USP7
protein-codingubiquitin specific peptidase 7, the group of Ubiquitin specific peptidases
Gene summary
The protein encoded by this gene belongs to the peptidase C19 family, which includes ubiquitinyl hydrolases. This protein deubiquitinates target proteins such as p53 (a tumor suppressor protein) and WASH (essential for endosomal protein recycling), and regulates their activities by counteracting the opposing ubiquitin ligase activity of proteins such as HDM2 and TRIM27, involved in the respective process. Mutations in this gene have been implicated in a neurodevelopmental disorder. [provided by RefSeq, Mar 2016]
- HAUSP
MANE transcript
Inheritance
ClinVar variants
Top phenotype
gnomAD constraint
Max pathogenic AF
Genomic locus
External References & Databases
Transcript & Mutation Effects
hg38 • Region Span ~83.2 kbGenCC Phenotypes & Disease Associations
Curated gene-disease validity assertions and inheritance patterns
Inheritance Pattern: AD
Disease ID:MONDO:0014805
Submitter: ClinGen
The USP7 gene is located on chromosome 16 at 16p13.2 and encodes the ubiquitin-specific protease 7, a deubiquitinating enzyme that controls stability and localization of proteins involved in DNA replication, epigenetic regulation, cell cycle, and cell survival (Rouge et al., 2016, 27452404). It is a component of the MAGEL2-USP7-TRIM27 (MUST) complex regulating WASH activity, endosomal actin assembly and protein recycling (Hao et al., 2015, PMID 26365382). USP7 also regulates MDM2-p53 pathway implicated in apoptosis and cell cycle (Kon et al., 2011, PMID 21350561). The USP7 gene was first reported in 2015 in relation to autosomal dominant neurodevelopmental disorder, which has been also referred to as Hao-Fountain syndrome and neurodevelopmental disorder with speech delays, altered behavior, and neurologic anomalies (PMID 26365382; Fountain et al., 2019, PMID 30679821; Online Mendelian Inheritance in Man, OMIM®. McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University (Baltimore, MD), 2021. World Wide Web URL: https://omim.org/). The USP7-related neurodevelopmental disorder is characterized by global developmental delay, significant speech delay, impaired intellectual development, behavioral abnormalities, including autism spectrum, and mild dysmorphic features. Additional features may include feeding problems, hypotonia, seizures, delayed motor development, hypogonadism in males, joint and ocular anomalies. Brain imaging shows abnormalities in some patients and may include white matter changes, shallow gyra pattern, and ventricle anomalies. At least eight unique de novo variants have been reported, including stop-gained, frameshift and missense variants. Evidence supporting this gene-disease relationship includes case-level data and experimental data. Variants in this gene have been reported in at least eight probands in two publications (PMID 26365382; PMID 30679821). More evidence is available in the literature, but the maximum score for genetic evidence has been reached. Currently, there is strong evidence supporting loss-of-function variants as disease mechanism, whereas the role of missense variants is less well-understood. This gene-disease association is supported by protein interaction of USP7 with MAGE-L2 and TRIM27 to form a ligase complex that regulates WASH-mediated endosomal protein recycling (Hao et al., 2013, PMID 23452853; PMID 26365382) and by interaction with and stabilization of KMT2E (Ding et al., 2015; PMID 26678539). This gene-disease association is also supported by data from a conditional knockout mouse model (PMID 21350561). In summary, USP7 is definitively associated with USP7-related neurodevelopmental disorder. This has been repeatedly demonstrated in both the research and clinical diagnostic settings and has been upheld over time.
Inheritance Pattern: AD
Disease ID:MONDO:0014805
Submitter: Illumina
The USP7 gene is located on chromosome 16 at 16p13.2 and encodes the ubiquitin-specific protease 7, a deubiquitinating enzyme that is a component of the MAGEL2-USP7-TRIM27 (MUST) complex regulating WASH activity, endosomal actin assembly and protein recycling. USP7 also regulates MDM2-p53 pathway implicated in apoptosis and cell cycle. USP7 was first reported in relation to autosomal dominant USP7-related neurodevelopmental disorder in 2015 (26365382: Hao et al. 2015). At least eight unique de novo variants have been reported, including missense, frameshift, and stop-gained variants. Evidence supporting this gene-disease relationship includes case-level data and experimental data. Variants in this gene have been reported in at least eight probands in two publications (26365382: Hao et al. 2015; 30679821: Fountain et al. 2019). More evidence is available in the literature, but the maximum score for genetic evidence has been reached. This gene-disease relationship is supported by protein interaction of USP with MAGE-L2 and TRIM27 to form a ligase complex that regulates WASH-mediated endosomal protein recycling (23452853: Hao et al. 2013) and a cell line with reduced USP7 showed impaired endosomal recycling (26365382: Hao et al. 2015). In summary, there is strong evidence to support the relationship between USP7 and autosomal dominant USP7-related neurodevelopmental disorder. An additional report in humans published three years from the first proposal of the association is needed to reach a definitive classification.
Inheritance Pattern: AD
Disease ID:MONDO:0958071
Submitter: PanelApp Australia
Inheritance Pattern: AD
Disease ID:MONDO:0958071
Submitter: G2P
Inheritance Pattern: AD
Disease ID:MONDO:0014805
Submitter: Ambry Genetics
Clinical Genomic Database (CGD)
Manifestation: Craniofacial; Genitourinary; Musculoskeletal; Neurologic; Ophthalmologic
Intervention: General
Rationale: Genetic knowledge may be beneficial related to issues such as selection of optimal supportive care, informed medical decision-making, prognostic considerations, and avoidance of unnecessary testing
ClinVar Associated Diseases & Phenotypes
Reported disease conditions connected to USP7 variants in ClinVar
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript NM_003470.3. Only rare variants are included.
We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.
Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.
| Effect | PathogenicP | Likely pathogenicLP | VUS | Likely benignLB | BenignB | Sum |
|---|---|---|---|---|---|---|
| synonymous | 8 | 89 | 8 | 105 | ||
| missense | 2 | 15 | 212 | 13 | 3 | 245 |
| nonsense | 6 | 7 | 1 | 14 | ||
| start loss | 0 | |||||
| frameshift | 8 | 7 | 1 | 16 | ||
| splice donor/acceptor (+/-2bp) | 5 | 7 | 10 | 22 | ||
| Total | 21 | 36 | 232 | 102 | 11 | 402 |
Highest pathogenic variant AF is 8.0314703e-7
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| RefSeq | NP_003461.2 | 31 | MANE Select | |
| Ensembl | ENSP00000343535.4 | 31 | MANE Select | |
| RefSeq | NP_001273386.2 | 31 | Standard | |
| RefSeq | NP_001273387.1 | 29 | Standard |
Model Organisms & Knockout Phenotypes
Observed phenotypic effects in mouse and zebrafish models
| Gene / Model | Organism | Observed Phenotype |
|---|---|---|
| usp7 | Danio rerio | Structure: caudal fin upper lobe Quality: fused with abnormal |
Gene Ontology (GO) Annotations & Pathways
Biological processes, molecular functions, cellular components and pathways
Pathways ConsensusPathDB
- FoxO signaling pathway - Homo sapiens (human)
- Viral carcinogenesis - Homo sapiens (human)
- Epstein-Barr virus infection - Homo sapiens (human)
- Herpes simplex infection - Homo sapiens (human)
- Regulation of toll-like receptor signaling pathway
Biological Process
- transcription-coupled nucleotide-excision repair
- ubiquitin-dependent protein catabolic process
- multicellular organism development
- maintenance of DNA methylation
- viral process
Molecular Function
- p53 binding
- cysteine-type endopeptidase activity
- thiol-dependent ubiquitin-specific protease activity
- protein binding
- protein C-terminus binding
Cellular Component
- nucleus
- nucleoplasm
- chromosome
- cytosol
- nuclear body
gnomAD Constraint
Source:
- Gene type
- protein_coding
- Transcript type
- protein_coding
- Transcript
- ENST00000344836
- Coding exons
- 31
- Length
- 72421
- Individuals with no LoFs
- 125739
- Homozygous LoFs
- 0
- Heterozygous LoFs
- 4
- Defined
- 125743
- p
- 0.0000159
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible | |
|---|---|---|---|---|---|---|
| Missense | 5.65 | 225 | 621 | 0.362 | 0.0000350 | 7419 |
| Missense (PolyPhen) | 13 | 197.05 | 0.065972 | 2321 | ||
| Synonymous | -2.44 | 279 | 232 | 1.20 | 0.0000146 | 1865 |
| Loss of Function | 8.04 | 1 | 77.2 | 0.0130 | 0.00000473 | 830 |
Population LoF Frequency
| Population | CAF | p-value | Status |
|---|---|---|---|
| African | 0 | 0.0 | absent |
| Latino/Admixed American | 0 | 0.0 | absent |
| Ashkenazi Jewish | 0 | 0.0 | absent |
| East Asian | 0 | 0.0 | absent |
| Finnish | 0 | 0.0 | absent |
| European (Non-Finnish) | 0.000035 | 0.000035 | rare |
| South Asian | 0 | 0.0 | absent |
| Other | 0 | 0.0 | absent |
dbNSFP Gene Annotations
Source:
- Function
- FUNCTION: Hydrolase that deubiquitinates target proteins such as FOXO4, p53/TP53, MDM2, ERCC6, DNMT1, UHRF1, PTEN, KMT2E/MLL5 and DAXX (PubMed:11923872, PubMed:15053880, PubMed:16964248, PubMed:18716620, PubMed:25283148, PubMed:26678539). Together with DAXX, prevents MDM2 self-ubiquitination and enhances the E3 ligase activity of MDM2 towards p53/TP53, thereby promoting p53/TP53 ubiquitination and proteasomal degradation (PubMed:15053880, PubMed:16845383, PubMed:18566590, PubMed:20153724). Deubiquitinates p53/TP53, preventing degradation of p53/TP53, and enhances p53/TP53-dependent transcription regulation, cell growth repression and apoptosis (PubMed:25283148). Deubiquitinates p53/TP53 and MDM2 and strongly stabilizes p53/TP53 even in the presence of excess MDM2, and also induces p53/TP53-dependent cell growth repression and apoptosis (PubMed:11923872). Deubiquitination of FOXO4 in presence of hydrogen peroxide is not dependent on p53/TP53 and inhibits FOXO4-induced transcriptional activity (PubMed:16964248). In association with DAXX, is involved in the deubiquitination and translocation of PTEN from the nucleus to the cytoplasm, both processes that are counteracted by PML (PubMed:18716620). Deubiquitinates KMT2E/MLL5 preventing KMT2E/MLL5 proteasomal-mediated degradation (PubMed:26678539). Involved in cell proliferation during early embryonic development. Involved in transcription-coupled nucleotide excision repair (TC- NER) in response to UV damage: recruited to DNA damage sites following interaction with KIAA1530/UVSSA and promotes deubiquitination of ERCC6, preventing UV-induced degradation of ERCC6 (PubMed:22466611, PubMed:22466612). Involved in maintenance of DNA methylation via its interaction with UHRF1 and DNMT1: acts by mediating deubiquitination of UHRF1 and DNMT1, preventing their degradation and promoting DNA methylation by DNMT1 (PubMed:21745816, PubMed:22411829). Deubiquitinates alkylation repair enzyme ALKBH3. OTUD4 recruits USP7 and USP9X to stabilize ALKBH3, thereby promoting the repair of alkylated DNA lesions (PubMed:25944111). Acts as a chromatin regulator via its association with the Polycomb group (PcG) multiprotein PRC1-like complex; may act by deubiquitinating components of the PRC1-like complex (PubMed:20601937). Able to mediate deubiquitination of histone H2B; it is however unsure whether this activity takes place in vivo (PubMed:20601937). Exhibits a preference towards 'Lys-48'-linked ubiquitin chains (PubMed:22689415). Increases regulatory T-cells (Treg) suppressive capacity by deubiquitinating and stabilizing the transcription factor FOXP3 which is crucial for Treg cell function (PubMed:23973222). {ECO:0000269|PubMed:11923872, ECO:0000269|PubMed:15053880, ECO:0000269|PubMed:16845383, ECO:0000269|PubMed:16964248, ECO:0000269|PubMed:18566590, ECO:0000269|PubMed:18716620, ECO:0000269|PubMed:20153724, ECO:0000269|PubMed:20601937, ECO:0000269|PubMed:21745816, ECO:0000269|PubMed:22411829, ECO:0000269|PubMed:22466611, ECO:0000269|PubMed:22466612, ECO:0000269|PubMed:22689415, ECO:0000269|PubMed:23973222, ECO:0000269|PubMed:25283148, ECO:0000269|PubMed:25944111, ECO:0000269|PubMed:26678539}.;
Recessive Scores
- pRec
- 0.226
Intolerance Scores
- LoFtool
- 0.0608
- RVIS EVS
- -1.33
- RVIS percentile EVS
- 4.67
Essentials
- Essential (CRISPR)
- N
- Essential (CRISPR2)
- E
- Essential (gene trap)
- K
- Indispensability pred.
- E
- Indispensability score
- 0.809
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | Medium | Medium | Medium |
| Primary Immunodeficiency | Medium | Medium | Medium |
| Cancer | Medium | Medium | Medium |