USP9X

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USP9X is a gene that makes an enzyme in humans called FAF-X. It belongs to the ubiquitin-specific protease family and acts as a deubiquitinase, removing ubiquitin from proteins. By doing this, it helps regulate how long proteins stay active or get broken down. Although the gene sits on the X chromosome, it escapes X-inactivation, so both copies can influence development in females.

In early development, USP9X is essential. Reducing USP9X in mouse embryos stops blastocyst formation and harms cell adhesion and polarity, showing its key role in early life. The gene also affects signaling pathways such as Notch, Wnt, EGF, and mTOR, and it is highly active in stem and progenitor cells, especially before cells differentiate.

USP9X has been linked to brain development and to certain brain-related diseases. Variants or deletions can contribute to neurodevelopmental disorders and X-linked intellectual disability, with symptoms ranging from intellectual disability and language problems in females to brain abnormalities in males. Some variants are also associated with neurodegenerative conditions like Alzheimer's, Parkinson's, and Huntington's diseases, partly through effects on the regulation of tau protein.

In research, mice lacking USP9X in hippocampal neurons show shorter axons and less branching, highlighting its role in neural connectivity. Because it is on the X chromosome and escapes inactivation, females with USP9X mutations can show symptoms even if only one copy is affected; males, with only one X, often have more severe effects, and a complete loss is usually lethal before birth.

Overall, USP9X is a conserved enzyme that controls protein life cycles and signaling, with important roles in brain development and disease.