title: Autosomal recessive phosphoglucomutase 3 (PGM3) mutations link glycosylation defects to atopy, immune deficiency, autoimmunity, and neurocognitive impairment.
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.
authors.affiliation: Laboratory of Host Defenses, National Institutes of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Md.
authors.forename: Yu
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Laboratory of Allergic Diseases, National Institutes of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Md.
authors.forename: Xiaomin
authors.initials: X
authors.lastname: Yu
authors.affiliation: Sanford-Burnham Medical Research Institute, La Jolla, Calif.
authors.forename: Mie
authors.initials: M
authors.lastname: Ichikawa
authors.affiliation: Laboratory of Allergic Diseases, National Institutes of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Md.
authors.forename: Jonathan J
authors.initials: JJ
authors.lastname: Lyons
authors.affiliation: Laboratory of Allergic Diseases, National Institutes of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Md.
authors.forename: Shrimati
authors.initials: S
authors.lastname: Datta
authors.affiliation: Laboratory of Host Defenses, National Institutes of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Md.
authors.forename: Ian T
authors.initials: IT
authors.lastname: Lamborn
authors.affiliation: Laboratory of Host Defenses, National Institutes of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Md.
authors.forename: Huie
authors.initials: H
authors.lastname: Jing
authors.affiliation: Laboratory of Host Defenses, National Institutes of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Md.
authors.forename: Emily S
authors.initials: ES
authors.lastname: Kim
authors.affiliation: Laboratory of Immunology, National Institutes of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Md.
authors.forename: Matthew
authors.initials: M
authors.lastname: Biancalana
authors.affiliation: Undiagnosed Diseases Program, National Human Genome Research Institute, Bethesda, Md.
authors.forename: Lynne A
authors.initials: LA
authors.lastname: Wolfe
authors.affiliation: Laboratory of Host Defenses, National Institutes of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Md.
authors.forename: Thomas
authors.initials: T
authors.lastname: DiMaggio
authors.affiliation: Laboratory of Immunology, National Institutes of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Md.
authors.forename: Helen F
authors.initials: HF
authors.lastname: Matthews
authors.affiliation: Section of Infections of the Nervous System, National Institute of Neurological Diseases and Stroke, National Institutes of Health, Bethesda, Md.
authors.forename: Sarah M
authors.initials: SM
authors.lastname: Kranick
authors.affiliation: Laboratory of Allergic Diseases, National Institutes of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Md.
authors.forename: Kelly D
authors.initials: KD
authors.lastname: Stone
authors.affiliation: Laboratory of Clinical Infectious Diseases, National Institutes of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Md.
authors.forename: Steven M
authors.initials: SM
authors.lastname: Holland
authors.affiliation: Neuroimmunology Branch, National Institute of Neurological Diseases and Stroke, National Institutes of Health, Bethesda, Md.
authors.forename: Daniel S
authors.initials: DS
authors.lastname: Reich
authors.affiliation: Merck Research Laboratories, Merck & Co, Boston, Mass.
authors.forename: Jason D
authors.initials: JD
authors.lastname: Hughes
authors.affiliation: Merck Research Laboratories, Merck & Co, Boston, Mass.
authors.forename: Huseyin
authors.initials: H
authors.lastname: Mehmet
authors.affiliation: Merck Research Laboratories, Merck & Co, Boston, Mass.
authors.forename: Joshua
authors.initials: J
authors.lastname: McElwee
authors.affiliation: Laboratory of Clinical Infectious Diseases, National Institutes of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Md.
authors.forename: Alexandra F
authors.initials: AF
authors.lastname: Freeman
authors.affiliation: Laboratory of Immunology, National Institutes of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Md.
authors.forename: Hudson H
authors.initials: HH
authors.lastname: Freeze
authors.affiliation: Laboratory of Host Defenses, National Institutes of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Md. Electronic address: hsu@niaid.nih.gov.
authors.forename: Helen C
authors.initials: HC
authors.lastname: Su
authors.affiliation: Laboratory of Allergic Diseases, National Institutes of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Md. Electronic address: jdmilner@niaid.nih.gov.
authors.forename: Joshua D
authors.initials: JD
authors.lastname: Milner
mesh_terms: D001327:Autoimmune Diseases / Q000201:enzymology / Q000235:genetics* / Q000276:immunology / Q000473:pathology; D001402:B-Lymphocytes / Q000201:enzymology / Q000276:immunology / Q000473:pathology; D018414:CD8-Positive T-Lymphocytes / Q000201:enzymology / Q000276:immunology / Q000473:pathology; D002648:Child; D002675:Child, Preschool; D003072:Cognition Disorders / Q000201:enzymology / Q000235:genetics* / Q000276:immunology / Q000473:pathology; D017074:Common Variable Immunodeficiency / Q000201:enzymology / Q000235:genetics* / Q000276:immunology / Q000473:pathology; D005190:Family; D005260:Female; D030342:Genetic Diseases, Inborn / Q000201:enzymology / Q000235:genetics* / Q000276:immunology / Q000473:pathology; D006801:Humans; D006967:Hypersensitivity / Q000201:enzymology / Q000235:genetics* / Q000276:immunology / Q000473:pathology; D007073:Immunoglobulin E / Q000235:genetics / Q000276:immunology; D008297:Male; D009154:Mutation; D010375:Pedigree; D010733:Phosphoglucomutase / Q000235:genetics* / Q000276:immunology / Q000378:metabolism; D058504:Th17 Cells / Q000201:enzymology / Q000276:immunology / Q000473:pathology; D018418:Th2 Cells / Q000201:enzymology / Q000276:immunology / Q000473:pathology; D055815:Young Adult
chemical_list: D007073:Immunoglobulin E; C549916:PGM3 protein, human; D010733:Phosphoglucomutase
keywords: Atopy; allergy; autoimmunity; glycosylation; hyper-IgE; immune deficiency; neurocognitive impairment; phosphoglucomutase 3