Alternative titles; symbols
HGNC Approved Gene Symbol: DIS3L2
SNOMEDCT: 722231005;
Cytogenetic location: 2q37.1 Genomic coordinates (GRCh38): 2:231,961,713-232,344,350 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 2q37.1 | Perlman syndrome | 267000 | Autosomal recessive | 3 |
The RNA exosome is an approximately 400-kD multimeric ribonucleolytic complex that participates in both endonucleolytic and 3-prime/5-prime exonucleolytic activity in RNA processing and in the degradation of a variety of RNA substrates. DIS3L2 shares high sequence similarity with catalytic exosome subunits that have 3-prime/5-prime exonucleolytic activity (summary by Tomecki et al., 2010).
By searching the human genomic database for sequences similar to DIS3L (614183), Staals et al. (2010) identified 5 potential splice variants of DIS3L2. The longest deduced protein contains 885 amino acids and has a calculated molecular mass of 99.2 kD. It has a poorly conserved N-terminal PIN domain, followed by a cold-shock domain, a putative RNB exonuclease catalytic domain, and a possible C-terminal S1 RNA-binding domain.
Crystal Structure
An oligoU tail added to pre-let7 (see MIRLET7A1, 605386) serves as a signal for pre-let7 to be rapidly degraded by DIS3L2. To examine the mechanism of DIS3L2 substrate recognition, Faehnle et al. (2014) determined the crystal structure of mouse Dis3l2 in complex with an oligoU RNA to mimic the uridylated tail of pre-let7. Three RNA-binding domains form an open funnel on one face of the catalytic domain that allows RNA to navigate a path to the active site different from that of its exosome counterpart. The resulting path reveals an extensive network of uracil-specific interactions spanning the first 12 nucleotides of an oligoU-tailed RNA. Faehnle et al. (2014) identified 3 U-specificity zones that explain how DIS3L2 recognizes, binds, and processes uridylated pre-LET7 in the final step of the LIN28 (611043)-LET7 pathway.
Hartz (2011) mapped the DIS3L2 gene to chromosome 2q37.2 based on an alignment of the DIS3L2 sequence (GenBank BC030113) with the genomic sequence (GRCh37).
In transfected COS-7 and HeLa cells, Astuti et al. (2012) observed that DIS3L2 was localized predominantly in the cytoplasm. RNA degradation assays using transfected HEK293 cells demonstrated that DIS3L2 has exonuclease activity. Knockdown studies in HeLa cells showed that DIS3L2 inactivation was associated with mitotic abnormalities and altered expression of mitotic checkpoint proteins, with lowered expression of TTK (604092), aurora B (AURKB; 604970), and phosphorylated CDC25C (157680), but upregulation of cyclin B1 (CCNB1; 123836), RAD21 (606462), and securin (PTTG1; 604147). DIS3L2 overexpression suppressed the growth of human cancer cell lines, and knockdown enhanced the growth of those cells. Astuti et al. (2012) concluded that DIS3L2 has a critical role in RNA metabolism and is essential for the regulation of cell growth and division.
The pluripotency factor LIN28 (611043) blocks the expression of LET7 (605386) microRNAs in undifferentiated cells during development by binding to pre-LET7 RNAs and recruiting RNA uridyltransferases ZCCHC11 (613692) and ZCCHC6 (613467) to uridylate pre-LET7. The identity of the RNase that degrades uridylated pre-LET7 was unknown. Chang et al. (2013) identified Dis3l2 as the 3-prime-5-prime exonuclease responsible for the decay of uridylated pre-let7 in mouse embryonic stem cells. Biochemical reconstitution assays showed that 3-prime oligouridylation stimulates Dis3l2 activity in vitro, and knockdown of Dis3l2 in mouse embryonic stem cells leads to the stabilization of pre-let7. Chang et al. (2013) concluded that their study established 3-prime oligouridylation as an RNA decay signal for DIS3L2 and identified the first physiologic RNA substrate of this exonuclease.
In 8 affected individuals from 6 families with Perlman syndrome (PRLMNS; 267000), Astuti et al. (2012) identified homozygosity or compound heterozygosity for mutations in the DIS3L2 gene (614184.0001-614184.0004).
In a brother and sister from a consanguineous Pakistani family with Perlman syndrome (267000), Astuti et al. (2012) identified homozygosity for an 82.8-kb deletion (367-41553_602+40962del) between exons 5 and 7 of the DIS3L2 gene, resulting in a truncated protein of 258 amino acids. Functional studies in HEK293 cells demonstrated that mutant DIS3L2 lacking exon 6 had substantially reduced ribonuclease activity. The mutation segregated with disease in the family and was not found in at least 300 ancestrally matched samples. The brother died at 3.5 years of age and the sister at 2 months of age.
In 3 patients from 2 Dutch families with Perlman syndrome (267000), previously reported by Henneveld et al. (1999), as well as an unrelated Dutch infant with this syndrome, Astuti et al. (2012) identified homozygosity for an approximately 22-kb deletion (951-?_1124+?del) between exons 8 and 10 of the DIS3L2 gene, resulting in loss of the RNB domain (gln318_arg375del). Functional studies in HEK293 cells demonstrated that mutant DIS3L2 lacking exon 9 had substantially reduced ribonuclease activity. The mutation segregated with disease in both families and was not found in at least 300 ancestrally matched samples. All 4 Dutch patients died in infancy. In addition, in a cell line from a 30-week amniotic fluid sample from a male patient with Perlman syndrome, the exon 9 deletion was found in compound heterozygosity with a 1466G-A transition in the DIS3L2 gene, resulting in a cys489-to-tyr (C489Y; 614184.0003) substitution at a highly conserved residue.
For discussion of the cys489-to-tyr (C489Y) mutation in the DIS3L2 gene that was found in compound heterozygous state in a patient with Perlman syndrome (267000) by Astuti et al. (2012), see 614184.0002.
In a cell line taken from a 14-year-old girl with Perlman syndrome (267000), previously reported by Neri et al. (1984), Astuti et al. (2012) identified a heterozygous G-to-A transition in exon 19 (2394+5G-A) of the DIS3L2 gene, predicted to cause skipping or deletion of exon 19. The mutation, which segregated with disease in the family, was not found in at least 300 ancestrally matched control samples. Although a second mutation was not detected, only the transcript lacking exon 19 was found, suggesting the presence of another mutation that might abolish transcription or cause mRNA instability.
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., and 9 others. Germline mutations in DIS3L2 cause the Perlman syndrome of overgrowth and Wilms tumor susceptibility. Nature Genet. 44: 277-284, 2012. [PubMed: 22306653] [Full Text: https://doi.org/10.1038/ng.1071]
Chang, H.-M., Triboulet, R., Thornton, J. E., Gregory, R. I. A role for the Perlman syndrome exonuclease Dis3l2 in the Lin28-let-7 pathway. Nature 497: 244-248, 2013. [PubMed: 23594738] [Full Text: https://doi.org/10.1038/nature12119]
Faehnle, C. R., Walleshauser, J., Joshua-Tor, L. Mechanism of Dis3l2 substrate recognition in the Lin28-let-7 pathway. Nature 514: 252-256, 2014. [PubMed: 25119025] [Full Text: https://doi.org/10.1038/nature13553]
Hartz, P. A. Personal Communication. Baltimore, Md. 7/13/2011.
Henneveld, H. T., van Lingen, R. A., Hamel, B. C. J., Stolte-Dijkstra, I., van Essen, A. J. Perlman syndrome: four additional cases and review. Am. J. Med. Genet. 86: 439-446, 1999. [PubMed: 10508986]
Neri, G., Martini-Neri, M. E., Katz, B. E., Opitz, B. E. The Perlman syndrome: familial renal dysplasia with Wilms tumor, fetal gigantism and multiple congenital anomalies. Am. J. Med. Genet. 19: 195-207, 1984. [PubMed: 6093533] [Full Text: https://doi.org/10.1002/ajmg.1320190120]
Staals, R. H. J., Bronkhorst, A. W., Schilders, G., Slomovic, S., Schuster, G., Heck, A. J. R., Raijmakers, R., Pruijn, G. J. M. Dis3-like 1: a novel exoribonuclease associated with the human exosome. EMBO J. 29: 2358-2367, 2010. [PubMed: 20531389] [Full Text: https://doi.org/10.1038/emboj.2010.122]
Tomecki, R., Kristiansen, M. S., Lykke-Andersen, S., Chlebowski, A., Larsen, K. M., Szczesny, R. J., Drazkowska, K., Pastula, A., Andersen, J. S., Stepien, P. P., Dziembowski, A., Jensen, T. H. The human core exosome interacts with differentially localized processive RNases: hDIS3 and hDIS3L. EMBO J. 29: 2342-2357, 2010. [PubMed: 20531386] [Full Text: https://doi.org/10.1038/emboj.2010.121]