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

2022Journal article Open access
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dc.contributor.authorCarvalhal, Sara
dc.contributor.authorBader, Ingrid
dc.contributor.authorRooimans, Martin A.
dc.contributor.authorOostra, Anneke B.
dc.contributor.authorBalk, Jesper A.
dc.contributor.authorFeichtinger, René G.
dc.contributor.authorBeichler, Christine
dc.contributor.authorSpeicher, Michael R.
dc.contributor.authorvan Hagen, Johanna M.
dc.contributor.authorWaisfisz, Quinten
dc.contributor.authorvan Haelst, Mieke
dc.contributor.authorBruijn, Martijn
dc.contributor.authorTavares, Alexandra
dc.contributor.authorMayr, Johannes A.
dc.contributor.authorWolthuis, Rob M. F.
dc.contributor.authorOliveira, Raquel A.
dc.contributor.authorde Lange, Job
dc.date.accessioned2022-07-19T09:35:25Z
dc.date.available2022-07-19T09:35:25Z
dc.date.issued2022
dc.description.abstractBudding 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.pt_PT
dc.description.versioninfo:eu-repo/semantics/publishedVersionpt_PT
dc.identifier.doi10.1126/sciadv.abk0114pt_PT
dc.identifier.issn2375-2548
dc.identifier.urihttp://hdl.handle.net/10400.1/18028
dc.language.isoengpt_PT
dc.peerreviewedyespt_PT
dc.publisherAmerican Association for the Advancement of Sciencept_PT
dc.relationNot Available
dc.relationNot Available
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/pt_PT
dc.subjectMosaic variegated aneuploidypt_PT
dc.subjectSpindle assembly checkpointpt_PT
dc.subjectTopoisomerase-IIpt_PT
dc.subjectKinetochorept_PT
dc.titleBiallelic BUB1 mutations cause microcephaly, developmental delay, and variable effects on cohesion and chromosome segregationpt_PT
dc.typejournal article
dspace.entity.typePublication
oaire.awardTitleNot Available
oaire.awardTitleNot Available
oaire.awardURIinfo:eu-repo/grantAgreement/FCT/CEEC IND 2018/CEECIND%2F03721%2F2018%2FCP1540%2FCT0003/PT
oaire.awardURIinfo:eu-repo/grantAgreement/FCT/CEEC IND 2017/CEECIND%2F01092%2F2017%2FCP1424%2FCT0002/PT
oaire.citation.issue3pt_PT
oaire.citation.titleScience Advancespt_PT
oaire.citation.volume8pt_PT
oaire.fundingStreamCEEC IND 2018
oaire.fundingStreamCEEC IND 2017
person.familyNameCarvalhal
person.givenNameSara
person.identifier.ciencia-idC511-8A34-30BE
person.identifier.orcid0000-0002-6004-3286
person.identifier.scopus-author-id56888576000
project.funder.identifierhttp://doi.org/10.13039/501100001871
project.funder.identifierhttp://doi.org/10.13039/501100001871
project.funder.nameFundação para a Ciência e a Tecnologia
project.funder.nameFundação para a Ciência e a Tecnologia
rcaap.rightsopenAccesspt_PT
rcaap.typearticlept_PT
relation.isAuthorOfPublication5b4befe5-cdb3-408a-839e-8c5adc64a162
relation.isAuthorOfPublication.latestForDiscovery5b4befe5-cdb3-408a-839e-8c5adc64a162
relation.isProjectOfPublication6a929813-2f26-4f1d-9dd9-71e2abb6a504
relation.isProjectOfPublication9282331d-9bb4-44a6-be72-e47ffe06749a
relation.isProjectOfPublication.latestForDiscovery9282331d-9bb4-44a6-be72-e47ffe06749a

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