Germline mutations in DIS3L2 cause the Perlman syndrome of overgrowth and Wilms tumor susceptibility

Abstract

Perlman syndrome is a congenital overgrowth syndrome inherited in an autosomal recessive manner that is associated with Wilms tumor susceptibility. We mapped a previously unknown susceptibility locus to 2q37.1 and identified germline mutations in DIS3L2, a homolog of the Schizosaccharomyces pombe dis3 gene, in individuals with Perlman syndrome. Yeast dis3 mutant strains have mitotic abnormalities. Yeast Dis3 and its human homologs, DIS3 and DIS3L1, have exoribonuclease activity and bind to the core RNA exosome complex. DIS3L2 has a different intracellular localization and lacks the PIN domain found in DIS3 and DIS3L1; nevertheless, we show that DIS3L2 has exonuclease activity. DIS3L2 inactivation was associated with mitotic abnormalities and altered expression of mitotic checkpoint proteins. DIS3L2 overexpression suppressed the growth of human cancer cell lines, and knockdown enhanced the growth of these cells. We also detected evidence of DIS3L2 mutations in sporadic Wilms tumor. These observations suggest that DIS3L2 has a critical role in RNA metabolism and is essential for the regulation of cell growth and division.

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Figure 1: DIS3L2 mutations in Perlman syndrome.
Figure 2: DIS3L2 shows exoribonuclease activity.
Figure 3: Knockdown of DIS3L2 increases the variability of chromosome number within individual cells.
Figure 4: Knockdown of DIS3L2 induces errors in cell division.
Figure 5: Loss of DIS3L2 expression dysregulates the expression of mitotic control proteins.
Figure 6: Effects of DIS3L2 expression level on cell growth.

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Acknowledgements

We thank J. Arrand for processing the Affymetrix 50k SNP chip. We thank the Association of International Cancer Research (07-0503) and Cancer Research UK (C485/A5441) for financial support.

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D.A. and M.R.M. designed, carried out and analyzed genetic and cell biological experiments; W.N.C. did initial autozygosity mapping and analysis; R.H.J.S. conducted the RNase assay; N.C.W. carried out and analyzed MLPA; H.G. did zebrafish analysis; G.A.F. and S.S. did aneuploidy studies; D.G. and C.J.R. provided technical assistance; T.C., A.J.v.E., R.A.v.L., G.N., J.M.O., P.R., I.S.-D. and E.R.M. recruited subjects, gathered clinical information and contributed clinical samples; F.M., G.J.M.P., F.L. and E.R.M. designed and supervised experiments and analyzed data; E.R.M. directed the research; E.R.M., D.A. and M.M. drafted the manuscript and all authors critically reviewed the manuscript.

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Correspondence to Eamonn R Maher.

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The authors declare no competing financial interests.

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Astuti, D., Morris, M., Cooper, W. et al. Germline mutations in DIS3L2 cause the Perlman syndrome of overgrowth and Wilms tumor susceptibility. Nat Genet 44, 277–284 (2012). https://doi.org/10.1038/ng.1071

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