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

J Allergy Clin Immunol. 2014 May;133(5):1400-9, 1409.e1-5. doi: 10.1016/j.jaci.2014.02.013.

Yu Zhang ¹, Xiaomin Yu ², Mie Ichikawa ³, Jonathan J Lyons ², Shrimati Datta ², Ian T Lamborn ¹, Huie Jing ¹, Emily S Kim ¹, Matthew Biancalana ⁴, Lynne A Wolfe ⁵, Thomas DiMaggio ¹, Helen F Matthews ⁴, Sarah M Kranick ⁶, Kelly D Stone ², Steven M Holland ⁷, Daniel S Reich ⁸, Jason D Hughes ⁹, Huseyin Mehmet ⁹, Joshua McElwee ⁹, Alexandra F Freeman ⁷, Hudson H Freeze ⁴, Helen C Su ¹⁰, Joshua D Milner ¹¹

Affiliations

1 Laboratory of Host Defenses, National Institutes of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Md.
2 Laboratory of Allergic Diseases, National Institutes of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Md.
3 Sanford-Burnham Medical Research Institute, La Jolla, Calif.
4 Laboratory of Immunology, National Institutes of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Md.
5 Undiagnosed Diseases Program, National Human Genome Research Institute, Bethesda, Md.
6 Section of Infections of the Nervous System, National Institute of Neurological Diseases and Stroke, National Institutes of Health, Bethesda, Md.
7 Laboratory of Clinical Infectious Diseases, National Institutes of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Md.
8 Neuroimmunology Branch, National Institute of Neurological Diseases and Stroke, National Institutes of Health, Bethesda, Md.
9 Merck Research Laboratories, Merck & Co, Boston, Mass.
10 Laboratory of Host Defenses, National Institutes of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Md. Electronic address: hsu@niaid.nih.gov.
11 Laboratory of Allergic Diseases, National Institutes of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Md. Electronic address: jdmilner@niaid.nih.gov.

PMID: 24589341 DOI: 10.1016/j.jaci.2014.02.013

Abstract

Background: Identifying genetic syndromes that lead to significant atopic disease can open new pathways for investigation and intervention in allergy.

Objective: We sought to define a genetic syndrome of severe atopy, increased serum IgE levels, immune deficiency, autoimmunity, and motor and neurocognitive impairment.

Methods: 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.

Results: Marked atopy and autoimmunity were associated with increased T(H)2 and T(H)17 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.

Conclusions: Autosomal recessive hypomorphic PGM3 mutations underlie a disorder of severe atopy, immune deficiency, autoimmunity, intellectual disability, and hypomyelination.

Keywords

Atopy; allergy; autoimmunity; glycosylation; hyper-IgE; immune deficiency; neurocognitive impairment; phosphoglucomutase 3.

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