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

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• 作者：Yu Zhang ; PhD^a ; ^&lowast ; ; Xiaomin Yu ; PhD^b ; ^&lowast ; ; Mie Ichikawa ; BSc^c ; Jonathan J. Lyons ; MD^b ; Shrimati Datta ; PhD^b ; Ian T. Lamborn ; BSc^a ; Huie Jing ; PhD^a ; Emily S. Kim ; BSc^a ; Matthew Biancalana ; BSc^d ; Lynne A. Wolfe ; CRNP^e ; Thomas DiMaggio ; ADN^a ; Helen F. Matthews ; BSN^d ; Sarah M. Kranick ; MD^f ; Kelly D. Stone ; MD ; PhD^b ; Steven M. Holland ; MD^g ; Daniel S. Reich ; MD ; PhD^h ; Jason D. Hughes ; PhDⁱ ; Huseyin Mehmet ; PhDⁱ ; Joshua McElwee ; PhDⁱ ; Alexandra F. Freeman ; MD^g ; Hudson H. Freeze ; PhD^c ; Helen C. Su ; MD ; PhD^a ; ^{hsu@niaid.nih.gov" class="auth_mail} ; Joshua D. Milner ; MD^b ; ^{jdmilner@niaid.nih.gov" class="auth_mail}
• 关键词：Atopy ; immune deficiency ; hyper-IgE ; neurocognitive impairment ; phosphoglucomutase 3 ; glycosylation ; allergy ; autoimmunity
• 刊名：Journal of Allergy and Clinical Immunology
• 出版年：May 2014
• 年：2014
• 卷：133
• 期：5
• 页码：1400-1409.e5
• 全文大小：2383 K

文摘

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_H2 and T_H17 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.