Alternative titles; symbolsUSP27USP22-LIKE; USP22LHGNC Approved Gene Symbol: USP27XCytogenetic location: Xp11.23 Genomic coordinates (GRCh38): X:49,879,483-4...
Alternative titles; symbols
HGNC Approved Gene Symbol: USP27X
Cytogenetic location: Xp11.23 Genomic coordinates (GRCh38): X:49,879,483-49,882,557 (from NCBI)
Ubiquitin conjugation at lysine residues regulates protein location, activity, and stability. USP27X belongs to a large family of cysteine proteinases that remove ubiquitin modifications from ubiquitin-conjugated proteins (Quesada et al., 2004).
▼ Cloning and Expression
Quesada et al. (2004) reported that USP27X has the classic USP structure of a Cys-box followed by a QQD-box and a His-box. It also has the catalytic triad of cys, his, and asp residues required for proteolytic activity.
By PCR, Weber et al. (2016) cloned USP27X from a HeLa cell cDNA library. The deduced mouse and human proteins contain 438 amino acids. Database analysis indicated widespread USP27X expression in normal tissues and in many tumors and tumor cell lines. Fluorescence-tagged mouse Usp27x was expressed in the nucleus and cytosol of transfected cells.
▼ Gene Function
Using mouse and human constructs and cells, Weber et al. (2016) found that the deubiquitinating activity of USP27X stabilized apoptotic BIM (BCL2L11; 603827) protein against degradation. USP27X interacted directly with phosphorylated BIM and rescued BIM from phorbol ester- or ERK (see MAPK3, 601797)-mediated degradation. Knockdown of USP27X enhanced BIM degradation due to oncogenic RAF (see RAF1, 164760). Overexpression of USP27X had apoptotic effects that was partly, but not completely, due to BIM stabilization. Catalytically inactive USP27X had no effect on BIM stability or apoptosis. Wildtype USP27X showed deubiquitination activity toward diubiquitin linkages at K48 and K63 in a test substrate in vitro.
Hartz (2016) mapped the USP27X gene to 2 positions on chromosome Xp22 based on an alignment of the USP27X sequence (GenBank AW851065) with the genomic sequence (GRCh38).
▼ Molecular Genetics
In 3 affected males from a family (D177) with X-linked intellectual developmental disorder-105 (XLID105; 300984), Hu et al. (2016) identified a hemizygous truncating mutation in the USP27X gene (300975.0001). An unrelated male patient (family L75) with XLID105 was found to carry a hemizygous missense mutation in the USP27X gene (Y381H; 300975.0002); 3 others males in this family were affected, but genetic studies were not performed. Carrier females in both families were unaffected. The mutations were found by X-chromosome exome sequencing of 405 probands with X-linked intellectual disability. Functional studies of the variants were not performed.
▼ ALLELIC VARIANTS ( 2 Selected Examples):
.0001 INTELLECTUAL DEVELOPMENTAL DISORDER, X-LINKED 105
USP27X, 5-BP DEL
In 3 affected males from a family (D177) with X-linked intellectual developmental disorder-105 (XLID105; 300984), Hu et al. (2016) identified a hemizygous 5-bp deletion (chrX.49,645,933_49,645,937delAAGTA, GRCh37) in the USP27X gene, resulting in a frameshift and premature stop codon (Ser342ArgfsTer14) that is expected to remove the C-terminal part of the protein. The mutation was found by X-chromosome exome sequencing and segregated with the disorder in the family. Functional studies of the variant were not performed.
.0002 INTELLECTUAL DEVELOPMENTAL DISORDER, X-LINKED 105
In a male patient (family L75) with X-linked intellectual developmental disorder-105 (XLID105; 300984), Hu et al. (2016) identified a hemizygous T-C transition (chrX.49,646,051T-C, GRCh37) in the USP27X gene, resulting in a tyr381-to-his (Y381H) substitution. There were 3 other affected males in the family, but genetic studies were not performed. The mutation was found by X-chromosome exome sequencing and was present in 2 unaffected female carriers. Functional studies of the variant were not performed.