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J Allergy Clin Immunol. 2014 May;133(5):1410-9, 1419.e1-13. doi: 10.1016/j.jaci.2014.02.025. Epub 2014 Apr 1.

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

Author information

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.

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

PMID:
24698316
PMCID:
PMC4825677
DOI:
10.1016/j.jaci.2014.02.025
[Indexed for MEDLINE]
Free PMC Article

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