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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 10

Senescence-mediated pathologies are conserved among MVA models.

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Senescence-mediated pathologies are conserved among MVA models.
(A) Imag...
(A) Images of SA-β-gal activity in adipose tissue (perirenal and IAT) from the indicated 8- to 10-month-old mice. (B) Venn diagrams of significantly DEGs from RNA sequencing analyses of 8- to 10-month-old fat (IAT) from the indicated mice (left).↑, upregulated genes; ↓, downregulated genes. Heatmap of expression (row Z-scores) of cell cycle inhibitors p16/p19 (Cdkn2a) in each of the individual samples (right). n = 4 independent mice/genotype were used for analyses. FC, fold change. (C) Venn diagrams of putative SASP factors within the upregulated DEGs from BubR1H/L1002P versus BubR1+/+ and BubR1H/H versus BubR1+/+ RNA sequencing results from fat, determined by overlap with a gene ontology (GO) GO:0005615 “Extracellular Space” gene list (top). Heatmap of expression of 53 select putative SASP factors significantly upregulated in BubR1H/L1002P and/or BubR1H/H fat (bottom). Gene names in bold text denote established SASP factors. Arrowheads indicate putative SASP factors present in fat and skeletal muscle. (D) Venn diagrams of significantly DEGs from RNA sequencing analyses of 8- to 10-month-old gastrocnemius skeletal muscle from the indicated mice (left), as above in B. Heatmap of expression (row Z-scores) of cell cycle inhibitors p16/p19 (Cdkn2a) in each of the individual samples (right), as above in B. n = 4 BubR1+/+ and BubR1H/L1002P, and n = 3 BubR1H/H mice were used for analyses. (E) Venn diagrams of putative SASP factors within the upregulated DEGs from BubR1H/L1002P versus BubR1+/+ and BubR1H/H versus BubR1+/+ RNA sequencing results from skeletal muscle, as above in C (top). Heatmap of expression of 26 select putative SASP factors significantly upregulated in BubR1H/L1002P and/or BubR1H/H skeletal muscle, as above in C (bottom). See Methods for statistical analyses for RNA sequencing (B and D). **P < 0.01; ***P < 0.001. NS, not significant.

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