USP7

Molecular characteristics

Overview
Our bodies are made up of trillions of cells. Within each cell is a nucleus, which contains X-shaped structures called chromosomes. Human body cells normally have 46 chromosomes. Pairs of human chromosomes numbered from 1 through 22 are called autosomes and the sex chromosomes are designated X and Y. Males have one X and one Y chromosome and females have two X chromosomes.
These chromosomes are made up of tightly wound strands of DNA, our genetic material. Segments of DNA that provide instructions for the body to make proteins are called genes. Proteins play a critical role in many functions of the body. When a change (mutation) in a gene occurs, the protein product may be faulty, inefficient, or absent. Depending upon the functions of the particular protein, this can affect many organ systems of the body, including the brain. The gene that is altered in patients with HAFOUS is the USP7 gene, located on the short (p) arm of chromosome 16.

Inheritance Pattern
Most genetic diseases are determined by the status of the two copies of a gene, one received from the father and one from the mother. The inheritance pattern of the disease caused by USP7 mutations is autosomal dominant, which means that only a single abnormal copy of the gene is necessary to cause the disease. Mutations in USP7 are either gene deletions, meaning the entire gene is missing, or point mutations, meaning just one letter in the DNA code is changed. The diagnosis of USP7 mutations takes place through either whole exome sequencing or chromosome microarray analysis (CMA).
Abnormal genes can either be inherited from a parent, or can result from de novo mutations, meaning that the parents are unaffected and the mutation arose spontaneously during the development of the parents’ sperm and egg cells. The majority of documented cases of HAFOUS are considered de novo mutations.
If the parents of an affected child are considering having another baby, the risk of recurrence in a sibling depends on the type of mutation. If the child has a de novo mutation, the risk for any future sibling to also be affected is <2%. If the child’s mutation was inherited from a parent, the risk for any child of that individual is 50%.

Underlying Pathophysiological Mechanism
The USP7 gene contains instructions for producing (encoding) the USP7 protein, which plays a role in tumor suppression, control over the process of converting DNA into a protein (transcriptional regulation), immune response, and endosomal protein recycling. Endosomes are compartments within cells that transport molecules such as proteins. Endosomes direct proteins in three different directions: 1) towards the cell membrane for recycling, 2) to the Golgi apparatus, which helps modify and package proteins to leave the cell, or 3) to the lysosome to be broken down (degraded).
Scientific studies have shown the important role USP7 plays in the precision control of the protein recycling process. Sometimes, endosomes mistakenly bring proteins inside the cell that are supposed to stay on the cell’s surface. When this happens, endosomes need to direct these proteins back to the cell membrane for recycling, and not to the lysosome where they would be broken down. In order for proteins to get back to the cell membrane, a protein called actin needs to be added to the endosome. Actin gets put on the endosome by a structure called WASH. For WASH to be working, it needs to be activated by a small protein called ubiquitin. Ubiquitin gets added to WASH by a structure called the MUST complex, which is made up of 3 proteins including the USP7 protein. To put it all together, USP7 is a component of MUST, which uses ubiquitin to activate WASH, which adds actin to the endosome, which instructs the endosome to send important proteins back to the surface of the cell where they belong.
Interestingly, USP7 actually has two functions on WASH: not only does it promote ubiquitination of WASH to activate it (which helps recycle proteins back to the membrane), but it also takes ubiquitin off of WASH to deactivate it (which would lead to proteins being degraded in the lysosome; see figure 1). Though these two functions seemingly oppose each other, USP7 helps with precision control of the protein recycling process.


Figure 1. Model for dual activities of USP7 in preventing TRIM27 from auto-ubiquitination-induced degradation, but also limiting WASH ubiquitination levels and activity (Hao et al. 2015). When the USP7 gene has a mutation, this process doesn’t work, and the recycling and degradation of proteins in the cell will be changed, causing the symptoms seen in USP7-related diseases.

When the USP7 gene has a mutation, this process doesn’t work, and the recycling and degradation of proteins in the cell will be changed, causing the symptoms seen in USP7-related diseases.