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Background: Hypomorphic mutations in the phosphoacetylglucosamine mutase 3 (PGM3) gene cause a glycosylation disorder that leads to immunodeficiency. It is often associated with recurrent infections and atopy. The exact etiology of this condition remains unclear. Objective: This study aimed to characterize the phenotypes and immunological features associated with PGM3 insufficiency and investigate potential disease mechanisms. Methods: A systematic review of 44 published cases of 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 the 12 reconstituted variants in human B cells. A PGM3 inhibitor was used to assess its effect on CD4+ T cell proliferation and differentiation. Results: Patients with PGM3 variants frequently presented with recurrent infections and atopy, accompanied by reduced naïve CD4+ T cell counts. A genotype–phenotype study showed that low levels of residual PGM3 expression are correlated with disease severity. Notably, inhibition of PGM3 activity impaired TCR-mediated CD4+ T cell proliferation and the synthesis of UDP-GlcNAc, complex N-glycans, O-GlcNAc, glycolytic stress, 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: PGM3 is a critical regulator of CD4+ T-cell proliferation and differentiation. These findings provide new insights into the diverse clinical manifestations and therapeutic development of PGM3 deficiency. [ABSTRACT FROM AUTHOR]

Background: Alpha-1,3-glucosyltransferase (ALG8), a key enzyme in protein glycosylation, is implicated in the oncogenesis and progression of several human malignancies. This study aimed to define the role of ALG8 in hepatocellular carcinoma (HCC) and uncover its mechanisms of action. Methods: ALG8 expression in HCC and normal tissues was analyzed using the TCGA and GEO databases, validated by RT-qPCR and western blot. Survival outcomes were evaluated via Cox analyses, and ALG8's impact on HCC behavior was examined through functional assays. GO, KEGG, and GSEA identified ALG8-related pathways, validated by biochemical assays. Results: In bioinformatics analyses, ALG8 was overexpressed in HCC tissues (p < 0.05 for all comparisons) and correlated with poorer survival (p = 0.006 and p = 0.025, respectively), establishing its role as an independent prognostic factor. In vitro experiments showed that knockdown of ALG8 reduced HCC cell proliferation, migration, and invasion. Using the STRING platform and TCGA-LIHC dataset, we identified ALG8-interacting genes and their associated differentially expressed genes (DEGs). GO and KEGG analyses further linked ALG8 to genes involved in glycosylation, signal release, and other processes, as well as pathways including neuroactive ligand-receptor interaction and N-Glycan biosynthesis. GSEA, corroborated by western blot and immunofluorescence, points to the Wnt/β-catenin signaling cascade as a probable mechanistic pathway through which ALG8 may modulate HCC progression. Conclusion: Elevated ALG8 expression in HCC is linked to worse outcomes and increased tumor aggressiveness, with silencing ALG8 reducing Wnt/β-catenin signaling, highlighting ALG8 as a potential therapeutic target. [ABSTRACT FROM AUTHOR]