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Alternative titles; symbolsUBIQUITIN-SPECIFIC PROTEASE, 43-KD; UBP43INTERFERON-STIMULATED GENE, 43-KD; ISG43HGNC Approved Gene Symbol: USP18Cytogenetic location:...

Alternative titles; symbols


HGNC Approved Gene Symbol: USP18

Cytogenetic location: 22q11.21 Genomic coordinates (GRCh38): 22:18,149,854-18,177,396 (from NCBI)

▼ Description
The USP18 gene encodes a type 1 interferon (IFN)-stimulated gene that had dual functions: it is a negative regulator of type 1 IFN signaling and is also an isopeptidase that is a member of the deubiquitinating protease family of enzymes (summary by Meuwissen et al., 2016).

▼ Cloning and Expression
Using the mouse homolog as a probe, Schwer et al. (2000) cloned USP18, which they called UBP43, from a human monocyte cDNA library and obtained the full-length sequence by 5-prime RACE. The deduced 372-amino acid protein has a calculated molecular mass of about 43 kD. It contains 6 domains conserved among members of the ubiquitin-binding protein family, including the cys box, which has putative transmembrane helices and a conserved putative active-site cysteine at cys64, and 3 blocks of the his box region. The sequence also contains an amidation site and 2 N-glycosylation sites. USP18 shares 70% sequence identity with mouse Usp18. Northern blot analysis revealed a single transcript of about 1.9-kb in several human cell lines. RNA dot blot analysis showed strongest expression in fetal spleen and adult liver and thymus, with lowest expression in brain tissues, bladder, uterus, testis, and appendix. Fluorescence microscopy in transfected HeLa cells demonstrated that USP18 localizes mainly to the cytosol, with less abundance in the nucleus.

Li et al. (2000) identified mouse Usp18, which they called Isg43, by differential display analysis of ribonuclease (RNase)-L (RNASEL; 180435)-deficient and competent mouse embryo fibroblasts. They cloned human USP18 by RT-PCR of fibrosarcoma total RNA.

Kang et al. (2001) cloned USP18 by rapid subtraction hybridization (RASH) followed by RACE of a human melanoma cell line induced to differentiate with interferon-beta (IFNB; 147640). Northern blot analysis of multiple human tissues showed expression in most tissues tested, with highest expression in liver, ovary, and thyroid, and no expression in brain, stomach, spinal cord, and bone marrow.

▼ Gene Structure
Schwer et al. (2000) determined that the USP18 gene contains 11 exons and spans 30 kb. Li et al. (2000), however, determined that the USP18 gene contains 10 exons spanning 15.7 kb. They identified a strong IFNB response element in the putative promoter region, and an AU-rich element (ARE) in the 3-prime untranslated region for the activation of 2-5A synthetase, or OAS1.

▼ Mapping
By FISH, Schwer et al. (2000) mapped the USP18 gene to chromosome 22q11.2 within a 2-Mb region consistently deleted in DiGeorge syndrome (DGS; 188400). They mapped the mouse Usp18 gene to chromosome 6.

▼ Gene Function
Liu et al. (1999) found that expression of Usp18 was restricted to 2 mouse monocytic cell lines out of the 9 hematopoietic cell lines tested, and expression was regulated during cytokine-induced monocytic cell differentiation. Overexpression blocked cytokine-induced terminal monocytic differentiation.

Using a ubiquitinated synthetic peptide, Schwer et al. (2000) confirmed ubiquitin-specific protease activity in recombinant USP18.

Using wildtype and RNase-L knockout mouse fibroblasts, Li et al. (2000) identified the 2-5A system (see OAS1, 164350) and RNase-L as the regulator of Usp18 mRNA levels. In the absence of RNase-L in the knockout cells, IFN treatment resulted in both an increase in Usp18 mRNA and increased mRNA half-life as compared with wildtype cells. Using mutant human cells lacking either JAK1 (147795) or STAT1 (600555), the authors determined that a functional JAK/STAT pathway is required for IFNA (147660) induction of USP18 in human fibrosarcoma cells.

Kang et al. (2001) found that expression of USP18 in human melanoma cells was upregulated within 2 hours of treatment with IFNB. By testing several interferons to induce differentiation, they determined that USP18 is a type I, IFNA/IFNB-inducible gene and that induction does not require protein synthesis. Through analysis of several cell lines carrying mutations in the JAK/STAT pathway, they found that IFNB-induction does not occur in cells defective in STAT1 or JAK1 or in cells lacking a functional type I interferon receptor, IFNAR2 (602376).

Using a small interfering RNA screen to identify ubiquitination-related genes that regulate the level of EGFR (131550) in squamous cell carcinoma (SCC) cells, Duex and Sorkin (2009) identified USP18. Depletion of USP18 in SCCs or COS-1 cells led to a dramatic downregulation in the steady-state level of EGFR protein, but not other receptor tyrosine kinases. Conversely, overexpression of USP18 in COS-1 cells led to Egfr upregulation. Fluorescence-tagged USP18 did not colocalize with EGFR in transfected COS-1 or HeLa cells, and EGFR degradation was only moderately increased in the absence of USP18. However, EGFR translation was dramatically decreased in the absence of USP18, and the effect of USP18 on EGFR translation required the native 3- and 5-prime ends of the EGFR transcript.

▼ Molecular Genetics
In 3 patients, born of consanguineous Turkish parents, with pseudo-TORCH syndrome-2 (PTORCH2; 617397), Meuwissen et al. (2016) identified a homozygous truncating mutation in the USP18 gene (Q218X; 607057.0001). The mutation, which was found by a combination of linkage analysis, whole-exome sequencing, and capillary DNA sequencing, segregated with the disorder in the family. Two German sibs with the disorder, previously reported by Knoblauch et al. (2003), were found to be compound heterozygous for the Q218X mutation and a cryptic 3-prime deletion of the USP18 gene (607057.0002). Haplotype analysis of the region containing the Q218X mutation suggested a founder effect. Cells from patients in both families showed complete absence of the USP18 protein. Patient fibroblasts showed enhanced induction of IFN-stimulated transcripts after stimulation with alpha-IFN (IFNA1; 147660) compared to controls, and transduction of patient cells with wildtype USP18 rescued these effects at the mRNA and protein level. The findings indicated that the disorder results from an aberrant response to type I IFN, rather than an increase in expression of IFN itself. Accordingly, patient cells had normal IFNB (147640) mRNA and protein levels. The results also indicated that USP18-mediated regulation of the IFN response is crucial for normal development of the central nervous system.

Alsohime et al. (2020) identified homozygosity for a splice site variant in the USP18 gene (607057.0003) in a male Saudi infant with PTORCH2. Unlike affected individuals from the 2 previously reported families, this patient had stable mRNA (with skipping of exon 10), and functional studies indicated that the mechanism of the mutation was not USP18 deficiency but lack of its ability to stabilize ISG15 (147571) and thereby suppress interferon signaling.

▼ ALLELIC VARIANTS ( 3 Selected Examples):

In 3 sibs, born of consanguineous Turkish parents (family A), with pseudo-TORCH syndrome-2 (PTORCH2; 617397), Meuwissen et al. (2016) identified a homozygous c.652C-T transition in exon 7 of the USP18 gene, resulting in a gln218-to-ter (Q218X) substitution. The mutation, which was found by a combination of linkage analysis, whole-exome sequencing, and capillary DNA sequencing, segregated with the disorder in the family. It was not found in the dbSNP or ExAC databases, in 190 Turkish control chromosomes, or in 952 DNA samples from the Complete Genomics database. Analysis of patient cells indicated that the mutation resulted in nonsense-mediated mRNA decay. Sanger sequencing of the USP18 gene in 2 German sibs (family B) with a similar phenotype, previously reported by Knoblauch et al. (2003), identified a heterozygous Q218X mutation on 1 allele. Haplotype analysis of the region containing the Q218X mutation suggested a common ancestor between the 2 families. Detailed analysis of patient cells yielded results indicating that the other allele in these sibs contained a large deletion at the 3-prime end of USP18 (cryptic 3-prime deletion; 607057.0002), showing that the patients were compound heterozygous for USP18 mutations. Western blot analysis of fibroblasts from patients from both families showed complete absence of the USP18 protein, consistent with a loss-of-function effect.

For discussion of the cryptic 3-prime deletion in the USP18 gene that was found in compound heterozygous state in 2 sibs with pseudo-TORCH syndrome-2 (PTORCH2; 617397) by Meuwissen et al. (2016), see 607057.0001.

USP18, IVS10, G-A, +1
In a Saudi Arabian boy with pseudo-TORCH syndrome-2 (PTORCH2; 617397) born to first-cousin parents, Alsohime et al. (2020) identified homozygosity for a splice-site mutation at the end of exon 10 of USP18, resulting in its skipping. The G-to-A transition at position c.1073+1 (c.1073+1G-A) was present in heterozygosity in both parents. RT-PCR of patient peripheral blood detected a lower molecular weight product than that of a sample from a healthy control, consistent with loss of exon 10. RACE PCR showed 2 transcripts, one with exon 10 omitted, resulting in frameshift with addition of 9 amino acids from the 3-prime UTR, accounting for 92% of transcripts, and the other with insertion of part of intron 9 and a premature termination codon at the end of exon 10, present in 8% of transcripts. No wildtype transcripts were detected. Functional studies showed that transcripts were stable, as was protein, but USP18 missing exon 10 was unable to stabilize ISG15 (147571), despite retaining catalytic activity; it was also unable to suppress type I interferon signaling (see 147660) as measured by phosphorylation of STAT1 (600555) and STAT2 (600556).

Tags: 22q11.21