Alt. symbols: ISG43 | PTORCH2 | UBP43

Approved name: ubiquitin specific peptidase 18
Alt. names: ubiquitin specific protease 18 | Ubl carboxyl-terminal hydrolase 18

Location: 22q11.21: 18149843 - 18177397 (+)
Gene type: protein_coding, 5 transcripts.

Scores: LoFtool: 0.519000 | pLI: 0.39259870 | LOEUF: 0.742

HGNC: 12616

NCBI: 11274, RefSeq: .0

Ensembl: ENSG00000184979.12

LRG_ | Status: none

OMIM: 607057

Expression | ProteinAtlas

USP18 encodes an isopeptidase that binds to and cleaves ISG15 from conjugated proteins, thus regulating the critical cellular balance of ISG15-conjugated proteins (PMID: 11788588). USP18 also competes with JAK1 for binding to the IFNAR2 complex to negatively regulate IFN signaling in a deconjugation-independent manner (PMID: 32957626, 28165510, 27325888).

Biallelic USP18 LOF causes a type I IFNopathy [OMIM: 617397] that is usually phenotypically more severe than ISG15 deficiency. Patients show a pseudoTORCH phenotype characterized by microcephaly, intra- and/or extra-cranial calcifications, structural CNS abnormalities, seizures, intracranial hemorrhage, bone marrow defects, metaphyseal changes on X-rays, liver dysfunction, respiratory failure, and hepatosplenomegaly. Knoblauch et al. (2003) showed that patient cells had an aberrant response to t ype I IFN, rather than increased IFN expression per se. Unlike previous LOF mutations, Alsohime et al. (2020) identified homozygosity for a splice variant that led to exon 10 skipping, producing a mutant USP18 protein with largely preserved deconjugation activity, but loss of ability to be stabilized by ISG15 or to suppress type I IFN signaling. This patient had largely normal immunophenotyping beyond isolated low levels of IgG and responded to treatment with high dose ruxolitinib (PMID: 31940699). [Load More]