X marks the spot: Does it matter that O-GlcNAc Transferase is an X-linked gene?

•OGT is located on the X-chromosome near XIST.•OGT expression could be sex-biased during early embryogenesis.•In females, OGT may escape X-inactivation altering O-GlcNAcylation and disease development.•Thus, the gender of animals/cells must be considered when conducting O-GlcNAcylation studies. O-GlcNAcylation has emerged as a critical post-translational modification important for a wide array of cellular processes. This modification has been identified on a large pool of intracellular proteins that have wide-ranging roles, including transcriptional regulation, cell cycle progression, and signaling, among others. Interestingly, in mammals the single gene encoding O-GlcNAc Transferase (OGT) is located on the X-chromosome near the Xist locus suggesting that tight dosage regulation is necessary for normal development. Herein, we highlight the importance of OGT dosage and consider how its genomic location can contribute to a gender-specific increased risk for a number of diseases.