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

Area of Science:

• Immunology
• Genetics
• Biochemistry

Background:

• Hypomorphic mutations in the phosphoacetylglucosamine mutase 3 (PGM3) gene cause a glycosylation disorder leading to immunodeficiency, recurrent infections, and atopy.
• The precise mechanisms underlying PGM3 deficiency-related immune dysfunction remain incompletely understood.

Purpose of the Study:

• To characterize the clinical phenotypes and immunological features of PGM3 insufficiency.
• To investigate the underlying molecular mechanisms of PGM3 deficiency, focusing on T-cell function.

Main Methods:

• Systematic review of 44 published cases with PGM3 variants.
• T-cell phenotyping in patients with PGM3 variants.
• Genotype-phenotypic correlation analysis and in vitro studies using a PGM3 inhibitor to assess effects on CD4+ T cells.

Main Results:

• PGM3 variants are associated with recurrent infections, atopy, and reduced naive CD4+ T cell counts.
• Lower residual PGM3 expression correlates with increased disease severity.
• PGM3 inhibition impairs CD4+ T cell proliferation, UDP-GlcNAc synthesis, N-glycan and O-GlcNAc production, and alters metabolic pathways. It also skews T-cell differentiation, enhancing Th1/Th2 responses while suppressing Th17/Treg differentiation.

Conclusions:

• PGM3 plays a critical role in regulating CD4+ T-cell proliferation and differentiation.
• These findings offer new insights into the clinical spectrum and potential therapeutic strategies for PGM3 deficiency.