期刊
JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY
卷 133, 期 5, 页码 1400-U658出版社
MOSBY-ELSEVIER
DOI: 10.1016/j.jaci.2014.02.013
关键词
Atopy; immune deficiency; hyper-IgE; neurocognitive impairment; phosphoglucomutase 3; glycosylation; allergy; autoimmunity
资金
- Intramural Research Programs of the National Institutes of Allergy and Infectious Diseases
- National Human Genome Research Institute
- National Institute of Neurological Diseases and Stroke
- National Institutes of Health
- Rocket Fund
- R01DK55615
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 RTPCR, 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.
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