De novo variants (six multigenic deletions, one nonsense variant) affecting the USP7 gene were identified in seven patients presenting with developmental delay/intellectual disability, with five of these cases having an additional diagnosis of ASD (Hao et al., 2015). Subsequent statistical analysis determined that there was a strong correlation between the seven patients having both a de novo USP7 variant and the expressed phenotype that was likely not due to chance (p<0.0001).
Molecular Function
Hydrolase that deubiquitinates target proteins such as FOXO4, p53/TP53, MDM2, ERCC6, DNMT1, UHRF1, PTEN and DAXX. 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. 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. In association with DAXX, is involved in the deubiquitination and translocation of PTEN from the nucleus to the cytoplasm. Involved in cell proliferation during early embryonic development.
External Links
References
Type
Title
Type of Disorder
Associated Disorders
Author, Year
Primary
USP7 Acts as a Molecular Rheostat to Promote WASH-Dependent Endosomal Protein Recycling and Is Mutated in a Human Neurodevelopmental Disorder.
Model Type:
Genetic
Model Genotype:
Homozygous
Mutation:
An IRES-lacZ-neo cassette is inserted into exon 14 of USP7 leading to the deletion of the first 29 nucleotides of exon 14 and resulting in a frameshift mutation. This C terminal truncated protein is unstable and not detectable (PMID 19946331).
Allele Type: Targeted (reporter, knockout)
Strain of Origin: Genetic Background: 129Sv * C57BL/6
ES Cell Line: Mutant ES Cell Line: Model Source: PMID 19946331
Model Type:
Genetic
Model Genotype:
Wildtype
Mutation:
Transgene delivered through AAV vector through bilateral intracerebroventricular (ICV) injections performed in FVB/NJ wildtype mouse, on postnatal day 0 (P0).
Allele Type: Overexpression
Strain of Origin: Genetic Background: FVB/NJ
ES Cell Line: Mutant ES Cell Line: Model Source: Jackson Laboratory
Model Type:
Genetic
Model Genotype:
Wildtype
Mutation:
Transgene delivered through AAV vector through In utero electroporation (IUE) performed on timed pregnant CD-1 dams at embryonic day 14.5 (E14.5).
Allele Type: Overexpression
Strain of Origin: Genetic Background: CD-1
ES Cell Line: Mutant ES Cell Line: Model Source: Charles River Laboratory
Description: No usp7 homozygous knockout mutant pups are recovered at birth revealing that null mutations in usp7 leads to embryonic lethality
Exp Paradigm: NA
Description: By e6.5 usp7 null embryos appear to be smaller with impaired patterning and at e7.5 , unlike controls, they show no recognizable structures
Exp Paradigm: NA
Description: Reduced cell proliferation is observed in e7.5 embryos, using brdu labeling, which authors suggest is at least partially responsible for embryonic lethality
Exp Paradigm: NA
Description: Mice injected with Usp7 virus showed increased overall activity levels, assessed by grooming, rearing, digging, climbing, circling and jumping compared to the controls.
Description: Although both the USP7 mice and the control mice spent a significantly longer time in the stranger-containing chamber than the empty chamber, USP7 mice showed a higher score in the preference index.
Description: Stronger expression of Usp7 was observed in layer III and layer V in the cortex, and significantly higher in AAV-USP7 groups compared to controls; the level of Xiap was also increased in the brains of mice injected with Usp7 virus.
Description: Cortical slices show a decrease in upper layer neuronal number and increase in lower layer and ventricular zone neuronal number for Usp7 neurons.
