Autosomal recessive phosphoglucomutase 3 (PGM3) mutations link glycosylation defects to atopy, immune deficiency, autoimmunity, and neurocognitive impairment

• Published in: Journal of allergy and clinical immunology Vol. 133; no. 5; pp. 1400 - 1409.e5
• Main Authors: Zhang, Yu, Yu, Xiaomin, Ichikawa, Mie, Lyons, Jonathan J., Datta, Shrimati, Lamborn, Ian T., Jing, Huie, Kim, Emily S., Biancalana, Matthew, Wolfe, Lynne A., DiMaggio, Thomas, Matthews, Helen F., Kranick, Sarah M., Stone, Kelly D., Holland, Steven M., Reich, Daniel S., Hughes, Jason D., Mehmet, Huseyin, McElwee, Joshua, Freeman, Alexandra F., Freeze, Hudson H., Su, Helen C., Milner, Joshua D.
• Format: Journal Article
• Language: English
• Published: New York, NY Elsevier Inc 01.05.2014; Elsevier; Elsevier Limited
• Subjects: Allergies; allergy; Allergy and Immunology; Asthma; Atopy; Autoimmune Diseases - enzymology; Autoimmune Diseases - genetics; Autoimmune Diseases - immunology; Autoimmune Diseases - pathology; autoimmunity; B-Lymphocytes - enzymology; B-Lymphocytes - immunology; B-Lymphocytes - pathology; Biological and medical sciences; CD8-Positive T-Lymphocytes - enzymology; CD8-Positive T-Lymphocytes - immunology; CD8-Positive T-Lymphocytes - pathology; Child; Child, Preschool; Cognition Disorders - enzymology; Cognition Disorders - genetics; Cognition Disorders - immunology; Cognition Disorders - pathology; Common Variable Immunodeficiency - enzymology; Common Variable Immunodeficiency - genetics; Common Variable Immunodeficiency - immunology; Common Variable Immunodeficiency - pathology; Defects; Dermatitis; Disease; Enzymes; Family; Female; Food allergies; Fundamental and applied biological sciences. Psychology; Fundamental immunology; Genetic Diseases, Inborn - enzymology; Genetic Diseases, Inborn - genetics; Genetic Diseases, Inborn - immunology; Genetic Diseases, Inborn - pathology; glycosylation; Humans; hyper-IgE; Hypersensitivity - enzymology; Hypersensitivity - genetics; Hypersensitivity - immunology; Hypersensitivity - pathology; immune deficiency; Immunodeficiencies; Immunodeficiencies. Immunoglobulinopathies; Immunoglobulin E - genetics; Immunoglobulin E - immunology; Immunopathology; Infections; Lasers; Male; Medical sciences; Mutation; neurocognitive impairment; NMR; Nuclear magnetic resonance; Patients; Pedigree; Phosphoglucomutase - genetics; Phosphoglucomutase - immunology; Phosphoglucomutase - metabolism; phosphoglucomutase 3; Proteins; Sarcoidosis. Granulomatous diseases of unproved etiology. Connective tissue diseases. Elastic tissue diseases. Vasculitis; Spectrum analysis; Th17 Cells - enzymology; Th17 Cells - immunology; Th17 Cells - pathology; Th2 Cells - enzymology; Th2 Cells - immunology; Th2 Cells - pathology; Viral infections; Young Adult; immune deficiency; MRI; DOCK8; CDG; hyper-IgE; Atopy; GlcNAc-1-P; GlcNAc-6-P; phosphoglucomutase 3; PGM3; GlcNAc; SNV; UDP; STAT3; glycosylation; allergy; CFSE; NIH; GATK; autoimmunity; APC; PE; neurocognitive impairment; indel; GC/MS; Dedicator of cytokinesis 8; Gas chromatography/mass spectrometry; National Institutes of Health; Signal transducer and activator of transcription 3; Allophycocyanin; Insertion/deletion; Single nucleotide variant; Uridine diphosphate; N-acetyl-D-glucosamine; Carboxyfluorescein succinimidyl ester; Magnetic resonance imaging; Phycoerythrin; Genome Analysis Toolkit; GlcNAc-1-phosphate; GlcNAc-6-phosphate; Congenital disorder of glycosylation; Autoimmunity; Allergy; Immunopathology; Cognitive disorder; Enzyme; IgE; Glycosylation; Immune deficiency; Genetic disease; Phosphoglucomutase; Isomerases; Immunology; Intramolecular transferases; Genetics; Mutation; Phosphotransferases
• ISSN: 0091-6749; 1097-6825; 1097-6825
• DOI: 10.1016/j.jaci.2014.02.013

Identifying genetic syndromes that lead to significant atopic disease can open new pathways for investigation and intervention in allergy. We sought to define a genetic syndrome of severe atopy, increased serum IgE levels, immune deficiency, autoimmunity, and motor and neurocognitive impairment. Eight patients from 2 families with similar syndromic features were studied. Thorough clinical evaluations, including brain magnetic resonance imaging and sensory evoked potentials, were performed. Peripheral lymphocyte flow cytometry, antibody responses, and T-cell cytokine production were measured. Whole-exome sequencing was performed to identify disease-causing mutations. Immunoblotting, quantitative RT-PCR, enzymatic assays, nucleotide sugar, and sugar phosphate analyses, along with matrix-assisted laser desorption/ionization–time-of-flight mass spectrometry of glycans, were used to determine the molecular consequences of the mutations. Marked atopy and autoimmunity were associated with increased TH2 and TH17 cytokine production by CD4+ T cells. Bacterial and viral infection susceptibility were noted along with T-cell lymphopenia, particularly of CD8+ T cells, and reduced memory B-cell numbers. Apparent brain hypomyelination resulted in markedly delayed evoked potentials and likely contributed to neurologic abnormalities. Disease segregated with novel autosomal recessive mutations in a single gene, phosphoglucomutase 3 (PGM3). Although PGM3 protein expression was variably diminished, impaired function was demonstrated by decreased enzyme activity and reduced uridine diphosphate–N-acetyl-D-glucosamine, along with decreased O- and N-linked protein glycosylation in patients' cells. These results define a new congenital disorder of glycosylation. Autosomal recessive hypomorphic PGM3 mutations underlie a disorder of severe atopy, immune deficiency, autoimmunity, intellectual disability, and hypomyelination.