Alternative titles; symbols
HGNC Approved Gene Symbol: RNASEL
Cytogenetic location: 1q25.3 Genomic coordinates (GRCh38): 1:182,573,634-182,589,256 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 1q25.3 | Prostate cancer 1 | 601518 | Autosomal dominant | 3 |
2-5A-dependent RNase is a component of the interferon-regulated 2-5A system that functions in the antiviral and antiproliferative roles of interferons. Treatment of cells with interferon results in enhanced levels of both 2-5A-dependent RNase and a group of synthetases that produce 5-prime-triphosphorylated, 2-prime,5-prime-oligoadenylates (2-5A) from ATP. The role of the 2-5A system in the control of viral and cellular growth suggests that defects in the 2-5A-dependent RNase gene could result in reduced immunity to virus infections and cancer (Hassel et al., 1993).
Bisbal et al. (1995) reviewed the mechanism of the interferon-induced 2-5A/RNase L pathway and identified an inhibitor of RNase 4, which they referred to as RNase L inhibitor (601213).
Using a mouse fibroblast cell line lacking Rnasel, Mda5 (606951), Rigi (609631), or Ips1 (610979), Malathi et al. (2007) observed a reduced capacity to express Ifnb (147640) in response to triphosphorylated (active) 2-prime,5-prime-linked oligoadenylate (2-5A) or expression of Sendai virus, a negative RNA strand virus. In a human prostate cancer cell line, knockdown of MDA5, RIGI, or IPS1 also inhibited IFNB expression. Infection of Rnasel-deficient mice with either positive- or, more markedly, negative-stranded RNA viruses also resulted in reduced Ifnb production. Malathi et al. (2007) concluded that RNASEL is crucial for enhancing IFNB production through the RIGI-MDA5-IPS1 cascade and that RNASEL contributes to the IFN antiviral response by directly clearing viral and even cellular RNA to support a broad antiviral state in the host.
Using a human lung cell line, Lin et al. (2009) showed that RNASEL played an antiviral role against Dengue virus (see 614371). Of the 10 OAS isoforms generated by alternative splicing of the 4 human OAS genes, only the p42 and p46 isoforms of OAS1 (164350) and the p100 isoform of OAS3 (603351) blocked Dengue virus replication by inducing RNASEL activity in infected cells.
Crystal Structure
Han et al. (2014) reported 2.8- and 2.1-angstrom crystal structures of human RNaseL in complexes with synthetic and natural ligands and a fragment of an RNA substrate. RNaseL forms a crossed homodimer stabilized by ankyrin (ANK; see 612641) and kinase homology (KH) domains, which positions 2 kinase extension nuclease (KEN) domains for asymmetric RNA recognition. One KEN protomer recognizes an identity nucleotide (U), whereas the other protomer cleaves RNA between nucleotides +1 and +2. Han et al. (2014) concluded that the coordinated action of the ANK, KH, and KEN domains thereby provides regulated, sequence-specific cleavage of viral and host RNA targets by RNaseL.
By fluorescence in situ hybridization, Squire et al. (1994) assigned the RNS4 gene to 1q25. Squire et al. (1994) pointed to several congenital and neoplastic disorders that map to that region of the long arm of chromosome 1.
One form of hereditary prostate cancer, HPC1 (601518), is linked to the 1q24-q25 region. By a positional cloning/candidate gene approach, Carpten et al. (2002) identified the RNASEL gene as the site of different germline mutations in 2 HPC1-linked families. They initially screened a set of DNA samples representing 1 affected individual from each of 26 families at high risk for prostate cancer, including 8 families that showed linkage to the HPC1 region and that had at least 4 affected individuals sharing an HPC1 haplotype. They identified a glu265-to-stop (180435.0001) mutation in a proband from 1 family and a G-to-A transition in the initiating methionine codon (AUG) of the RNase L transcript (180435.0002) in a second family.
Rokman et al. (2002) screened for RNASEL germline mutations in 66 Finnish patients with HPC and determined the frequency of the mutations in the index patients from 116 families with HPC, in 492 patients with unselected prostate cancer (PRCA), in 223 patients with benign prostatic hyperplasia (BPH), and in 566 controls. A truncating mutation, E265X (180435.0001), was found in 5 (4.3%) of the 116 patients from families with HPC; this was significantly higher than the frequency in controls (1.8%). The highest frequency of this mutation (9.5%) was found in patients from families with 4 or more affected members. The median age at disease onset for E265X carriers was 11 years less than that for noncarriers in the same families. A missense mutation, R462Q, showed an association with HPC (OR = 1.96). Rokman et al. (2002) concluded that, although RNASEL mutations did not explain disease segregation in Finnish families with HPC, the variants are enriched in families with more than 2 affected members and may also be associated with age at onset of disease. This suggested a possible modifying role in cancer predisposition.
Zhou et al. (1997) generated mice with a targeted disruption of the RNase L gene to determine the physiologic roles of the 2-5A system. The antiviral effect of interferon alpha was impaired in RNase L-deficient mice, providing the first evidence that the 2-5A system functions as an antiviral pathway in animals. In addition, remarkably enlarged thymi in the RNase L -/- mice resulted from a suppression of apoptosis. There was a 2-fold decrease in apoptosis in vivo in the thymi and spleens of RNase L -/- mice. Furthermore, apoptosis was substantially suppressed in RNase L -/- thymocytes and fibroblasts treated with different apoptotic agents. Based on these results, Zhou et al. (1997) concluded that both interferon action and apoptosis can be controlled at the level of RNA stability by RNase L, and suggested that the 2-5A system is likely to contribute to the antiviral activity of interferon by inducing apoptosis of infected cells.
In 4 brothers with prostate cancer (601518), Carpten et al. (2002) identified a heterozygous 795G-T transversion in exon 2 of the RNASEL gene, predicted to result in a conversion of a glutamic acid codon to a termination codon at amino acid position 265 (E265X), with loss of function of that allele. The prostate cancer in 3 of the 4 brothers had clinical features associated with poor prognosis, i.e., Gleason score greater than or equal to 7, stage greater than or equal to T2B, and/or evidence of disseminated disease.
Carpten et al. (2002) found a germline mutation of the RNASEL gene in an African American family in which 6 brothers had prostate cancer (601518). The average age at diagnosis in this family was 59 years. The mutation was a G-to-A transition at the third nucleotide of the initiating methionine codon (AUG), predicted to change the initiating codon from methionine to isoleucine (M1I). The mutation was inherited heterozygously by 4 of the 6 affected brothers. Whereas 3 of the 4 mutation carriers had cancers with poor prognostic indicators, the 2 affected nonmutation carriers had cancers with clinical features associated with more favorable disease outcomes.
In addition to the rare inactivating germline mutations associated with hereditary prostate cancer linked to HPC1 (601518), some relatively common RNASEL variants have been found in some families. Casey et al. (2002) found that one of these, arg462 to gln (R462Q), is associated with 3 times less enzymatic activity than the wildtype and is significantly associated with prostate cancer risk (P = 0.007). At least one copy of the mutated allele that causes this substitution was carried by nearly 60% of the men in their study. Men who were heterozygous with respect to the mutated allele had 50% greater risk of prostate cancer than noncarriers, and homozygotes had more than double the risk.
Urisman et al. (2006) reported an association of xenotropic murine leukemia-related virus (XMRV) with prostate tumors in patients homozygous for the R462Q variant; based on other reports refuting this association, the editors of PloS Pathogens retracted the article by Urisman et al. (2006).
Bisbal, C., Martinand, C., Silhol, M., Lebleu, B., Salehzada, T. Cloning and characterization of a RNase L inhibitor: a new component of the interferon-regulated 2-5A pathway. J. Biol. Chem. 270: 13308-13317, 1995. [PubMed: 7539425] [Full Text: https://doi.org/10.1074/jbc.270.22.13308]
Carpten, J., Nupponen, N., Isaacs, S., Sood, R., Robbins, C., Xu, J., Faruque, M., Moses, T., Ewing, C., Gillanders, E., Hu, P., Bujnovszky, P., and 29 others. Germline mutations in the ribonuclease L gene in families showing linkage with HPC1. Nature Genet. 30: 181-184, 2002. [PubMed: 11799394] [Full Text: https://doi.org/10.1038/ng823]
Casey, G., Neville, P. J., Plummer, S. J., Xiang, Y., Krumroy, L. M., Klein, E. A., Catalona, W. J., Nupponen, N., Carpten, J. D., Trent, J. M., Silverman, R. H., Witte, J. S. RNASEL arg462gln variant is implicated in up to 13% of prostate cancer cases. Nature Genet. 32: 581-583, 2002. [PubMed: 12415269] [Full Text: https://doi.org/10.1038/ng1021]
Han, Y., Donovan, J., Rath, S., Whitney, G., Chitrakar, A., Korennykh, A. Structure of human RNase L reveals the basis for regulated RNA decay in the IFN response. Science 343: 1244-1248, 2014. [PubMed: 24578532] [Full Text: https://doi.org/10.1126/science.1249845]
Hassel, B. A., Zhou, A., Sotomayor, C., Maran, A., Silverman, R. H. A dominant negative mutant of 2-5A-dependent RNase suppresses antiproliferative and antiviral effects of interferon. EMBO J. 12: 3297-3304, 1993. [PubMed: 7688298] [Full Text: https://doi.org/10.1002/j.1460-2075.1993.tb05999.x]
Lin, R.-J., Yu, H.-P., Chang, W.-C., Liao, C.-L., Lin, Y.-L. Distinct antiviral roles for human 2-prime,5-prime-oligoadenylate synthetase family members against Dengue virus infection. J. Immun. 183: 8035-8043, 2009. [PubMed: 19923450] [Full Text: https://doi.org/10.4049/jimmunol.0902728]
Malathi, K., Dong, B., Gale, M., Jr., Silverman, R. H. Small self-RNA generated by RNase L amplifies antiviral innate immunity. Nature 448: 816-819, 2007. [PubMed: 17653195] [Full Text: https://doi.org/10.1038/nature06042]
Rokman, A., Ikonen, T., Seppala, E. H., Nupponen, N., Autio, V., Mononen, N., Bailey-Wilson, J., Trent, J., Carpten, J., Matikainen, M. P., Koivisto, P. A., Tammela, T. L. J., Kallioniemi, O.-P., Schleutker, J. Germline alterations of the RNASEL gene, a candidate HPC1 gene at 1q25, in patients and families with prostate cancer. Am. J. Hum. Genet. 70: 1299-1304, 2002. Note: Erratum: Am. J. Hum. Genet. 71: 215 only, 2002. Note: Erratum: Am. J. Hum. Genet. 75: 1158 only, 2004. [PubMed: 11941539] [Full Text: https://doi.org/10.1086/340450]
Squire, J., Zhou, A., Hassel, B. A., Nie, H., Silverman, R. H. Localization of the interferon-induced, 2-5A-dependent RNase gene (RNS4) to human chromosome 1q25. Genomics 19: 174-175, 1994. [PubMed: 7514564] [Full Text: https://doi.org/10.1006/geno.1994.1033]
Urisman, A., Molinaro, R. J., Fischer, N., Plummer, S. J., Casey, G., Klein, E. A., Malathi, K., Magi-Galluzzi, C., Tubbs, R. R., Ganem, D., Silverman, R. H., DeRisi, J. L. Identification of a novel Gammaretrovirus in prostate tumors of patients homozygous for R462Q RNASEL variant. PLoS Pathog. 2: e25, 2006. Note: Electronic Article. Retraction published online. [PubMed: 16609730] [Full Text: https://doi.org/10.1371/journal.ppat.0020025]
Zhou, A., Paranjape, J., Brown, T. L., Nie, H., Naik, S., Dong, B., Chang, A., Trapp, B., Fairchild, R., Colmenares, C., Silverman, R. H. Interferon action and apoptosis are defective in mice devoid of 2-prime,5-prime-oligoadenylate-dependent RNase L. EMBO J. 16: 6355-6363, 1997. [PubMed: 9351818] [Full Text: https://doi.org/10.1093/emboj/16.21.6355]