Biallelic BUB1 mutations cause microcephaly, developmental delay, and variable effects on cohesion and chromosome
Sara Carvalhal1,2,3, Ingrid Bader4, Martin A Rooimans5
1Instituto Gulbenkian de Ciência, R. Q.ta Grande 6, 2780-156 Oeiras, Portugal.
Science Advances
|January 19, 2022
Summary
Germline mutations in Budding Uninhibited by Benzimidazoles 1 (BUB1) cause a neurodevelopmental disorder. These BUB1 mutations lead to mitotic defects, aneuploidy, and intellectual disability in patients.
Area of Science:
- Genetics
- Cell Biology
- Developmental Biology
Background:
- The Budding Uninhibited by Benzimidazoles 1 (BUB1) protein is crucial for accurate chromosome segregation during mitosis.
- Germline mutations in genes regulating mitosis can lead to severe neurodevelopmental disorders.
Observation:
- The study reports the first two patients with biallelic BUB1 germline mutations.
- Both patients presented with microcephaly and intellectual disability, alongside unique clinical features.
Findings:
- The identified BUB1 mutations resulted in reduced protein levels and kinase activity, causing distinct mitotic defects.
- Cells from patients exhibited prolonged mitosis, chromosome segregation errors, and aneuploidy.
- Impaired BUB1 kinase activity affected the recruitment of key proteins like Aurora B, SGO1, and TOP2A, leading to anaphase bridges and defective sister chromatid cohesion.
Implications:
- BUB1 mutations cause a novel neurodevelopmental disorder with overlapping features of microcephaly, aneuploidy syndromes, and cohesinopathies.
- Understanding BUB1's role in mitosis and its link to neurodevelopment can inform future research and potential therapeutic strategies.
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