PGM3 insufficiency: a glycosylation disorder causing a notable T cell defect

Background: Hypomorphicmutations in thegenePhosphoacetylglucosamine mutase 3 (PGM3) cause a glycosylation disorder leading to immunodeficiency (1). This disorder is often associated with recurrent infections and atopy. The exact etiology remains unclear. Objective: This study aims to characterize the phenotypes and immunological features associated with PGM3 insufficiency and to investigate potential disease mechanisms. Methods: A systematic review of 44 published cases with PGM3 variants was performed, followed by T-cell phenotyping of two patients with PGM3 variants. A genotype-phenotypic severity study was conducted by comparing the residual PGM3 expression of 12 reconstituted variants in human B cells. A PGM3 inhibitor, FR054, was then used to assess its effect on CD4+ T cell proliferation and differentiation. Results: Patients identifiedwithPGM3 variants frequently presentedwith recurrent infections and atopy, accompanied by reduced naïveCD4+T cell counts. Agenotype-phenotype study showed that low levels of residual PGM3 expression correlates with disease severity. Notably, inhibition of PGM3 activity by using the inhibitor FR054 (2, 3), impaired TCR mediated CD4+ T cell proliferation, the synthesis of UDP-GlcNAc, complex N-glycans, O-GlcNAc, glycolysis, and mitochondrial respiration during proliferation in a dose-dependent manner. Partial loss of PGM3 activity was observed to preferentially enhance Th1 and Th2 differentiation while attenuating Th17 and Treg differentiation, consistent with clinical observations. Conclusion: PGM3emergesasacritical regulator of CD4+ T cell proliferation and differentiation. These findings provide new insights into the diverse clinical symptoms and therapeutic development of PGM3 insufficiency.