause microcephaly, developmental delay, and variable effects on cohesion and chromosome segregation
title_full_unstemmed Biallelic BUB1 mutations cause microcephaly, developmental delay, and variable effects on cohesion and chromosome segregation
title_short Biallelic BUB1 mutations cause microcephaly, developmental delay, and variable effects on cohesion and chromosome segregation
title_sort biallelic bub1 mutations cause microcephaly, developmental delay, and variable effects on cohesion and chromosome segregation
topic Biomedicine and Life Sciences
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8769543/
https://www.ncbi.nlm.nih.gov/pubmed/35044816
http://dx.doi.org/10.1126/sciadv.abk0114
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