2. Academic Validation
  3. Biallelic BUB1 mutations cause microcephaly, developmental delay, and variable effects on cohesion and chromosome segregation

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

  • Sci Adv. 2022 Jan 21;8(3):eabk0114. doi: 10.1126/sciadv.abk0114.
Sara Carvalhal 1 2 3,  Ingrid Bader 4,  Martin A Rooimans 5,  Anneke B Oostra 5,  Jesper A Balk 5,  René G Feichtinger 6,  Christine Beichler 7,  Michael R Speicher 7,  Johanna M van Hagen 8,  Quinten Waisfisz 8,  Mieke van Haelst 8,  Martijn Bruijn 9,  Alexandra Tavares 1,  Johannes A Mayr 6,  Rob M F Wolthuis 5,  Raquel A Oliveira 1,  Job de Lange 5
Affiliations

Affiliations

  • 1 Instituto Gulbenkian de Ciência, R. Q.ta Grande 6, 2780-156 Oeiras, Portugal.
  • 2 Algarve Biomedical Center Research Institute, Universidade do Algarve, 8005-139 Faro, Portugal.
  • 3 Centre for Biomedical Research, Universidade do Algarve, 8005-139 Faro, Portugal.
  • 4 Unit of Clinical Genetics, Paracelsus Medical University, Salzburg, Austria.
  • 5 Cancer Center Amsterdam, Amsterdam University Medical Centers, Oncogenetics Section, De Boelelaan 1118, 1081 HV Amsterdam, Netherlands.
  • 6 Department of Pediatrics, University Hospital Salzburg, Paracelsus Medical University, Salzburg, Austria.
  • 7 Institute of Human Genetics, Diagnostic and Research Center for Molecular BioMedicine, Medical University of Graz, Graz, Austria.
  • 8 Department of Clinical Genetics, Amsterdam UMC, Vrije Universiteit Amsterdam, De Boelelaan 1118, 1081 HV Amsterdam, Netherlands.
  • 9 Northwest Clinics, Wilhelminalaan 12, 1815 JD Alkmaar, Netherlands.
PMID: 35044816 DOI: 10.1126/sciadv.abk0114
Abstract

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.

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-103020
    99.05%, BUB1 Kinase Inhibitor