Reduced Life- and Healthspan in Mice Carrying a Mono-Allelic BubR1 MVA Mutation

Tobias Wijshake,Darren J Baker,Bart Van De Sluis,Liviu A Malureanu,Karthik B Jeganathan,Jan M Van Deursen,Paul Hasty

doi:10.1371/journal.pgen.1003138

Abstract

Mosaic Variegated Aneuploidy (MVA) syndrome is a rare autosomal recessive disorder characterized by inaccurate chromosome segregation and high rates of near-diploid aneuploidy. Children with MVA syndrome die at an early age, are cancer prone, and have progeroid features like facial dysmorphisms, short stature, and cataracts. The majority of MVA cases are linked to mutations in BUBR1, a mitotic checkpoint gene required for proper chromosome segregation. Affected patients either have bi-allelic BUBR1 mutations, with one allele harboring a missense mutation and the other a nonsense mutation, or mono-allelic BUBR1 mutations combined with allelic variants that yield low amounts of wild-type BubR1 protein. Parents of MVA patients that carry single allele mutations have mild mitotic defects, but whether they are at risk for any of the pathologies associated with MVA syndrome is unknown. To address this, we engineered a mouse model for the nonsense mutation 2211insGTTA (referred to as GTTA) found in MVA patients with bi-allelic BUBR1 mutations. Here we report that both the median and maximum lifespans of the resulting BubR1 +/GTTA mice are significantly reduced. Furthermore, BubR1 +/GTTA mice develop several aging-related phenotypes at an accelerated rate, including cataract formation, lordokyphosis, skeletal muscle wasting, impaired exercise ability, and fat loss. BubR1 +/GTTA mice develop mild aneuploidies and show enhanced growth of carcinogen-induced tumors. Collectively, these data demonstrate that the BUBR1 GTTA mutation compromises longevity and healthspan, raising the interesting possibility that mono-allelic changes in BUBR1 might contribute to differences in aging rates in the general population.

Highlights

Separation of duplicated chromosomes during mitosis is an intricate biological process whose molecular basis is incompletely understood
Mosaic Variegated Aneuploidy (MVA) syndrome is rare due to its recessive nature, individuals carrying heterozygous BUBR1 mutations associated with MVA would be much more prevalent
We engineered mice to carry an analogous mutation to the human MVA BUBR1 nonsense mutation 2211insGTTA

Summary

Introduction

Separation of duplicated chromosomes during mitosis is an intricate biological process whose molecular basis is incompletely understood. The mitotic checkpoint is a multi-protein network that inhibits sister chromatid separation until all chromosomes are properly attached to the mitotic spindle [8]. One of the core components of this checkpoint is BubR1, a modular protein that acts to inhibit the activity of the large multi-protein E3 ubiquitin ligase known as the anaphase promoting complex/cyclosome (APC/C), by binding to the co-activating subunit Cdc20 [9]. Once all chromosomes have achieved bi-orientation, BubR1 dissociates from Cdc leading to the polyubiquitination of securin and cyclin B1, two inhibitors of separase, a protease that initiates anaphase by cleaving cohesin rings that physically join duplicated sister chromosomes together. BubR1 promotes accurate chromosome segregation in its role as a Cdc inhibitor, and acts to stabilize microtubule-kinetochore attachments [10]

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Conclusion