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

Yu Zhang, Xiaomin Yu, Mie Ichikawa, Jonathan J. Lyons, Shrimati Datta, Ian T. Lamborn, Huie Jing, Emily S. Kim, Matthew Biancalana, Lynne A. Wolfe, Thomas Dimaggio, Helen F. Matthews, Sarah M. Kranick, Kelly D. Stone, Steven M. Holland, Daniel S. Reich, Jason D. Hughes, Huseyin Mehmet, Joshua McElwee, Alexandra F. FreemanHudson H. Freeze, Helen C. Su, Joshua D. Milner

Research output: Contribution to journalArticlepeer-review

133 Scopus citations


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

Original languageEnglish (US)
Pages (from-to)1400-1409.e5
JournalJournal of Allergy and Clinical Immunology
Issue number5
StatePublished - May 2014
Externally publishedYes


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

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology


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