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Biallelic TRIP13 mutations predispose to Wilms tumor and chromosome missegregation

Nature Genetics volume 49, pages 1148–1151 (2017)Cite this article

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Abstract

Through exome sequencing, we identified six individuals with biallelic loss-of-function mutations in TRIP13. All six developed Wilms tumor. Constitutional mosaic aneuploidies, microcephaly, developmental delay and seizures, which are features of mosaic variegated aneuploidy (MVA) syndrome1,2, were more variably present. Through functional studies, we show that TRIP13-mutant patient cells have no detectable TRIP13 and have substantial impairment of the spindle assembly checkpoint (SAC), leading to a high rate of chromosome missegregation. Accurate segregation, as well as SAC proficiency, is rescued by restoring TRIP13 function. Individuals with biallelic TRIP13 or BUB1B mutations have a high risk of embryonal tumors3, and here we show that their cells display severe SAC impairment. MVA due to biallelic CEP57 mutations4, or of unknown cause, is not associated with embryonal tumors and cells from these individuals show minimal SAC deficiency. These data provide insights into the complex relationships between aneuploidy and carcinogenesis.

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Figure 1: TRIP13 loss-of-function mutations cause chromosome segregation errors and SAC deficiency.
Figure 2: TRIP13 loss-of-function mutations cause reduced levels of MAD2 on unattached kinetochores.
Figure 3: SAC deficiency and CIN caused by TRIP13 loss of function is rescued with wild-type but not mutant TRIP13.
Figure 4: Patient cells with TRIP13 or BUB1B mutations have a severely compromised SAC.

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References

  1. García-Castillo, H., Vásquez-Velásquez, A.I., Rivera, H. & Barros-Núñez, P. Clinical and genetic heterogeneity in patients with mosaic variegated aneuploidy: delineation of clinical subtypes. Am. J. Med. Genet. A. 146A, 1687–1695 (2008).

    Article  Google Scholar 

  2. Warburton, D., Anyane-Yeboa, K., Taterka, P., Yu, C.Y. & Olsen, D. Mosaic variegated aneuploidy with microcephaly: a new human mitotic mutant? Ann. Genet. 34, 287–292 (1991).

    CAS  PubMed  Google Scholar 

  3. Hanks, S. et al. Constitutional aneuploidy and cancer predisposition caused by biallelic mutations in BUB1B. Nat. Genet. 36, 1159–1161 (2004).

    Article  CAS  Google Scholar 

  4. Snape, K. et al. Mutations in CEP57 cause mosaic variegated aneuploidy syndrome. Nat. Genet. 43, 527–529 (2011).

    Article  CAS  Google Scholar 

  5. Ricke, R.M. & van Deursen, J.M. Aneuploidy in health, disease, and aging. J. Cell Biol. 201, 11–21 (2013).

    Article  CAS  Google Scholar 

  6. Holland, A.J. & Cleveland, D.W. Boveri revisited: chromosomal instability, aneuploidy and tumorigenesis. Nat. Rev. Mol. Cell Biol. 10, 478–487 (2009).

    Article  CAS  Google Scholar 

  7. Torres, E.M., Williams, B.R. & Amon, A. Aneuploidy: cells losing their balance. Genetics 179, 737–746 (2008).

    Article  CAS  Google Scholar 

  8. Thompson, S.L., Bakhoum, S.F. & Compton, D.A. Mechanisms of chromosomal instability. Curr. Biol. 20, R285–R295 (2010).

    Article  CAS  Google Scholar 

  9. Kajii, T. et al. Cancer-prone syndrome of mosaic variegated aneuploidy and total premature chromatid separation: report of five infants. Am. J. Med. Genet. 104, 57–64 (2001).

    Article  CAS  Google Scholar 

  10. Jacquemont, S., Bocéno, M., Rival, J.M., Méchinaud, F. & David, A. High risk of malignancy in mosaic variegated aneuploidy syndrome. Am. J. Med. Genet. 109, 17–21, discussion 16 (2002).

    Article  Google Scholar 

  11. Ruark, E. et al. OpEx—a validated, automated pipeline optimised for clinical exome sequence analysis. Sci. Rep. 6, 31029 (2016).

    Article  CAS  Google Scholar 

  12. Mahamdallie, S.S. et al. Mutations in the transcriptional repressor REST predispose to Wilms tumor. Nat. Genet. 47, 1471–1474 (2015).

    Article  CAS  Google Scholar 

  13. Lek, M. et al. Analysis of protein-coding genetic variation in 60,706 humans. Nature 536, 285–291 (2016).

    Article  CAS  Google Scholar 

  14. Ruark, E. et al. The ICR1000 UK exome series: a resource of gene variation in an outbred population. F1000Res 4, 883 (2015).

    Article  Google Scholar 

  15. Vader, G. Pch2TRIP13: controlling cell division through regulation of HORMA domains. Chromosoma 124, 333–339 (2015).

    Article  CAS  Google Scholar 

  16. Eytan, E. et al. Disassembly of mitotic checkpoint complexes by the joint action of the AAA-ATPase TRIP13 and p31comet. Proc. Natl. Acad. Sci. USA 111, 12019–12024 (2014).

    Article  CAS  Google Scholar 

  17. Ye, Q. et al. TRIP13 is a protein-remodeling AAA+ ATPase that catalyzes MAD2 conformation switching. eLife 4, e07367 (2015).

    Article  Google Scholar 

  18. Wang, K. et al. Thyroid hormone receptor interacting protein 13 (TRIP13) AAA-ATPase is a novel mitotic checkpoint–silencing protein. J. Biol. Chem. 289, 23928–23937 (2014).

    Article  CAS  Google Scholar 

  19. Nelson, C.R., Hwang, T., Chen, P.H. & Bhalla, N. TRIP13PCH-2 promotes Mad2 localization to unattached kinetochores in the spindle checkpoint response. J. Cell Biol. 211, 503–516 (2015).

    Article  CAS  Google Scholar 

  20. Ma, H.T. & Poon, R.Y. TRIP13 regulates both the activation and inactivation of the spindle-assembly checkpoint. Cell Rep. 14, 1086–1099 (2016).

    Article  CAS  Google Scholar 

  21. Vleugel, M., Hoogendoorn, E., Snel, B. & Kops, G.J. Evolution and function of the mitotic checkpoint. Dev. Cell 23, 239–250 (2012).

    Article  CAS  Google Scholar 

  22. Lunter, G. & Goodson, M. Stampy: a statistical algorithm for sensitive and fast mapping of Illumina sequence reads. Genome Res. 21, 936–939 (2011).

    Article  CAS  Google Scholar 

  23. Rimmer, A. et al. Integrating mapping-, assembly- and haplotype-based approaches for calling variants in clinical sequencing applications. Nat. Genet. 46, 912–918 (2014).

    Article  CAS  Google Scholar 

  24. Münz, M. et al. CSN and CAVA: variant annotation tools for rapid, robust next-generation sequencing analysis in the clinical setting. Genome Med. 7, 76 (2015).

    Article  Google Scholar 

  25. Abecasis, G.R. et al. An integrated map of genetic variation from 1,092 human genomes. Nature 491, 56–65 (2012).

    Article  Google Scholar 

  26. Gibson, D.G. et al. Enzymatic assembly of DNA molecules up to several hundred kilobases. Nat. Methods 6, 343–345 (2009).

    Article  CAS  Google Scholar 

  27. Drost, J. et al. Sequential cancer mutations in cultured human intestinal stem cells. Nature 521, 43–47 (2015).

    Article  CAS  Google Scholar 

  28. Carpenter, A.E. et al. CellProfiler: image analysis software for identifying and quantifying cell phenotypes. Genome Biol. 7, R100 (2006).

    Article  Google Scholar 

Download references

Acknowledgements

We thank the families for their participation and the researchers who recruited them, including K. Asakura-Hay, S. Bernardo de Sousa, P. Callier, D. Chitayat, J. Clayton-Smith, S. Fernandes, D. FitzPatrick, L. Florentin, J. Hurst, B. Isidor, S. Jacquemont, R. Marin Iglesias, M. Micale and J. Tolmie. We thank H.J. Snippert (UMC Utrecht) for providing the lentiviral H2B plasmid. We thank A. Renwick, S. Mahamdallie, C. Loveday and members of the Kops laboratory for helpful discussions and A. Strydom and B. Rex for assistance in preparing the manuscript. We acknowledge NHS funding to the Royal Marsden/ICR NIHR Biomedical Research Centre. This research was supported by the Wellcome Trust (100210/Z/12/Z), by the Netherlands Organisation for Scientific Research (NWO-ALW 823.02.004 to G.J.P.L.K.) and by the Dutch Cancer Society (KWF Kankerbestrijding to R.M.d.V., KUN2014-6666).

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Author notes

  1. Shawn Yost, Bas de Wolf and Sandra Hanks: These authors contributed equally to this work.

  2. Geert J P L Kops and Nazneen Rahman: These authors jointly directed this work.

Authors and Affiliations

  1. Division of Genetics and Epidemiology, The Institute of Cancer Research, London, UK

    Shawn Yost, Sandra Hanks, Anna Zachariou, Matthew Clarke, Emma Ramsay, Harriet Wylie, Anna Elliott, Sheila Seal, Elise Ruark & Nazneen Rahman

  2. Hubrecht Institute–KNAW (Royal Netherlands Academy of Arts and Sciences), Utrecht, The Netherlands

    Bas de Wolf, Richarda M de Voer, Banafsheh Etemad, Esther Uijttewaal & Geert J P L Kops

  3. Division of Cancer Biology, The Institute of Cancer Research, London, UK

    Chiara Marcozzi & Jonathon Pines

  4. Gurdon Institute and Department of Zoology, University of Cambridge, Cambridge, UK

    Chiara Marcozzi & Jonathon Pines

  5. Department of Human Genetics, Radboud University Medical Center, Nijmegen, The Netherlands

    Richarda M de Voer

  6. Children's and Adolescent Oncology and Haematology Unit, Leeds General Infirmary, Leeds, UK

    Susan Picton

  7. Yorkshire Regional Clinical Genetics Service, Chapel Allerton Hospital, Leeds, UK

    Audrey Smith

  8. Clinical Genetics Service, St Michael's Hospital, Bristol, UK

    Sarah Smithson

  9. Center for Medical Genetics, Haukeland University Hospital, Bergen, Norway

    Gunnar Houge

  10. Cancer Genomics Netherlands, Utrecht, The Netherlands

    Geert J P L Kops

  11. Center for Molecular Medicine, University Medical Center Utrecht, Utrecht, The Netherlands

    Geert J P L Kops

  12. Cancer Genetics Unit, Royal Marsden NHS Foundation Trust, London, UK

    Nazneen Rahman

Authors
  1. Shawn Yost
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Contributions

N.R. designed and oversaw the study. G.J.P.L.K. designed and oversaw the functional experiments. E. Ramsay undertook the exome sequencing. S.H., H.W. and S. Seal performed the molecular analyses. S.Y., M.C. and E. Ruark performed bioinformatic analyses. B.d.W., E.U., R.M.d.V., B.E. and C.M. undertook functional analyses under the supervision of G.J.P.L.K., and J.P., S.P., A.S., S. Smithson and G.H. provided samples and data, coordinated by A.Z. and A.E. S.Y., S.H., B.d.W., A.Z., G.J.P.L.K. and N.R. wrote the manuscript with input from the other authors.

Corresponding authors

Correspondence to Geert J P L Kops or Nazneen Rahman.

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The authors declare no competing financial interests.

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Yost, S., de Wolf, B., Hanks, S. et al. Biallelic TRIP13 mutations predispose to Wilms tumor and chromosome missegregation. Nat Genet 49, 1148–1151 (2017). https://doi.org/10.1038/ng.3883

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