Germline mutations in DIS3L2 cause the Perlman syndrome of overgrowth and Wilms tumor susceptibility.
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.
Centre for Rare Diseases and Personalised Medicine, School of Clinical and Experimental Medicine, College of Medical and Dental Sciences, University of Birmingham, UK.
Dewi
D
Astuti
Mark R
MR
Morris
Wendy N
WN
Cooper
Raymond H J
RH
Staals
Naomi C
NC
Wake
Graham A
GA
Fews
Harmeet
H
Gill
Dean
D
Gentle
Salwati
S
Shuib
Christopher J
CJ
Ricketts
Trevor
T
Cole
Anthonie J
AJ
van Essen
Richard A
RA
van Lingen
Giovanni
G
Neri
John M
JM
Opitz
Patrick
P
Rump
Irene
I
Stolte-Dijkstra
Ferenc
F
Müller
Ger J M
GJ
Pruijn
Farida
F
Latif
Eamonn R
ER
Maher
D000293:Adolescent; D001483:Base Sequence; D002455:Cell Division / Q000235:genetics; D049109:Cell Proliferation; D002675:Child, Preschool; D002889:Chromosomes, Human, Pair 2 / Q000235:genetics*; D005095:Exoribonucleases / Q000235:genetics*; D005320:Fetal Macrosomia / Q000235:genetics*; D005786:Gene Expression Regulation / Q000235:genetics*; D055785:Gene Knockdown Techniques; D018816:Genes, cdc / Q000235:genetics; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D018095:Germ-Line Mutation / Q000235:genetics*; D006367:HeLa Cells; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D007680:Kidney Neoplasms / Q000235:genetics*; D008969:Molecular Sequence Data; D012313:RNA / Q000378:metabolism; D017422:Sequence Analysis, DNA; D009396:Wilms Tumor / Q000235:genetics*
D012313:RNA; C571454:DIS3L2 protein, human; D005095:Exoribonucleases