This gene is a member of the peptidase C19 family and encodes a protein that is similar to ubiquitin-specific proteases. Though this gene is located on the X chromosome, it escapes X-inactivation.
Depletion of USP9X from two-cell mouse embryos halts blastocyst development and results in slower blastomere cleavage rate, impaired cell adhesion and a loss of cell polarity. It has also been implicated that USP9X is likely to influence developmental processes through signaling pathways of Notch, Wnt, EGF, and mTOR. USP9X has been recognized in studies of mouse and human stem cells involving embryonic, neural and hematopoietic stem cells. High expression is retained in undifferentiated progenitor and stem cells and decreases as differentiation continues. USP9X is a protein-coding gene that has been implicated either directly through mutations or indirectly in a number of neurodevelopmental and neurodegenerative disorders. Three mutations have been connected with X-linked intellectual disability through disrupted neuronal growth and cell migration. Neurodegenerative disorders, such as Alzheimer's, Parkinson's and Huntington's disease, have also been linked to USP9X. Specifically, USP9X has been implicated in the regulation of the phosphorylation and expression of the microtule-associated protein tau, which forms pathological aggregates in Alzheimer's and other tauopathies. Scientists have generated a knockout model where they isolated hippocampal neurons from an USP9X-knockout male mouse, which showed a 43% reduction in axonal length and arborization compared to wild type.
Variants of the USP9X gene have been found to cause a neurodevelopmental USP9X syndrome in both males and females. USP9X is strongly evolutionarily conserved in humans and is intolerant to variation. This is due to the important role of the USP9X enzyme, which reverses protein ubiquitylation, thereby decreasing the enzymatic degradation and increasing the longevity of those proteins. Being on the X chromosome, USP9X syndrome manifests differently in females compared to males. In females, loss of function variations in one copy of the gene results in haploinsufficiency. This is because USP9X escapes the usually-protective process of X-inactivation. As a result, even “carrier” females exhibit the syndrome.
USP9X variants seen in surviving males cause loss of function in brain-specific processes only, since total loss of function of this gene is fatal in the embryonic stage. Males are hemizygous for this gene because they possess only one X chromosome. Symptoms seen in affected males include intellectual disability, problems with language, speech, behaviour and sight, and facial dysmorphia. Specific brain abnormalities include white matter disturbances, a thin corpus callosum, and widened ventricles.
Noma T, Kanai Y, Kanai-Azuma M, Ishii M, Fujisawa M, Kurohmaru M, Kawakami H, Wood SA, Hayashi Y (2002). "Stage- and sex-dependent expressions of Usp9x, an X-linked mouse ortholog of Drosophila Fat facets, during gonadal development and oogenesis in mice". Gene Expr. Patterns. 2 (1–2): 87–91. doi:10.1016/S0925-4773(02)00290-3. PMID12617843.
Bouwmeester T, Bauch A, Ruffner H, Angrand PO, Bergamini G, Croughton K, Cruciat C, Eberhard D, Gagneur J, Ghidelli S, Hopf C, Huhse B, Mangano R, Michon AM, Schirle M, Schlegl J, Schwab M, Stein MA, Bauer A, Casari G, Drewes G, Gavin AC, Jackson DB, Joberty G, Neubauer G, Rick J, Kuster B, Superti-Furga G (2004). "A physical and functional map of the human TNF-alpha/NF-kappa B signal transduction pathway". Nat. Cell Biol. 6 (2): 97–105. doi:10.1038/ncb1086. PMID14743216. S2CID11683986.
Fu GK, Wang JT, Yang J, Au-Young J, Stuve LL (2004). "Circular rapid amplification of cDNA ends for high-throughput extension cloning of partial genes". Genomics. 84 (1): 205–10. doi:10.1016/j.ygeno.2004.01.011. PMID15203218.
Rush J, Moritz A, Lee KA, Guo A, Goss VL, Spek EJ, Zhang H, Zha XM, Polakiewicz RD, Comb MJ (2005). "Immunoaffinity profiling of tyrosine phosphorylation in cancer cells". Nat. Biotechnol. 23 (1): 94–101. doi:10.1038/nbt1046. PMID15592455. S2CID7200157.
Al-Hakim AK, Göransson O, Deak M, Toth R, Campbell DG, Morrice NA, Prescott AR, Alessi DR (2005). "14-3-3 cooperates with LKB1 to regulate the activity and localization of QSK and SIK". J. Cell Sci. 118 (Pt 23): 5661–73. doi:10.1242/jcs.02670. PMID16306228.
Beausoleil SA, Villén J, Gerber SA, Rush J, Gygi SP (2006). "A probability-based approach for high-throughput protein phosphorylation analysis and site localization". Nat. Biotechnol. 24 (10): 1285–92. doi:10.1038/nbt1240. PMID16964243. S2CID14294292.