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BubR1 allelic effects drive phenotypic heterogeneity in mosaic-variegated aneuploidy progeria syndrome
Cynthia J. Sieben, … , Darren J. Baker, Jan M. van Deursen
Cynthia J. Sieben, … , Darren J. Baker, Jan M. van Deursen
Published November 18, 2019
Citation Information: J Clin Invest. 2020;130(1):171-188. https://doi.org/10.1172/JCI126863.
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Research Article Aging Oncology Article has an altmetric score of 8

BubR1 allelic effects drive phenotypic heterogeneity in mosaic-variegated aneuploidy progeria syndrome

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Abstract

Mosaic-variegated aneuploidy (MVA) syndrome is a rare childhood disorder characterized by biallelic BUBR1, CEP57, or TRIP13 aberrations; increased chromosome missegregation; and a broad spectrum of clinical features, including various cancers, congenital defects, and progeroid pathologies. To investigate the mechanisms underlying this disorder and its phenotypic heterogeneity, we mimicked the BUBR1L1012P mutation in mice (BubR1L1002P) and combined it with 2 other MVA variants, BUBR1X753 and BUBR1H, generating a truncated protein and low amounts of wild-type protein, respectively. Whereas BubR1X753/L1002P and BubR1H/X753 mice died prematurely, BubR1H/L1002P mice were viable and exhibited many MVA features, including cancer predisposition and various progeroid phenotypes, such as short lifespan, dwarfism, lipodystrophy, sarcopenia, and low cardiac stress tolerance. Strikingly, although these mice had a reduction in total BUBR1 and spectrum of MVA phenotypes similar to that of BubR1H/H mice, several progeroid pathologies were attenuated in severity, which in skeletal muscle coincided with reduced senescence-associated secretory phenotype complexity. Additionally, mice carrying monoallelic BubR1 mutations were prone to select MVA-related pathologies later in life, with predisposition to sarcopenia correlating with mTORC1 hyperactivity. Together, these data demonstrate that BUBR1 allelic effects beyond protein level and aneuploidy contribute to disease heterogeneity in both MVA patients and heterozygous carriers of MVA mutations.

Authors

Cynthia J. Sieben, Karthik B. Jeganathan, Grace G. Nelson, Ines Sturmlechner, Cheng Zhang, Willemijn H. van Deursen, Bjorn Bakker, Floris Foijer, Hu Li, Darren J. Baker, Jan M. van Deursen

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Figure 3

Surveillance mechanisms that ensure high-fidelity chromosome segregation are defective in monoallelic BubR1 MVA mutant MEFs.

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Surveillance mechanisms that ensure high-fidelity chromosome segregation...
(A) Incidence of aneuploidy and PCS in mitotically arrested passage-5 MEFs. (B) Chromosome segregation errors in passage-5 MEFs assessed by live-cell imaging of MEFs expressing H2B-mRFP. Each n indicates independent MEF lines for all genotypes, except for BubR1+/L1002P and BubR1+/X753, where technical replicates were performed on 4 and 3 independent lines, respectively. (C) Colcemid-challenge assay on passage-5 MEFs measuring SAC activity. (D) Error correction in the indicated passage-5 MEFs assessed by monastrol washout assay. Representative images are shown. Yellow arrowheads indicate misaligned chromosomes. (E and F) Incidence of slow centrosome movement (E) and non-perpendicular spindles (F) in the indicated passage-5 MEFs. Representative images are shown. Yellow arrowheads indicate the location of the centrosomes. Each n indicates independent MEF lines, unless otherwise noted. Data are presented as mean ± SD (A) and mean ± SEM (B–F), and dots represent individual samples. Scale bars: 3 μm (D and E) and 2 μm (F). Statistical significance was determined using 1-way ANOVA with the Holm-Šídák post hoc test. *P < 0.05; **P < 0.01; ***P < 0.001. NS, not significant.

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ISSN: 0021-9738 (print), 1558-8238 (online)

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