Presentation is loading. Please wait.

Presentation is loading. Please wait.

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

Published byMarjorie Cain Modified over 6 years ago

Similar presentations

Presentation on theme: "Autosomal recessive phosphoglucomutase 3 (PGM3) mutations link glycosylation defects to atopy, immune deficiency, autoimmunity, and neurocognitive impairment "— Presentation transcript:

1 Autosomal recessive phosphoglucomutase 3 (PGM3) mutations link glycosylation defects to atopy, immune deficiency, autoimmunity, and neurocognitive impairment  Yu Zhang, PhD, Xiaomin Yu, PhD, Mie Ichikawa, BSc, Jonathan J. Lyons, MD, Shrimati Datta, PhD, Ian T. Lamborn, BSc, Huie Jing, PhD, Emily S. Kim, BSc, Matthew Biancalana, BSc, Lynne A. Wolfe, CRNP, Thomas DiMaggio, ADN, Helen F. Matthews, BSN, Sarah M. Kranick, MD, Kelly D. Stone, MD, PhD, Steven M. Holland, MD, Daniel S. Reich, MD, PhD, Jason D. Hughes, PhD, Huseyin Mehmet, PhD, Joshua McElwee, PhD, Alexandra F. Freeman, MD, Hudson H. Freeze, PhD, Helen C. Su, MD, PhD, Joshua D. Milner, MD  Journal of Allergy and Clinical Immunology  Volume 133, Issue 5, Pages e5 (May 2014) DOI: /j.jaci Copyright © Terms and Conditions

2 Fig 1 Pedigrees of the 2 families in the study. A, Family I. B, Family II. Solid symbols denote affected status, and a slash through a symbol represents a deceased person. Journal of Allergy and Clinical Immunology  , e5DOI: ( /j.jaci ) Copyright © Terms and Conditions

3 Fig 2 Clinical findings in patients. A, Severe atopic dermatitis in patient I.1 before and after wet-wrap therapy with topical corticosteroids and emollients. Note scoliosis. B, Brain MRI. Shown are axial T2-FLAIR images of patient I.2 showing stable hyperintensity in the white matter semiovale (blue arrows) at ages 22 (left), 31 (middle), and 35 (right) years, which is suggestive of stable dysmyelination. These findings were typical across our cohort. C, Visual evoked potentials in patient II.1 demonstrate prolonged p100 in both eyes (OS 200 ms and OD 197 ms) at check size 16. Blue arrows, Consistent with demyelinating optic neuropathy; x-axis, 30 ms per box; y-axis, 10 μV per box. Normal p100 peak latency us indicated by gray areas ( ms). Journal of Allergy and Clinical Immunology  , e5DOI: ( /j.jaci ) Copyright © Terms and Conditions

4 Fig 3 Genetic analysis of PGM3 deficiency. A, Compound heterozygous PGM3 mutations in family I and homozygous missense PGM3 mutation in family II. B, PGM3 domain structure. The mutations detected in family I (blue) and family II (yellow) are indicated by arrowheads. C, Multiple sequence alignment of PGM3 from different species, showing conservation of residues that are mutated in the patients. D, Structural model of PGM3. Left, Three-dimensional structural model of PGM3 protein based on the structure of the closest available homolog from Candida albicans. Relative locations of the patient's missense mutations are denoted as circles (E325 in yellow and Q529 in blue). Right, Positions of both mutations relative to the active site and bound substrate. Hydrogen bonds between the focal amino acid and any adjacent residues are shown as yellow dashes. The charge of the side chain is denoted, if applicable. E, PGM3 protein levels in cell lysates from cycling T cells (left) and EBV cell lines (right) prepared from patients of both families, parents of family II, and healthy control subjects. β-Actin levels were measured as a loading control. Journal of Allergy and Clinical Immunology  , e5DOI: ( /j.jaci ) Copyright © Terms and Conditions

5 Fig 4 Impaired function in PGM3-deficient patients. A, PGM3 enzymatic activities. The rate of GlcNAc-1-P formation from GlcNAc-6-P was measured in fibroblast lysates from patients (n = 3) or healthy control subjects (n = 2). B, Sugar phosphate analysis was performed on samples from Fig 4, A. C, Nucleotide sugar phosphate analysis after overnight treatment of fibroblasts (3 patients with 2 healthy control subjects) with (+) or without (−) 10 mmol/L GlcNAc. Exogenous GlcNAc supplementation increased UDP-GlcNAc and UDP–N-acetylgalactosamine (UDP-GalNAc) levels. D, Increased TH2 and TH17 cytokine levels in patients with PGM3 mutations. Percentage of CD3+CD4+CD45RO+ cells producing IL-4, IL-5, IL-17, or IFN-γ in response to phorbol 12-myristate 13-acetate and ionomycin in PBMCs from healthy control subjects and patients. Horizontal bars represent the mean percentage for each of the groups. Experiments were performed 2 to 4 times for each patient. ns, Not significant. *P < .05 and **P < .01. Journal of Allergy and Clinical Immunology  , e5DOI: ( /j.jaci ) Copyright © Terms and Conditions

6 Fig E1 Quantitative RT-PCR analysis of PGM3 expression in patients from both families. PGM3 expression is shown normalized to β-actin. Journal of Allergy and Clinical Immunology  , e5DOI: ( /j.jaci ) Copyright © Terms and Conditions

7 Fig E2 Increased TH2 and TH17 cytokine levels in patients with PGM3 mutations. Representative dot plots of data shown in Fig 4. CD3+CD4+CD45RO+ gated cells producing IL-4, IL-5, IL-17, or IFN-γ in nonstimulated (NS) and phorbol 12-myristate 13-acetate and ionomycin (PMA/I)–stimulated PBMCs from healthy control subjects and patients. Journal of Allergy and Clinical Immunology  , e5DOI: ( /j.jaci ) Copyright © Terms and Conditions

8 Fig E3 T-cell proliferation of patients with PGM3 mutations. Total PBMCs from healthy control subjects and patients were labeled with CFSE and stimulated with either staphylococcal enterotoxin B (SEB; 1 μg/mL) or PHA-P (5 μg/mL) for 4.5 days. Cells were gated on CD4+ or CD8+ T cells for flow cytometric analysis. A representative histogram of 2 patients tested in 4 to 6 different experiments is shown. Journal of Allergy and Clinical Immunology  , e5DOI: ( /j.jaci ) Copyright © Terms and Conditions

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

Similar presentations

Monica G. Lawrence, MD, Jennifer W. Leiding, MD, Jonathan J

Monica G. Lawrence, MD, Jennifer W. Leiding, MD, Jonathan J
Impaired TH17 responses in patients with chronic mucocutaneous candidiasis with and without autoimmune polyendocrinopathy–candidiasis–ectodermal dystrophy 

Impaired TH17 responses in patients with chronic mucocutaneous candidiasis with and without autoimmune polyendocrinopathy–candidiasis–ectodermal dystrophy 
Targeted next-generation sequencing revealed MYD88 deficiency in a child with chronic yersiniosis and granulomatous lymphadenitis  Giuliana Giardino,

Targeted next-generation sequencing revealed MYD88 deficiency in a child with chronic yersiniosis and granulomatous lymphadenitis  Giuliana Giardino,
Immune deficiency caused by impaired expression of nuclear factor-κB essential modifier (NEMO) because of a mutation in the 5′ untranslated region of.

Immune deficiency caused by impaired expression of nuclear factor-κB essential modifier (NEMO) because of a mutation in the 5′ untranslated region of.
Autoimmunity due to RAG deficiency and estimated disease incidence in RAG1/2 mutations  Karin Chen, MD, Wilfred Wu, MD, Divij Mathew, BA, Yuhua Zhang,

Autoimmunity due to RAG deficiency and estimated disease incidence in RAG1/2 mutations  Karin Chen, MD, Wilfred Wu, MD, Divij Mathew, BA, Yuhua Zhang,
Homozygous N-terminal missense mutation in TRNT1 leads to progressive B-cell immunodeficiency in adulthood  Glynis Frans, MPharm, Leen Moens, PhD, Heidi.

Homozygous N-terminal missense mutation in TRNT1 leads to progressive B-cell immunodeficiency in adulthood  Glynis Frans, MPharm, Leen Moens, PhD, Heidi.
William A. Comrie, PhD, Aiman J

William A. Comrie, PhD, Aiman J
Impaired TH17 responses in patients with chronic mucocutaneous candidiasis with and without autoimmune polyendocrinopathy–candidiasis–ectodermal dystrophy 

Impaired TH17 responses in patients with chronic mucocutaneous candidiasis with and without autoimmune polyendocrinopathy–candidiasis–ectodermal dystrophy 
Differential cytokine induction by the human skin–associated autoallergen thioredoxin in sensitized patients with atopic dermatitis and healthy control.

Differential cytokine induction by the human skin–associated autoallergen thioredoxin in sensitized patients with atopic dermatitis and healthy control.
T-cell regulation during viral and nonviral asthma exacerbations

T-cell regulation during viral and nonviral asthma exacerbations
Penicillium marneffei infection and impaired IFN-γ immunity in humans with autosomal- dominant gain-of-phosphorylation STAT1 mutations  Pamela P.W. Lee,

Penicillium marneffei infection and impaired IFN-γ immunity in humans with autosomal- dominant gain-of-phosphorylation STAT1 mutations  Pamela P.W. Lee,
Anti–IL-5 (mepolizumab) therapy reduces eosinophil activation ex vivo and increases IL- 5 and IL-5 receptor levels  Miguel L. Stein, MD, Joyce M. Villanueva,

Anti–IL-5 (mepolizumab) therapy reduces eosinophil activation ex vivo and increases IL- 5 and IL-5 receptor levels  Miguel L. Stein, MD, Joyce M. Villanueva,
RASGRP1 mutation in autoimmune lymphoproliferative syndrome-like disease  Huawei Mao, MD, PhD, Wanling Yang, PhD, Sylvain Latour, PhD, Jing Yang, PhD,

RASGRP1 mutation in autoimmune lymphoproliferative syndrome-like disease  Huawei Mao, MD, PhD, Wanling Yang, PhD, Sylvain Latour, PhD, Jing Yang, PhD,
Defective killing of Staphylococcus aureus in atopic dermatitis is associated with reduced mobilization of human β-defensin-3  Kevin O. Kisich, PhD, Charles.

Defective killing of Staphylococcus aureus in atopic dermatitis is associated with reduced mobilization of human β-defensin-3  Kevin O. Kisich, PhD, Charles.
Reduction of CRKL expression in patients with partial DiGeorge syndrome is associated with impairment of T-cell functions  Mauro Giacomelli, PhD, Rajesh.

Reduction of CRKL expression in patients with partial DiGeorge syndrome is associated with impairment of T-cell functions  Mauro Giacomelli, PhD, Rajesh.
Defects in lymphocyte telomere homeostasis contribute to cellular immune phenotype in patients with cartilage-hair hypoplasia  Geraldine Aubert, PhD,

Defects in lymphocyte telomere homeostasis contribute to cellular immune phenotype in patients with cartilage-hair hypoplasia  Geraldine Aubert, PhD,
Molecular mechanisms of functional natural killer deficiency in patients with partial DiGeorge syndrome  Peilin Zheng, PhD, Lenora M. Noroski, MD, Imelda.

Molecular mechanisms of functional natural killer deficiency in patients with partial DiGeorge syndrome  Peilin Zheng, PhD, Lenora M. Noroski, MD, Imelda.
Lung T-cell responses to nontypeable Haemophilus influenzae in patients with chronic obstructive pulmonary disease  Paul T. King, MD, PhD, Steven Lim,

Lung T-cell responses to nontypeable Haemophilus influenzae in patients with chronic obstructive pulmonary disease  Paul T. King, MD, PhD, Steven Lim,
Recurrent viral infections associated with a homozygous CORO1A mutation that disrupts oligomerization and cytoskeletal association  Christina S. Yee,

Recurrent viral infections associated with a homozygous CORO1A mutation that disrupts oligomerization and cytoskeletal association  Christina S. Yee,
Mutation in IRF2BP2 is responsible for a familial form of common variable immunodeficiency disorder  Michael D. Keller, MD, Rahul Pandey, PhD, Dong Li,

Mutation in IRF2BP2 is responsible for a familial form of common variable immunodeficiency disorder  Michael D. Keller, MD, Rahul Pandey, PhD, Dong Li,

Similar presentations

Ads by Google