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Updated: Mar 31, 2026
Author Spotlight: Identifying Compensatory Pathways in Malaria Parasites Containing Hypomorphic Allele of Essential Protein Kinases
Published on: November 22, 2024
Susceptibility to infections, without concomitant hyper-IgE, reported in 1976, is caused by hypomorphic mutation in
Karin E Lundin1, Abdulrahman Hamasy1, Paul Hoff Backe2
1Clinical Research Center, Karolinska Institutet, Department of Laboratory Medicine, Karolinska University Hospital, S-141 86 Huddinge, Sweden.
Abstract:
Phosphoglucomutase 3 (PGM3) is an enzyme converting N-acetyl-glucosamine-6-phosphate to N-acetyl-glucosamine-1-phosphate, a precursor important for glycosylation. Mutations in the PGM3 gene have recently been identified as the cause of novel primary immunodeficiency with a hyper-IgE like syndrome. Here we report the occurrence of a homozygous mutation in the PGM3 gene in a family with immunodeficient children, described already in 1976. DNA from two of the immunodeficient siblings was sequenced and shown to encode the same homozygous missense mutation, causing a destabilized protein with reduced enzymatic capacity. Affected individuals were highly prone to infections, but lack the developmental defects in the nervous and skeletal systems, reported in other families. Moreover, normal IgE levels were found. Thus, belonging to the expanding group of congenital glycosylation defects, PGM3 deficiency is characterized by immunodeficiency, with or without increased IgE levels, and with variable forms of developmental defects affecting other organ systems.
Insights
Phosphoglucomutase 3 (PGM3) deficiency causes severe immunodeficiency due to a destabilized enzyme. This genetic defect leads to recurrent infections, highlighting PGM3
Area of Science:
- Biochemistry
- Immunology
- Genetics
Background:
- Phosphoglucomutase 3 (PGM3) is crucial for N-acetyl-glucosamine metabolism, a key step in protein glycosylation.
- Mutations in PGM3 have been linked to primary immunodeficiency and hyper-IgE syndrome.
Observation:
- A family with immunodeficient children, first described in 1976, was investigated.
- Two affected siblings were found to have the same homozygous missense mutation in the PGM3 gene.
Findings:
- The identified PGM3 mutation results in a destabilized protein with reduced enzymatic activity.
- Affected individuals exhibit severe immunodeficiency and are highly susceptible to infections.
- Notably, these patients lack the neurological and skeletal developmental defects seen in other PGM3 deficiency cases and have normal IgE levels.
Implications:
- PGM3 deficiency represents a congenital glycosylation disorder primarily manifesting as immunodeficiency.
- The variable clinical presentation underscores the complex genotype-phenotype correlations in PGM3-related disorders.
- This study expands the understanding of PGM3's role in immune function and development.
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