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      Mosaic-variegated aneuploidy syndrome mutation or haploinsufficiency in Cep57 impairs tumor suppression

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          Abstract

          A homozygous truncating frameshift mutation in CEP57 (CEP57 T/T) has been identified in a subset of mosaic-variegated aneuploidy (MVA) patients; however, the physiological roles of the centrosome-associated protein CEP57 that contribute to disease are unknown. To investigate these, we have generated a mouse model mimicking this disease mutation. Cep57 T/T mice died within 24 hours after birth with short, curly tails and severely impaired vertebral ossification. Osteoblasts in lumbosacral vertebrae of Cep57 T/T mice were deficient for Fgf2, a Cep57 binding partner implicated in diverse biological processes, including bone formation. Furthermore, a broad spectrum of tissues of Cep57 T/T mice had severe aneuploidy at birth, consistent with the MVA patient phenotype. Cep57 T/T mouse embryonic fibroblasts and patient-derived skin fibroblasts failed to undergo centrosome maturation in G 2 phase, causing premature centriole disjunction, centrosome amplification, aberrant spindle formation, and high rates of chromosome missegregation. Mice heterozygous for the truncating frameshift mutation or a Cep57-null allele were overtly indistinguishable from WT mice despite reduced Cep57 protein levels, yet prone to aneuploidization and cancer, with tumors lacking evidence for loss of heterozygosity. This study identifies Cep57 as a haploinsufficient tumor suppressor with biologically diverse roles in centrosome maturation and Fgf2-mediated bone formation.

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          BubR1 insufficiency causes early onset of aging-associated phenotypes and infertility in mice.

          Faithful segregation of replicated chromosomes is essential for maintenance of genetic stability and seems to be monitored by several mitotic checkpoints. Various components of these checkpoints have been identified in mammals, but their physiological relevance is largely unknown. Here we show that mutant mice with low levels of the spindle assembly checkpoint protein BubR1 develop progressive aneuploidy along with a variety of progeroid features, including short lifespan, cachectic dwarfism, lordokyphosis, cataracts, loss of subcutaneous fat and impaired wound healing. Graded reduction of BubR1 expression in mouse embryonic fibroblasts causes increased aneuploidy and senescence. Male and female mutant mice have defects in meiotic chromosome segregation and are infertile. Natural aging of wild-type mice is marked by decreased expression of BubR1 in multiple tissues, including testis and ovary. These results suggest a role for BubR1 in regulating aging and infertility.
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            Merotelic Kinetochore Orientation Is a Major Mechanism of Aneuploidy in Mitotic Mammalian Tissue Cells

            In mitotic cells, an error in chromosome segregation occurs when a chromosome is left near the spindle equator after anaphase onset (lagging chromosome). In PtK1 cells, we found 1.16% of untreated anaphase cells exhibiting lagging chromosomes at the spindle equator, and this percentage was enhanced to 17.55% after a mitotic block with 2 μM nocodazole. A lagging chromosome seen during anaphase in control or nocodazole-treated cells was found by confocal immunofluorescence microscopy to be a single chromatid with its kinetochore attached to kinetochore microtubule bundles extending toward opposite poles. This merotelic orientation was verified by electron microscopy. The single kinetochores of lagging chromosomes in anaphase were stretched laterally (1.2–5.6-fold) in the directions of their kinetochore microtubules, indicating that they were not able to achieve anaphase poleward movement because of pulling forces toward opposite poles. They also had inactivated mitotic spindle checkpoint activities since they did not label with either Mad2 or 3F3/2 antibodies. Thus, for mammalian cultured cells, kinetochore merotelic orientation is a major mechanism of aneuploidy not detected by the mitotic spindle checkpoint. The expanded and curved crescent morphology exhibited by kinetochores during nocodazole treatment may promote the high incidence of kinetochore merotelic orientation that occurs after nocodazole washout.
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              Constitutional aneuploidy and cancer predisposition caused by biallelic mutations in BUB1B.

              Mosaic variegated aneuploidy is a rare recessive condition characterized by growth retardation, microcephaly, childhood cancer and constitutional mosaicism for chromosomal gains and losses. In five families with mosaic variegated aneuploidy, including two with embryonal rhabdomyosarcoma, we identified truncating and missense mutations of BUB1B, which encodes BUBR1, a key protein in the mitotic spindle checkpoint. These data are the first to relate germline mutations in a spindle checkpoint gene with a human disorder and strongly support a causal link between aneuploidy and cancer development.
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                Author and article information

                Contributors
                Journal
                J Clin Invest
                J. Clin. Invest
                J Clin Invest
                The Journal of Clinical Investigation
                American Society for Clinical Investigation
                0021-9738
                1558-8238
                23 July 2018
                1 August 2018
                1 August 2018
                : 128
                : 8
                : 3517-3534
                Affiliations
                [1 ]Department of Biochemistry and Molecular Biology and
                [2 ]Department of Pediatric and Adolescent Medicine, Mayo Clinic, Rochester, Minnesota, USA.
                [3 ]Division of Genetics and Epidemiology, The Institute of Cancer Research, London, United Kingdom.
                Author notes
                Address correspondence to: Jan M. van Deursen, Mayo Clinic, 200 First Street SW, Rochester, Minnesota 55905, USA. Phone: 507.284.2524; Email: vandeursen.jan@ 123456mayo.edu .
                Article
                120316
                10.1172/JCI120316
                6063474
                30035751
                17c4230a-c1e1-4ad8-b36d-1bb89fa1861b
                Copyright © 2018 Aziz et al.

                This work is licensed under the Creative Commons Attribution 4.0 International License. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

                History
                : 2 February 2018
                : 6 June 2018
                Funding
                Funded by: National Institutes of Health, https://doi.org/10.13039/100000002;
                Award ID: CA96985,CA126828
                Categories
                Research Article

                cell biology,oncology,bone development,genetic diseases
                cell biology, oncology, bone development, genetic diseases

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