TY - JOUR
T1 - Biallelic BUB1 mutations cause microcephaly, developmental delay, and variable effects on cohesion and chromosome segregation
AU - Carvalhal, Sara
AU - Bader, Ingrid
AU - Rooimans, Martin A
AU - Oostra, Anneke B
AU - Balk, Jesper A
AU - Feichtinger, René G
AU - Beichler, Christine
AU - Speicher, Michael R
AU - van Hagen, Johanna M
AU - Waisfisz, Quinten
AU - van Haelst, Mieke
AU - Bruijn, Martijn
AU - Tavares, Alexandra
AU - Mayr, Johannes A
AU - Wolthuis, Rob M F
AU - Oliveira, Raquel A
AU - de Lange, Job
N1 - Funding Information: This work was supported by the Dutch Cancer Society (KWF grants 10701 and 13645 to J.d.L.), the European Molecular Biology Laboratory (EMBO installation grant IG2778 to R.A.O.), Fundação para a Ciência e Tecnologia (CEECIND/01092/2017 to R.A.O. and CEECIND/03721/2018 to S.C.), and the Austrian Science Fund (FWF; I4695-B, GENOMIT to J.A.M.). Publisher Copyright: 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).
PY - 2022/1/21
Y1 - 2022/1/21
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85123300720&partnerID=8YFLogxK
U2 - https://doi.org/10.1126/sciadv.abk0114
DO - https://doi.org/10.1126/sciadv.abk0114
M3 - Article
C2 - 35044816
SN - 2375-2548
VL - 8
SP - eabk0114
JO - Science advances
JF - Science advances
IS - 3
M1 - eabk0114
ER -