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

Dewi Astuti; Mark R. Morris; Wendy N. Cooper; Raymond H. J. Staals; Naomi C. Wake; Graham A. Fews; Harmeet Gill; Dean Gentle; Salwati Shuib; Christopher J. Ricketts; Trevor Cole; Anthonie J. Van Essen; Richard A. van Lingen; Giovanni Neri; John M. Opitz; Patrick Rump; Irene Stolte-Dijkstra; Ferenc Müller; Ger J. M. Pruijn; Farida Latif; Eamonn R. Maher

doi:10.1038/ng.1071

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

Dewi Astuti, Mark R. Morris, Wendy N. Cooper, Raymond H. J. Staals, Naomi C. Wake, Graham A. Fews, Harmeet Gill, Dean Gentle, Salwati Shuib, Christopher J. Ricketts, Trevor Cole, Anthonie J. Van Essen, Richard A. van Lingen, Giovanni Neri, John M. Opitz, Patrick Rump, Irene Stolte-Dijkstra, Ferenc Müller, Ger J. M. Pruijn, Farida LatifEamonn R. Maher^*

^*Corresponding author for this work

Aston Medical School

Research output: Contribution to journal › Article › peer-review

201 Citations (SciVal)

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.

Original language	English
Pages (from-to)	277-284
Number of pages	8
Journal	Nature Genetics
Volume	44
Issue number	3
Early online date	5 Feb 2012
DOIs	https://doi.org/10.1038/ng.1071
Publication status	Published - Mar 2012

Funding

The authors 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.

Funders	Funder number
Association for International Cancer Research	07-0503
Cancer Research UK	C485/A5441

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Astuti, D., Morris, M. R., Cooper, W. N., Staals, R. H. J., Wake, N. C., Fews, G. A., Gill, H., Gentle, D., Shuib, S., Ricketts, C. J., Cole, T., Van Essen, A. J., van Lingen, R. A., Neri, G., Opitz, J. M., Rump, P., Stolte-Dijkstra, I., Müller, F., Pruijn, G. J. M., ... Maher, E. R. (2012). Germline mutations in DIS3L2 cause the Perlman syndrome of overgrowth and Wilms tumor susceptibility. Nature Genetics, 44(3), 277-284. https://doi.org/10.1038/ng.1071

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title = "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.",

author = "Dewi Astuti and Morris, {Mark R.} and Cooper, {Wendy N.} and Staals, {Raymond H. J.} and Wake, {Naomi C.} and Fews, {Graham A.} and Harmeet Gill and Dean Gentle and Salwati Shuib and Ricketts, {Christopher J.} and Trevor Cole and {Van Essen}, {Anthonie J.} and {van Lingen}, {Richard A.} and Giovanni Neri and Opitz, {John M.} and Patrick Rump and Irene Stolte-Dijkstra and Ferenc M{\"u}ller and Pruijn, {Ger J. M.} and Farida Latif and Maher, {Eamonn R.}",

year = "2012",

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doi = "10.1038/ng.1071",

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Astuti, D, Morris, MR, Cooper, WN, Staals, RHJ, Wake, NC, Fews, GA, Gill, H, Gentle, D, Shuib, S, Ricketts, CJ, Cole, T, Van Essen, AJ, van Lingen, RA, Neri, G, Opitz, JM, Rump, P, Stolte-Dijkstra, I, Müller, F, Pruijn, GJM, Latif, F & Maher, ER 2012, 'Germline mutations in DIS3L2 cause the Perlman syndrome of overgrowth and Wilms tumor susceptibility', Nature Genetics, vol. 44, no. 3, pp. 277-284. https://doi.org/10.1038/ng.1071

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AU - Wake, Naomi C.

AU - Fews, Graham A.

AU - Gill, Harmeet

AU - Gentle, Dean

AU - Shuib, Salwati

AU - Ricketts, Christopher J.

AU - Cole, Trevor

AU - Van Essen, Anthonie J.

AU - van Lingen, Richard A.

AU - Neri, Giovanni

AU - Opitz, John M.

AU - Rump, Patrick

AU - Stolte-Dijkstra, Irene

AU - Müller, Ferenc

AU - Pruijn, Ger J. M.

AU - Latif, Farida

AU - Maher, Eamonn R.

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N2 - 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.

AB - 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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ER -

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

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