Alternative titles; symbols
HGNC Approved Gene Symbol: RNASET2
SNOMEDCT: 720825005;
Cytogenetic location: 6q27 Genomic coordinates (GRCh38): 6:166,922,113-166,956,550 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 6q27 | Leukoencephalopathy, cystic, without megalencephaly | 612951 | Autosomal recessive | 3 |
RNASET2 belongs to the RNase T2 family (EC 3.1.27.1) of proteins that are present in all phyla and primarily function in the extracellular milieu. In some microorganisms and plants, T2 RNases mediate phosphate uptake by digesting extracellular RNAs. In other species, they provide host protection against pathogens or trigger cellular senescence. Human RNASET2 appears to suppress tumorigenicity (Monti et al., 2008).
By searching for coding sequences in a region of chromosome 6 that is frequently rearranged in malignancies, followed by screening a pooled tissue cDNA library, Trubia et al. (1997) cloned RNASET2. The deduced 191-amino acid protein contains 2 highly conserved pentameric catalytic motifs. Northern blot analysis detected a 1.2-kb transcript in all tissues examined.
Using Northern blot analysis, Acquati et al. (2001) detected ubiquitous expression of a 1.4-kb RNASET2 transcript. Highest expression was in liver and heart, and lowest expression was in lung and placenta.
Campomenosi et al. (2006) stated that full-length human RNASET2 has 256 amino acids and shares 67.4% identity with mouse Rnaset2. Western blot analysis detected RNASET2 in most ovarian cancer cell lines at an apparent molecular mass of 31 kD. Proteins of 36 and 27 kD were also detected in some cell lines, and the 36-kD protein was secreted into the culture medium. Subcellular fractionation of transfected ovarian cancer cells revealed full-length RNASET2 in the endoplasmic reticulum fraction and the 2 smaller RNASET2 isoforms in the lysosome fraction.
Acquati et al. (2005) identified an N-terminal signal sequence and 3 putative N-glycosylation sites in full-length RNASET2. Fluorescence-tagged RNASET2 localized to the Golgi apparatus of transfected human embryonic kidney cells, and the 36-kD protein was secreted into the culture medium. Western blot analysis detected 4 RNASET2 species between 31 and 36 kD. Endoglycosylase treatment of in vitro-translated RNASET2 resulted in disappearance of the higher molecular mass forms and accumulation of the 31-kD protein. Acquati et al. (2005) concluded that RNASET2 is a secreted glycoprotein.
By RT-PCR analysis, Henneke et al. (2009) found strong RNASET2 expression in temporal lobe and fetal brain, followed by capsula interna, cerebral cortex, hippocampus, and corpus callosum, and low expression in amygdala.
Abnormalities of chromosome 6q are associated with several solid neoplasms, including carcinomas of the ovary (167000). Using PCR, Acquati et al. (2001) found that expression of RNASET2 was reduced in 30% of 55 primary ovarian tumors with alterations at 6q26-qter. Downregulation of RNASET2 was also detected in 75% of ovarian tumor cell lines. Transfection of RNASET2 into HEY4 and SG10G ovarian tumor cell lines suppressed their tumorigenicity following injection into nude mice. RNASET2 induced cell senescence in HEY4 cells when expressed over a certain threshold, while suppression of tumorigenicity in mice required only minimal RNASET2 expression.
Using zymogram gel electrophoresis, Campomenosi et al. (2006) showed that recombinant RNASET2 had optimum catalytic activity at pH 5. PolyU and polyA were efficiently cleaved, whereas polyG and polyC were resistant to cleavage. Activity of RNASET2 did not depend on glycosylation.
Acquati et al. (2005) introduced 2 mutations into RNASET2 (his65 to phe and his118 to phe) that reduced its ribonuclease activity to less than 1% of wildtype. Using HEY4 cells and a highly metastatic HEY4 subclone, they found that the mutations did not alter the ability of RNASET2 to suppress metastasis following injection into nude mice.
Malignant melanoma (see 155600) is associated with chromosomal rearrangements in the 6q27 region. Using real-time PCR, Monti et al. (2008) found that RNASET2 expression was downregulated in 4 of 8 melanoma cell lines, including the SK-MEL28 cell line. Transfection of SK-MEL28 cells with RNASET2 reduced their tumorigenicity upon injection into nude mice, but it had no effect on their growth or clonogenicity in culture.
Acquati et al. (2001) determined that the RNASET2 gene contains 9 exons and spans about 27 kb. The proximal promoter region shows greatest CpG density close to the transcription start site.
By YAC analysis, Trubia et al. (1997) mapped the RNASET2 gene to chromosome 6q27. Southern blot analysis showed that RNASET2 is a single-copy gene.
By linkage analysis followed by candidate gene sequencing in 2 consanguineous Turkish families with cystic leukoencephalopathy without megalencephaly (612951), Henneke et al. (2009) identified 2 different homozygous mutations in the RNASET2 gene (612944.0001 and 612944.0002, respectively) that segregated with the disorder. Analysis of 3 additional unrelated individuals with the disorder identified homozygous or compound heterozygous RNASET2 mutations (612944.0003-612944.0006). All of the mutations were predicted to result in loss of protein function. The phenotype was characterized by normo- or microcephaly, early onset of severe psychomotor retardation, cystic changes in the anterior temporal lobes, and multifocal white matter lesions; the phenotype was indistinguishable from neonatal asymptomatic cytomegalovirus (CMV) infection.
In 2 sibs, born of Turkish consanguineous parents, with cystic leukoencephalopathy without megalencephaly (612951), Henneke et al. (2009) identified a homozygous 550T-C transition in exon 8 of the RNASET2 gene, resulting in a cys184-to-arg (C184R) substitution in a highly conserved disulfide bond, predicted to interfere with the native protein conformation. Both unaffected parents were heterozygous for the mutation. In vitro functional expression studies showed that the C184R-mutant protein showed defective trafficking to the extracellular medium, consistent with impaired protein folding or stability. The patients had onset of neurologic impairment by age 3 months.
In 2 Turkish sibs, born of consanguineous parents, with cystic leukoencephalopathy (612951), Henneke et al. (2009) identified a homozygous 2.5-kb deletion including exon 2 and part of introns 1 and 2 of the RNASET2 gene. Both unaffected parents were heterozygous for the mutation. The patients had onset of neurologic impairment by age 1 month.
In a Turkish girl, born of consanguineous parents, with cystic leukoencephalopathy (612951), Henneke et al. (2009) identified a homozygous A-to-G transition in intron 5 of the RNASET2 gene, resulting in a splice site mutation and altered transcripts with either deletion of exons or frameshifts. Both unaffected parents were heterozygous for the mutation. The patient had onset of neurologic impairment by age 12 months. At age 4 years, she could sit and walk without aid, showed spasticity, and had developed comprehensible speech.
In a Spanish boy with cystic leukoencephalopathy (612951), Henneke et al. (2009) identified a homozygous 1-bp deletion (332+1delG) in the donor splice site of exon 5 of the RNASET2 gene, resulting in altered transcripts with deleted exons. The patient had onset of neurologic impairment by age 3 months. At age 2 years, he had no head control, no use of his hands, seizures, and poor social contact.
In a girl of German and Turkish ancestry with cystic leukoencephalopathy (612951), Henneke et al. (2009) identified compound heterozygosity for 2 mutations in the RNASET2 gene: a 15-bp deletion in exon 1, resulting in an in-frame loss of 5 residues within the putative signal peptide, and a 567G-A transition at the last nucleotide of exon 8 (612944.0006) that does not change residue gln189, but disrupts the splicing process, leading to the skipping of exon 8. She had onset of neurologic impairment by age 7 months. Age age 10, she had microcephaly, seizures, and could sit alone, but needed aid to walk. She had no speech development.
For discussion of the 567G-A transition in exon 8 of the RNASET2 gene that was found in compound heterozygous state in a patient with cystic leukoencephalopathy (612951) by Henneke et al. (2009), see 612944.0005.
Acquati, F., Morelli, C., Cinquetti, R., Bianchi, M. G., Porrini, D., Varesco, L., Gismondi, V., Rocchetti, R., Talevi, S., Possati, L., Magnanini, C., Tibiletti, M. G., Bernasconi, B., Daidone, M. G., Shridhar, V., Smith, D. I., Negrini, M., Barbanti-Brodano, G., Taramelli, R. Cloning and characterization of a senescence inducing and class II tumor suppressor gene in ovarian carcinoma at chromosome region 6q27. Oncogene 20: 980-988, 2001. [PubMed: 11314033] [Full Text: https://doi.org/10.1038/sj.onc.1204178]
Acquati, F., Possati, L., Ferrante, L., Campomenosi, P., Talevi, S., Bardelli, S., Margiotta, C., Russo, A., Bortoletto, E., Rocchetti, R., Calza, R., Cinquetti, R., Monti, L., Salis, S., Barbanti-Brodano, G., Taramelli, R. Tumor and metastasis suppression by the human RNASET2 gene. Int. J. Oncol. 26: 1159-1168, 2005. [PubMed: 15809705]
Campomenosi, P., Salis, S., Lindqvist, C., Mariani, D., Nordstrom, T., Acquati, F., Taramelli, R. Characterization of RNASET2, the first human member of the Rh/T2/S family of glycoproteins. Arch. Biochem. Biophys. 449: 17-26, 2006. [PubMed: 16620762] [Full Text: https://doi.org/10.1016/j.abb.2006.02.022]
Henneke, M., Diekmann, S., Ohlenbusch, A., Kaiser, J., Engelbrecht, V., Kohlschutter, A., Kratzner, R., Madruga-Garrido, M., Mayer, M., Opitz, L., Rodriguez, D., Ruschendorf, F., Schumacher, J., Thiele, H., Thoms, S., Steinfeld, R., Nurnberg, P., Gartner, J. RNASET2-deficient cystic leukoencephalopathy resembles congenital cytomegalovirus brain infection. Nature Genet. 41: 773-775, 2009. [PubMed: 19525954] [Full Text: https://doi.org/10.1038/ng.398]
Monti, L., Rodolfo, M., Lo Russo, G., Noonan, D., Acquati, F., Taramelli, R. RNASET2 as a tumor antagonizing gene in a melanoma cancer model. Oncol. Res. 17: 69-74, 2008. Note: Erratum: Oncol. Res. 17: 191 only, 2008. [PubMed: 18543608] [Full Text: https://doi.org/10.3727/096504008784523658]
Trubia, M., Sessa, L., Taramelli, R. Mammalian Rh/T2/S-glycoprotein ribonuclease family genes: cloning of a human member located in a region of chromosome 6 (6q27) frequently deleted in human malignancies. Genomics 42: 342-344, 1997. [PubMed: 9192857] [Full Text: https://doi.org/10.1006/geno.1997.4679]