The USP7 gene (Ubiquitin-Specific Peptidase 7, also known as HAUSP) encodes a deubiquitinating enzyme (DUB) that removes ubiquitin from target proteins, regulating their stability and function. USP7 is a master regulator of protein stability with roles in DNA damage response, epigenetics, and neuronal proteostasis.
The USP7 gene is located on chromosome 16p13.2 and encodes a 128 kDa cysteine protease that cleaves ubiquitin from diverse substrates[1]. USP7 is one of approximately 100 DUBs in the human genome and is among the most extensively studied due to its central roles in stabilizing p53, MDM2, and numerous epigenetic regulators[2]. In the nervous system, USP7 regulates synaptic protein turnover, neuronal survival signaling, and chromatin remodeling essential for neural development and maintenance[3]. [1]
| | | [2]
|---|---| [3]
| Gene Symbol | USP7 |
| Full Name | Ubiquitin-Specific Peptidase 7 |
| Aliases | HAUSP (Herpesvirus-Associated USP) |
| Chromosomal Location | 16p13.2 |
| NCBI Gene ID | 7874 |
| OMIM | 602519 |
| Ensembl | ENSG00000187555 |
| UniProt | Q93009 |
| Associated Diseases | Hao-Fountain syndrome (NDD), cancer, neurodegeneration |
USP7 removes ubiquitin from target proteins, preventing their proteasomal degradation[1]:
USP7 stabilizes proteins in several critical pathways[2]:
USP7 has specific roles in the nervous system[3]:
Heterozygous loss-of-function variants in USP7 cause a recognizable neurodevelopmental syndrome[4]:
| Feature | Frequency |
|---|---|
| Intellectual disability | >90% (mild to moderate) |
| Speech/language delay | >90% |
| Autism spectrum features | ~60% |
| Seizures | ~30% |
| Feeding difficulties | ~70% |
| Hypogonadism | ~50% (males) |
| Behavioral issues | >80% (anxiety, ADHD-like) |
The mechanism involves haploinsufficiency affecting epigenetic regulation and synaptic protein stability[4].
USP7 is a therapeutic target in oncology[5]:
USP7 connects to neurodegenerative disease through several mechanisms[3]:
| Variant | Effect | Phenotype |
|---|---|---|
| Heterozygous LoF (various) | Haploinsufficiency | Hao-Fountain syndrome |
| p.C223A | Catalytic dead | Loss of deubiquitinase activity (used experimentally) |
| Missense in catalytic domain | Reduced activity | Variable NDD phenotype |
| Missense in TRAF/UBL domains | Altered substrate binding | Milder developmental phenotype |
USP7 is broadly expressed with notable enrichment in[1]:
Kategaya L et al. USP7 small-molecule inhibitors interfere with ubiquitin binding (2017). 2017. ↩︎
Hao YH et al. USP7 acts as a molecular rheostat to promote WASH-dependent endosomal protein recycling and is mutated in a human neurodevelopmental disorder (2015). 2015. ↩︎
Turnbull AP et al. Molecular basis of USP7 inhibition by selective small-molecule inhibitors (2017). 2017. ↩︎