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

Atfa Sassi (1) , Sandra Lazaroski (2) , Gang Wu (3) , Stuart M Haslam (2) , Manfred Fliegauf (2) , Fethi Mellouli (4) , Turkan Patiroglu (5, 5) , Ekrem Unal (5) , Mehmet Akif Ozdemir (5) , Zineb Jouhadi (6) , Khadija Khadir (6) , Leila Ben-Khemis (1) , Meriem Ben-Ali (1) , Imen Ben-Mustapha (1) , Lamia Borchani (7) , Dietmar Pfeifer (8) , Thilo Jakob (8) , Monia Khemiri (9) , a Charlotta Asplund (10) , Manuela O Gustafsson (10) , Karin E Lundin (10) , Elin Falk-Sörqvist (11) , Lotte N Moens (12) , Hatice Eke Gungor (5) , Karin R Engelhardt (11) , Magdalena Dziadzio (11) , Hans Stauss (11) , Bernhard Fleckenstein (13) , 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 (14) , Sellama Nadifi (15) , Mats Nilsson (12) , Mohamed Bejaoui (16) , Alejandro A Schäffer (17) , C I Edvard Smith (10) , Anne Dell (10) , Mohamed-Ridha Barbouche (1) , Bodo Grimbacher (2, 11)

1 LVGM - Laboratoire d'Immunopathologie, Vaccinologie et Génétique Moléculaire
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 Erciyes University
6 Department of Pediatric Infectious Diseases, CHU IBN ROCHD, Hassan II University, Casablanca, Morocco
7 LR11IPT08 - Laboratoire des Venins et Biomolécules Thérapeutiques - Laboratory of Venoms and Therapeutic Biomolecules
8 Department of Medicine I, Specialties: Hematology, Oncology, and Stem-Cell Transplantation, University Medical Center Freiburg, Freiburg, Germany
9 Pediatrics Department A, Children's Hospital of Tunis, Tunis, Tunisia
10 Clinical Research Center, Department of Laboratory Medicine, Karolinska Institutet, Karolinska University Hospital Huddinge, Huddinge, Sweden
11 UCL - University College of London [London]
12 Department of Immunology, Genetics and Pathology, Uppsala University, Rudbeck Laboratory, Uppsala, Sweden
13 Institute of Virology, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany
14 Division of Immunology, Labor Berlin and Institute of Medical Immunology, Charité, Campus Virchow Klinikum, Berlin, Germany
15 Department of Genetics, Hassan II University, Casablanca, Morocco
16 Pediatrics Department, Bone Marrow Transplantation Center, Tunis, Tunisia.
17 National Center for Biotechnology Information, National Institutes of Health, Department of Health and Human Services, Bethesda, Md

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.

Domains: Life Sciences [q-bio]; Life Sciences [q-bio]; Immunology

Atfa Sassi, Sandra Lazaroski, Gang Wu, Stuart M Haslam, Manfred Fliegauf, et al.. Hypomorphic homozygous mutations in phosphoglucomutase 3 (PGM3) impair immunity and increase serum IgE levels.. Journal of Allergy and Clinical Immunology, 2014, 133 (5), pp.1410-9, 1419.e1-13. ⟨10.1016/j.jaci.2014.02.025⟩. ⟨pasteur-01060838⟩