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Biallelic TRIP13 mutations predispose to Wilms tumor and chromosome missegregation


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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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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Authors and Affiliations



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.

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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).

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