2. Academic Validation
  3. Hypomorphic homozygous mutations in phosphoglucomutase 3 (PGM3) impair immunity and increase serum IgE levels

Hypomorphic homozygous mutations in phosphoglucomutase 3 (PGM3) impair immunity and increase serum IgE levels

  • J Allergy Clin Immunol. 2014 May;133(5):1410-9, 1419.e1-13. doi: 10.1016/j.jaci.2014.02.025.
Atfa Sassi 1,  Sandra Lazaroski 2,  Gang Wu 3,  Stuart M Haslam 3,  Manfred Fliegauf 2,  Fethi Mellouli 4,  Turkan Patiroglu 5,  Ekrem Unal 6,  Mehmet Akif Ozdemir 6,  Zineb Jouhadi 7,  Khadija Khadir 7,  Leila Ben-Khemis 1,  Meriem Ben-Ali 1,  Imen Ben-Mustapha 1,  Lamia Borchani 8,  Dietmar Pfeifer 9,  Thilo Jakob 10,  Monia Khemiri 11,  A Charlotta Asplund 12,  Manuela O Gustafsson 12,  Karin E Lundin 12,  Elin Falk-Sörqvist 13,  Lotte N Moens 13,  Hatice Eke Gungor 14,  Karin R Engelhardt 15,  Magdalena Dziadzio 15,  Hans Stauss 15,  Bernhard Fleckenstein 16,  Rebecca Meier 2,  Khairunnadiya Prayitno 2,  Andrea Maul-Pavicic 2,  Sandra Schaffer 2,  Mirzokhid Rakhmanov 2,  Philipp Henneke 2,  Helene Kraus 2,  Hermann Eibel 2,  Uwe Kölsch 17,  Sellama Nadifi 18,  Mats Nilsson 13,  Mohamed Bejaoui 4,  Alejandro A Schäffer 19,  C I Edvard Smith 12,  Anne Dell 3,  Mohamed-Ridha Barbouche 1,  Bodo Grimbacher 20
Affiliations

Affiliations

  • 1 Laboratory of Immunopathology, Vaccinology and Molecular Genetics, Pasteur Institute of Tunis and University Tunis El Manar, Tunis, Tunisia.
  • 2 Center for Chronic Immunodeficiency (CCI), University Medical Center Freiburg, Freiburg, Germany.
  • 3 Department of Life Sciences, Imperial College London, London, United Kingdom.
  • 4 Pediatrics Department, Bone Marrow Transplantation Center, Tunis, Tunisia.
  • 5 Department of Pediatrics, Division of Pediatric Hematology and Oncology, Faculty of Medicine, Erciyes University, Kayseri, Turkey; Department of Pediatrics, Division of Pediatric Immunology, Faculty of Medicine, Erciyes University, Kayseri, Turkey.
  • 6 Department of Pediatrics, Division of Pediatric Hematology and Oncology, Faculty of Medicine, Erciyes University, Kayseri, Turkey.
  • 7 Department of Pediatric Infectious Diseases, CHU IBN ROCHD, Hassan II University, Casablanca, Morocco.
  • 8 Laboratory of Venoms and Therapeutic Molecules, Institut Pasteur de Tunis, Tunis, Tunisia.
  • 9 Department of Medicine I, Specialties: Hematology, Oncology, and Stem-Cell Transplantation, University Medical Center Freiburg, Freiburg, Germany.
  • 10 Allergy Research Group, Department of Dermatology, University Medical Center Freiburg, Freiburg, Germany.
  • 11 Pediatrics Department A, Children's Hospital of Tunis, Tunis, Tunisia.
  • 12 Clinical Research Center, Department of Laboratory Medicine, Karolinska Institutet, Karolinska University Hospital Huddinge, Huddinge, Sweden.
  • 13 Department of Immunology, Genetics and Pathology, Uppsala University, Rudbeck Laboratory, Uppsala, Sweden.
  • 14 Department of Pediatrics, Division of Pediatric Immunology, Faculty of Medicine, Erciyes University, Kayseri, Turkey.
  • 15 Royal Free Hospital, Institute of Immunity & Transplantation, University College London, London, United Kingdom.
  • 16 Institute of Virology, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany.
  • 17 Division of Immunology, Labor Berlin and Institute of Medical Immunology, Charité, Campus Virchow Klinikum, Berlin, Germany.
  • 18 Department of Genetics, Hassan II University, Casablanca, Morocco.
  • 19 National Center for Biotechnology Information, National Institutes of Health, Department of Health and Human Services, Bethesda, Md.
  • 20 Center for Chronic Immunodeficiency (CCI), University Medical Center Freiburg, Freiburg, Germany; Royal Free Hospital, Institute of Immunity & Transplantation, University College London, London, United Kingdom. Electronic address: bodo.grimbacher@uniklinik-freiburg.de.
PMID: 24698316 DOI: 10.1016/j.jaci.2014.02.025
Abstract

Background: Recurrent Bacterial and Fungal infections, eczema, and increased serum IgE levels characterize patients with the hyper-IgE syndrome (HIES). Known genetic causes for HIES are mutations in signal transducer and activator of transcription 3 (STAT3) and dedicator of cytokinesis 8 (DOCK8), which are involved in signal transduction pathways. However, glycosylation defects have not been described in patients with HIES. One crucial Enzyme in the glycosylation pathway is phosphoglucomutase 3 (PGM3), which catalyzes a key step in the synthesis of uridine diphosphate N-acetylglucosamine, which is required for the biosynthesis of N-glycans.

Objective: We sought to elucidate the genetic cause in patients with HIES who do not carry mutations in STAT3 or DOCK8.

Methods: After establishing a linkage interval by means of SNPchip genotyping and homozygosity mapping in 2 families with HIES from Tunisia, mutational analysis was performed with selector-based, high-throughput Sequencing. Protein expression was analyzed by means of Western blotting, and glycosylation was profiled by using mass spectrometry.

Results: Mutational analysis of candidate genes in an 11.9-Mb linkage region on chromosome 6 shared by 2 multiplex families identified 2 homozygous mutations in PGM3 that segregated with disease status and followed recessive inheritance. The mutations predict amino acid changes in PGM3 (p.Glu340del and p.Leu83Ser). A third homozygous mutation (p.Asp502Tyr) and the p.Leu83Ser variant were identified in 2 other affected families, respectively. These hypomorphic mutations have an effect on the biosynthetic reactions involving uridine diphosphate N-acetylglucosamine. Glycomic analysis revealed an aberrant glycosylation pattern in leukocytes demonstrated by a reduced level of tri-antennary and tetra-antennary N-glycans. T-cell proliferation and differentiation were impaired in patients. Most patients had developmental delay, and many had psychomotor retardation.

Conclusion: Impairment of PGM3 function leads to a novel primary (inborn) error of development and immunity because biallelic hypomorphic mutations are associated with impaired glycosylation and a hyper-IgE-like phenotype.

Keywords

Hyper-IgE syndrome; Staphylococcus aureus; dedicator of cytokinesis 8; glycosylation; phosphoglucomutase 3; signal transducer and activator of transcription 3.

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