PGM3 – Immunodeficiency 23

Phosphoglucomutase 3 (PGM3) is a cytosolic enzyme that converts N-acetyl-glucosamine-6-phosphate to N-acetyl-glucosamine-1-phosphate, a key precursor for UDP-GlcNAc biosynthesis and N-glycosylation. Biallelic hypomorphic or loss-of-function variants in PGM3 underlie Autosomal Recessive Immunodeficiency 23, a congenital glycosylation disorder characterized by recurrent infections, eczema, neutropenia, lymphopenia, and variable serum IgE levels.

Clinical Validity (Definitive)

PGM3–Immunodeficiency 23 meets ClinGen Definitive criteria based on: over 20 probands across ≥10 unrelated families; robust segregation in siblings and multiplex kindreds (13 affected relatives); and concordant functional studies across multiple publications.

Genetic Evidence (Strong)

Autosomal recessive inheritance is established by homozygous and compound heterozygous PGM3 variants segregating with disease in multiple families. Two siblings carrying homozygous c.965T>C (p.Ile322Thr) displayed severe infections with normal IgE and no developmental defects ([PMID:26482871]). Three patients from two kindreds harboring novel homozygous missense variants p.Gly359Asp and p.Met423Thr exhibited severe combined immunodeficiency and skeletal dysplasia ([PMID:33534079]). Large cohorts revealed biallelic truncating and missense changes—e.g., c.1104T>G (p.Tyr368Ter), c.1432C>T (p.Gln478Ter), c.398_413del (p.Ser133fs)—in three unrelated children with leukopenia and bone marrow failure ([PMID:24931394]). An eight-patient series demonstrated recessive PGM3 mutations in atopy with immune deficiency and neurocognitive impairment ([PMID:24589341]).

Functional Evidence (Moderate)

Recombinant expression and patient fibroblast assays show severely reduced PGM3 enzymatic activity. Glycomic profiling of patient leukocytes reveals defective tri- and tetra-antennary N-glycans ([PMID:24698316]). Hematopoietic stem cell transplantation corrects neutropenia and lymphopenia in two children ([PMID:24931394]). Mass spectrometry and glycan analyses confirm impaired glycosylation consistent with clinical severity.

Conflicting Evidence

A heterozygous c.253C>G (p.Pro85Ala) variant identified in a single patient with recurrent eczematous dermatitis remains of uncertain significance and does not fit the recessive model ([PMID:37720709]). Monoallelic PGM3 variants linked to idiopathic focal epilepsy suggest a dosage-sensitive effect distinct from Immunodeficiency 23.

Integration & Clinical Utility

Genetic and functional data definitively associate biallelic PGM3 variants with Immunodeficiency 23. Early molecular diagnosis enables targeted management, including antimicrobial prophylaxis and consideration of hematopoietic stem cell transplantation. Key take-home: PGM3 sequencing is essential in patients with autosomal recessive immunodeficiency featuring recurrent infections, eczema, cytopenias, and abnormal IgE.

References

• Clinical Immunology (Orlando, Fla.) • 2015 • Susceptibility to infections, without concomitant hyper-IgE, reported in 1976, is caused by hypomorphic mutation in the phosphoglucomutase 3 (PGM3) gene. PMID:26482871
• Journal of Clinical Immunology • 2021 • Two Novel Homozygous Mutations in Phosphoglucomutase 3 Leading to Severe Combined Immunodeficiency, Skeletal Dysplasia, and Malformations. PMID:33534079
• American Journal of Human Genetics • 2014 • PGM3 mutations cause a congenital disorder of glycosylation with severe immunodeficiency and skeletal dysplasia. PMID:24931394
• The Journal of Allergy and Clinical Immunology • 2014 • Autosomal recessive phosphoglucomutase 3 (PGM3) mutations link glycosylation defects to atopy, immune deficiency, autoimmunity, and neurocognitive impairment. PMID:24589341
• The Journal of Allergy and Clinical Immunology • 2014 • Hypomorphic homozygous mutations in phosphoglucomutase 3 (PGM3) impair immunity and increase serum IgE levels. PMID:24698316
• Clinical Case Reports • 2023 • Hyper IgE syndrome-related disease treated with dupilumab: A case report. PMID:37720709

Evidence Based Scoring (AI generated)