1. Hypomorphic homozygous mutations in phosphoglucomutase 3 (PGM3) impair immunity and increase serum IgE levels
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Karin R. Engelhardt, Bernhard Fleckenstein, Ekrem Unal, C. I. Edvard Smith, Dietmar Pfeifer, Mohamed-Ridha Barbouche, Meriem Ben-Ali, Hans J. Stauss, Mohamed Bejaoui, Mirzokhid Rakhmanov, Lamia Borchani, Monia Khemiri, Stuart M. Haslam, Zineb Jouhadi, Khadija Khadir, Imen Ben-Mustapha, Bodo Grimbacher, Karin E. Lundin, A. Charlotta Asplund, Manfred Fliegauf, Uwe Kölsch, Gang Wu, A. Sassi, Sandra Lazaroski, Turkan Patiroglu, Magdalena Dziadzio, Anne Dell, Mats Nilsson, Sellama Nadifi, Khairunnadiya Prayitno, Mehmet Akif Ozdemir, Fethi Mellouli, Andrea Maul-Pavicic, Manuela O. Gustafsson, Helene Kraus, Hermann Eibel, Lotte Moens, Hatice Eke Gungor, Thilo Jakob, Elin Falk-Sörqvist, Alejandro A. Schäffer, Sandra Schaffer, Rebecca Meier, Leila Ben-Khemis, Philipp Henneke, Laboratoire d'Immunopathologie, Vaccinologie et Génétique Moléculaire (LVGM), Institut Pasteur de Tunis, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP), Center for Chronic Immunodeficiency (CCI), University Medical Center Freiburg, Freiburg, Germany, Department of Life Sciences, Imperial College London, London, United Kingdom, Pediatrics Department, Bone Marrow Transplantation Center, Tunis,Tunisia, Pediatrics Department, Bone Marrow Transplantation Center, Tunis, Tunisia, 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, Department of Pediatric Infectious Diseases, CHU IBN ROCHD, Hassan II University, Casablanca, Morocco, Laboratoire des Venins et Biomolécules Thérapeutiques - Laboratory of Venoms and Therapeutic Biomolecules (LR11IPT08), Department of Medicine I, Specialties: Hematology, Oncology, and Stem-Cell Transplantation, University Medical Center Freiburg, Freiburg, Germany, Pediatrics Department A, Children's Hospital of Tunis, Tunis, Tunisia, Clinical Research Center, Department of Laboratory Medicine, Karolinska Institutet, Karolinska University Hospital Huddinge, Huddinge, Sweden, Karolinska Institutet [Stockholm]-Karolinska University Hospital [Stockholm], Royal Free Hospital, Institute of Immunity & Transplantation, University College London, London, United Kingdom, Department of Immunology, Genetics and Pathology, Uppsala University, Rudbeck Laboratory, Uppsala, Sweden, Institute of Virology, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany, Division of Immunology, Labor Berlin and Institute of Medical Immunology, Charité, Campus Virchow Klinikum, Berlin, Germany, Department of Genetics, Hassan II University, Casablanca, Morocco, Pediatrics Department, Bone Marrow Transplantation Center, Tunis, Tunisia., National Center for Biotechnology Information, National Institutes of Health, Department of Health and Human Services, Bethesda, Md, National Institutes of Health [Bethesda] (NIH), and Supported by the German Federal Ministry of Education and Research (BMBF 01 EO 0803). The research was supported in part by the Intramural Research Program of the National Library of Medicine–National Institutes of Health. Parts of the study were supported by the Tunisian Ministry for Higher Education and Research, the Swedish Medical Research Council, the Swedish Cancer Society and the Stockholm County Council (research grant ALF), and the European Community’s 6th and 7th Framework Programs FP7/2007-2013 under grant agreement Health-F5-2008-223292 (Euro-Gene-Scan). This work was also supported by the Biotechnology and Biological Sciences Research Council (BBF0083091 and BB/ K016164/1 to A.D. and S.M.H).
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Male ,Candidate gene ,Glycosylation ,Allergy ,Genetic Linkage ,[SDV]Life Sciences [q-bio] ,T-Lymphocytes ,medicine.disease_cause ,chemistry.chemical_compound ,MESH: Child ,2.1 Biological and endogenous factors ,Immunology and Allergy ,Aetiology ,Child ,MESH: Immunity ,Genetics ,Mutation ,MESH: Immunoglobulin E ,Homozygote ,MESH: Glycosylation ,Disease gene identification ,MESH: Amino Acid Substitution ,MESH: Infant ,Phenotype ,3. Good health ,Hyper-IgE syndrome ,Genetic Diseases ,signal transducer and activator of transcription 3 ,[SDV.IMM]Life Sciences [q-bio]/Immunology ,Chromosomes, Human, Pair 6 ,Female ,Pair 6 ,Dock8 ,MESH: Tunisia ,MESH: Phosphoglucomutase ,Job Syndrome ,MESH: Homozygote ,Human ,Adult ,MESH: Genetic Diseases, Inborn ,Staphylococcus aureus ,Tunisia ,MESH: Chromosomes, Human, Pair 6 ,Immunology ,Mutation, Missense ,MESH: Genetic Linkage ,Biology ,phosphoglucomutase 3 ,Article ,Chromosomes ,Rare Diseases ,Clinical Research ,Genetic linkage ,MESH: Cell Proliferation ,medicine ,Humans ,Cell Proliferation ,MESH: Mutation, Missense ,MESH: Humans ,MESH: Job Syndrome ,Genetic Diseases, Inborn ,Immunity ,Infant ,MESH: Adult ,Immunoglobulin E ,medicine.disease ,Molecular biology ,MESH: Male ,MESH: T-Lymphocytes ,Inborn ,Emerging Infectious Diseases ,Phosphoglucomutase ,Amino Acid Substitution ,chemistry ,Missense ,dedicator of cytokinesis 8 ,MESH: Female ,Congenital disorder of glycosylation - Abstract
International audience; 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.
- Published
- 2014
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