Journal Article

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

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

2012

Overview

Eamonn Maher and colleagues report germline mutations in DIS3L2 causing the Perlman syndrome of overgrowth and susceptibility to Wilms tumor. DIS3L2 encodes a protein with exoribonuclease activity in the RNA exosome complex. 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.

• Publisher: Nature Publishing Group US,Nature Publishing Group
• Subject: 631/208/2489/144 / 631/208/68 / 631/208/737 / Adolescent / Agriculture / Animal Genetics and Genomics / Base Sequence / Biological and medical sciences / Biomedical and Life Sciences / Biomedicine / Cancer / Cancer Research / Cell Division - genetics / Cell Proliferation / Child, Preschool / Chromosomes, Human, Pair 2 - genetics / Exoribonucleases - genetics / Fetal Macrosomia - genetics / Fundamental and applied biological sciences. Psychology / Gene Expression Regulation - genetics / Gene Function / Gene Knockdown Techniques / Gene mutations / Genes / Genes, cdc - genetics / Genetic aspects / Genetic Predisposition to Disease - genetics / Genetics / Genetics of eukaryotes. Biological and molecular evolution / Germ-Line Mutation - genetics / Hamartoma / HeLa Cells / Human Genetics / Humans / Inactivation / Infant / Infant, Newborn / Kidney Neoplasms - genetics / Kidneys / Medical research / Medical sciences / Molecular Sequence Data / Mutation / Nephrology. Urinary tract diseases / Risk factors / RNA - metabolism / Schizosaccharomyces pombe / Sequence Analysis, DNA / Tumors of the urinary system / Wilms Tumor - genetics / Yeasts