Biallelic BUB1 mutations cause microcephaly, developmental delay, and variable effects on cohesion and chromosome segregation
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2022 Jan 21;8(3):eabk0114.
doi: 10.1126/sciadv.abk0114.
Epub 2022 Jan 19.
Sara Carvalhal 1 2 3 ,
Ingrid Bader 4 ,
Martin A Rooimans 5 ,
Anneke B Oostra 5 ,
Jesper A Balk 5 ,
Rene 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
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Affiliations
1 Instituto Gulbenkian de Ciencia, 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
PMCID: PMC8769543
DOI: 10.1126/sciadv.abk0114
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Sara Carvalhal et al.
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2022 Jan 21;8(3):eabk0114.
doi: 10.1126/sciadv.abk0114.
Epub 2022 Jan 19.
Authors
Sara Carvalhal 1 2 3 ,
Ingrid Bader 4 ,
Martin A Rooimans 5 ,
Anneke B Oostra 5 ,
Jesper A Balk 5 ,
Rene 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
1 Instituto Gulbenkian de Ciencia, 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
PMCID: PMC8769543
DOI: 10.1126/sciadv.abk0114
Cite
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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.
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Figures
Fig. 1.. Biallelic germline mutations in BUB1…
Fig. 1.. Biallelic germline mutations in BUB1 cause reduced protein levels.
( A ) Family…
Fig. 2.. BUB1 patient cells display impaired…
Fig. 2.. BUB1 patient cells display impaired mitotic fidelity.
( A ) Cells were filmed…
Fig. 3.. BUB1 patients’ cells have a…
Fig. 3.. BUB1 patients’ cells have a functional SAC.
( A ) Cumulative mitotic exit…
Fig. 4.. Key molecular targets of BUB1…
Fig. 4.. Key molecular targets of BUB1 are differentially affected in patient cells.
( A…
Fig. 5.. Cohesion defects do not accelerate…
Fig. 5.. Cohesion defects do not accelerate cohesion fatigue in BUB1 patient cells.
( A…
Fig. 6.. BUB1 patient cells show impaired…
Fig. 6.. BUB1 patient cells show impaired centromeric recruitment of TOP2A.
( A ) Representative…
Fig. 7.. Comparison of clinical features in…
Fig. 7.. Comparison of clinical features in selected syndromes.
DD, developmental delay. Red, feature present…
See this image and copyright information in PMC
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References
Foley E. A., Kapoor T. M., Microtubule attachment and spindle assembly checkpoint signalling at the kinetochore. Nat. Rev. Mol. Cell Biol. 14, 25–37 (2013). - PMC - PubMed
Maiato H., Gomes A. M., Sousa F., Barisic M., Mechanisms of chromosome congression during mitosis. Biology 6, 13 (2017). - PMC - PubMed
Vasudevan A., Schukken K. M., Sausville E. L., Girish V., Adebambo O. A., Sheltzer J. M., Aneuploidy as a promoter and suppressor of malignant growth. Nat. Rev. Cancer 21, 89–103 (2021). - PubMed
de Wolf B., Kops G., Kinetochore malfunction in human pathologies. Adv. Exp. Med. Biol. 1002, 69–91 (2017). - PubMed
Degrassi F., Damizia M., Lavia P., The mitotic apparatus and kinetochores in microcephaly and neurodevelopmental diseases. Cell 9, 49 (2019). - PMC - PubMed
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Aneuploidy Actions Search in PubMed Search in MeSH Add to Search
Chromosome Segregation* / genetics Actions Search in PubMed Search in MeSH Add to Search
Humans Actions Search in PubMed Search in MeSH Add to Search
Microcephaly* / genetics Actions Search in PubMed Search in MeSH Add to Search
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Protein Serine-Threonine Kinases / genetics Actions Search in PubMed Search in MeSH Add to Search
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BUB1 protein, human Actions Search in PubMed Search in MeSH Add to Search
Protein Serine-Threonine Kinases Actions Search in PubMed Search in MeSH Add to Search
Related information
ClinVar
Gene
Gene (GeneRIF)
MedGen
Nucleotide (RefSeq)
OMIM (cited)
PMC images
Protein
Protein (RefSeq)
LinkOut - more resources
Full Text Sources Atypon Europe PubMed Central Ovid Technologies, Inc. PubMed Central
Medical Genetic Alliance
Molecular Biology Databases GlyGen glycoinformatics resource The Weizmann Institute of Science GeneCards and MalaCards databases
Miscellaneous NCI CPTAC Assay Portal
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Search in PubMed. Search in NLM Catalog. Add to Search. . 2022 Jan 21;8(3):eabk0114. doi: 10.1126/sciadv.abk0114. Epub 2022 Jan 19. Sara Carvalhal 1 2 3 , Ingrid Bader 4 , Martin A Rooimans 5 , Anneke B Oostra 5 , Jesper A Balk 5 , Rene 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. Expand. Affiliations. 1 Instituto Gulbenkian de Ciencia, 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. PMCID: PMC8769543. DOI: 10.1126/sciadv.abk0114. Free PMC article. Sara Carvalhal et al. Sci Adv . 2022 . Free PMC article. Show details. Display options. Format. Search in PubMed. Search in NLM Catalog. Add to Search. . 2022 Jan 21;8(3):eabk0114. doi: 10.1126/sciadv.abk0114. Epub 2022 Jan 19. Authors. Sara Carvalhal 1 2 3 , Ingrid Bader 4 , Martin A Rooimans 5 , Anneke B Oostra 5 , Jesper A Balk 5 , Rene 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. 1 Instituto Gulbenkian de Ciencia, 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. PMCID: PMC8769543. DOI: 10.1126/sciadv.abk0114. Cite. Display options. Format. 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. PubMed Disclaimer. Figures. Fig. 1.. Biallelic germline mutations in BUB1… Fig. 1.. Biallelic germline mutations in BUB1 cause reduced protein levels. ( A ) Family… Fig. 2.. BUB1 patient cells display impaired… Fig. 2.. BUB1 patient cells display impaired mitotic fidelity. ( A ) Cells were filmed… Fig. 3.. BUB1 patients’ cells have a… Fig. 3.. BUB1 patients’ cells have a functional SAC. ( A ) Cumulative mitotic exit… Fig. 4.. Key molecular targets of BUB1… Fig. 4.. Key molecular targets of BUB1 are differentially affected in patient cells. ( A… Fig. 5.. Cohesion defects do not accelerate… Fig. 5.. Cohesion defects do not accelerate cohesion fatigue in BUB1 patient cells. ( A… Fig. 6.. BUB1 patient cells show impaired… Fig. 6.. BUB1 patient cells show impaired centromeric recruitment of TOP2A. ( A ) Representative… Fig. 7.. Comparison of clinical features in… Fig. 7.. Comparison of clinical features in selected syndromes. DD, developmental delay. Red, feature present… See this image and copyright information in PMC. Similar articles. Nearly complete deletion of BubR1 causes microcephaly through shortened mitosis and massive cell death. Simmons AJ, Park R, Sterling NA, Jang MH, van Deursen JMA, Yen TJ, Cho SH, Kim S. Simmons AJ, et al. Hum Mol Genet. 2019 Jun 1;28(11):1822-1836. doi: 10.1093/hmg/ddz022. Hum Mol Genet. 2019. PMID: 30668728 Free PMC article. The multiple roles of Bub1 in chromosome segregation during mitosis and meiosis. Marchetti F, Venkatachalam S. Marchetti F, et al. Cell Cycle. 2010 Jan 1;9(1):58-63. doi: 10.4161/cc.9.1.10348. Epub 2010 Jan 18. Cell Cycle. 2010. PMID: 20016277. Sgo1 establishes the centromeric cohesion protection mechanism in G2 before subsequent Bub1-dependent recruitment in mitosis. Perera D, Taylor SS. Perera D, et al. J Cell Sci. 2010 Mar 1;123(Pt 5):653-9. doi: 10.1242/jcs.059501. Epub 2010 Feb 2. J Cell Sci. 2010. PMID: 20124418. The expanding phenotypes of cohesinopathies: one ring to rule them all! Piche J, Van Vliet PP, Puceat M, Andelfinger G. Piche J, et al. Cell Cycle. 2019 Nov;18(21):2828-2848. doi: 10.1080/15384101.2019.1658476. Epub 2019 Sep 13. Cell Cycle. 2019. PMID: 31516082 Free PMC article. Review. Killing two birds with one stone: how budding yeast Mps1 controls chromosome segregation and spindle assembly checkpoint through phosphorylation of a single kinetochore protein. Benzi G, Piatti S. Benzi G, et al. Curr Genet. 2020 Dec;66(6):1037-1044. doi: 10.1007/s00294-020-01091-x. Epub 2020 Jul 6. Curr Genet. 2020. PMID: 32632756 Review. See all similar articles. Cited by. Toxicology knowledge graph for structural birth defects. Evangelista JE, Clarke DJB, Xie Z, Marino GB, Utti V, Jenkins SL, Ahooyi TM, Bologa CG, Yang JJ, Binder JL, Kumar P, Lambert CG, Grethe JS, Wenger E, Taylor D, Oprea TI, de Bono B, Ma'ayan A. Evangelista JE, et al. Commun Med (Lond). 2023 Jul 17;3(1):98. doi: 10.1038/s43856-023-00329-2. Commun Med (Lond). 2023. PMID: 37460679 Free PMC article. Genetic Primary Microcephalies: When Centrosome Dysfunction Dictates Brain and Body Size. Farcy S, Hachour H, Bahi-Buisson N, Passemard S. Farcy S, et al. Cells. 2023 Jul 7;12(13):1807. doi: 10.3390/cells12131807. Cells. 2023. PMID: 37443841 Free PMC article. Review. Short-Term Effects of Human versus Bovine Sialylated Milk Oligosaccharide Microinjection on Zebrafish Larvae Survival, Locomotor Behavior and Gene Expression. Licitra R, Naef V, Marchese M, Damiani D, Ogi A, Doccini S, Fronte B, Yan J, Santorelli FM. Licitra R, et al. Int J Mol Sci. 2023 Mar 13;24(6):5456. doi: 10.3390/ijms24065456. Int J Mol Sci. 2023. PMID: 36982531 Free PMC article. Congenital Microcephaly: A Debate on Diagnostic Challenges and Etiological Paradigm of the Shift from Isolated/Non-Syndromic to Syndromic Microcephaly. Asif M, Abdullah U, Nurnberg P, Tinschert S, Hussain MS. Asif M, et al. Cells. 2023 Feb 16;12(4):642. doi: 10.3390/cells12040642. Cells. 2023. PMID: 36831309 Free PMC article. Review. Biallelic germline mutations in MAD1L1 induce a syndrome of aneuploidy with high tumor susceptibility. Villarroya-Beltri C, Osorio A, Torres-Ruiz R, Gomez-Sanchez D, Trakala M, Sanchez-Belmonte A, Mercadillo F, Hurtado B, Pitarch B, Hernandez-Nunez A, Gomez-Caturla A, Rueda D, Perea J, Rodriguez-Perales S, Malumbres M, Urioste M. Villarroya-Beltri C, et al. Sci Adv. 2022 Nov 4;8(44):eabq5914. doi: 10.1126/sciadv.abq5914. Epub 2022 Nov 2. Sci Adv. 2022. PMID: 36322655 Free PMC article. See all "Cited by" articles. References. Foley E. A., Kapoor T. M., Microtubule attachment and spindle assembly checkpoint signalling at the kinetochore. Nat. Rev. Mol. Cell Biol. 14, 25–37 (2013). - PMC - PubMed. Maiato H., Gomes A. M., Sousa F., Barisic M., Mechanisms of chromosome congression during mitosis. Biology 6, 13 (2017). - PMC - PubMed. Vasudevan A., Schukken K. M., Sausville E. L., Girish V., Adebambo O. A., Sheltzer J. M., Aneuploidy as a promoter and suppressor of malignant growth. Nat. Rev. Cancer 21, 89–103 (2021). - PubMed. de Wolf B., Kops G., Kinetochore malfunction in human pathologies. Adv. Exp. Med. Biol. 1002, 69–91 (2017). - PubMed. Degrassi F., Damizia M., Lavia P., The mitotic apparatus and kinetochores in microcephaly and neurodevelopmental diseases. Cell 9, 49 (2019). - PMC - PubMed. Publication types. Case Reports Actions Search in PubMed Search in MeSH Add to Search. Research Support, Non-U.S. Gov't Actions Search in PubMed Search in MeSH Add to Search. MeSH terms. Aneuploidy Actions Search in PubMed Search in MeSH Add to Search. Chromosome Segregation* / genetics Actions Search in PubMed Search in MeSH Add to Search. Humans Actions Search in PubMed Search in MeSH Add to Search. Microcephaly* / genetics Actions Search in PubMed Search in MeSH Add to Search. Mutation Actions Search in PubMed Search in MeSH Add to Search. Protein Serine-Threonine Kinases / genetics Actions Search in PubMed Search in MeSH Add to Search. Substances. BUB1 protein, human Actions Search in PubMed Search in MeSH Add to Search. Protein Serine-Threonine Kinases Actions Search in PubMed Search in MeSH Add to Search. Related information. ClinVar. Gene. Gene (GeneRIF) MedGen. Nucleotide (RefSeq) OMIM (cited) PMC images. Protein. Protein (RefSeq) LinkOut - more resources. Full Text Sources Atypon Europe PubMed Central Ovid Technologies, Inc. PubMed Central. Medical Genetic Alliance. Molecular Biology Databases GlyGen glycoinformatics resource The Weizmann Institute of Science GeneCards and MalaCards databases. Miscellaneous NCI CPTAC Assay Portal.