Reduced life- and healthspan in mice carrying a mono-allelic BubR1 MVA mutation.
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, sho...
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Public Library of Science (PLoS)
2012-01-01
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| Series: | PLoS Genetics |
| Online Access: | https://journals.plos.org/plosgenetics/article/file?id=10.1371/journal.pgen.1003138&type=printable |
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| author | Tobias Wijshake Liviu A Malureanu Darren J Baker Karthik B Jeganathan Bart van de Sluis Jan M van Deursen |
| author_facet | Tobias Wijshake Liviu A Malureanu Darren J Baker Karthik B Jeganathan Bart van de Sluis Jan M van Deursen |
| author_sort | Tobias Wijshake |
| collection | DOAJ |
| description | 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. |
| format | Article |
| id | doaj-art-e660110b9f42454f9f63639bbd07ba42 |
| institution | OA Journals |
| issn | 1553-7390 1553-7404 |
| language | English |
| publishDate | 2012-01-01 |
| publisher | Public Library of Science (PLoS) |
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| series | PLoS Genetics |
| spelling | doaj-art-e660110b9f42454f9f63639bbd07ba422025-08-20T02:15:30ZengPublic Library of Science (PLoS)PLoS Genetics1553-73901553-74042012-01-01812e100313810.1371/journal.pgen.1003138Reduced life- and healthspan in mice carrying a mono-allelic BubR1 MVA mutation.Tobias WijshakeLiviu A MalureanuDarren J BakerKarthik B JeganathanBart van de SluisJan M van DeursenMosaic 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.https://journals.plos.org/plosgenetics/article/file?id=10.1371/journal.pgen.1003138&type=printable |
| spellingShingle | Tobias Wijshake Liviu A Malureanu Darren J Baker Karthik B Jeganathan Bart van de Sluis Jan M van Deursen Reduced life- and healthspan in mice carrying a mono-allelic BubR1 MVA mutation. PLoS Genetics |
| title | Reduced life- and healthspan in mice carrying a mono-allelic BubR1 MVA mutation. |
| title_full | Reduced life- and healthspan in mice carrying a mono-allelic BubR1 MVA mutation. |
| title_fullStr | Reduced life- and healthspan in mice carrying a mono-allelic BubR1 MVA mutation. |
| title_full_unstemmed | Reduced life- and healthspan in mice carrying a mono-allelic BubR1 MVA mutation. |
| title_short | Reduced life- and healthspan in mice carrying a mono-allelic BubR1 MVA mutation. |
| title_sort | reduced life and healthspan in mice carrying a mono allelic bubr1 mva mutation |
| url | https://journals.plos.org/plosgenetics/article/file?id=10.1371/journal.pgen.1003138&type=printable |
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