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


CONCLUSIONS
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.
Laboratory of Immunopathology, Vaccinology and Molecular Genetics, Pasteur Institute of Tunis and University Tunis El Manar, Tunis, Tunisia.
Atfa
A
Sassi
Center for Chronic Immunodeficiency (CCI), University Medical Center Freiburg, Freiburg, Germany.
Sandra
S
Lazaroski
Department of Life Sciences, Imperial College London, London, United Kingdom.
Gang
G
Wu
Department of Life Sciences, Imperial College London, London, United Kingdom.
Stuart M
SM
Haslam
Center for Chronic Immunodeficiency (CCI), University Medical Center Freiburg, Freiburg, Germany.
Manfred
M
Fliegauf
Pediatrics Department, Bone Marrow Transplantation Center, Tunis, Tunisia.
Fethi
F
Mellouli
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.
Turkan
T
Patiroglu
Department of Pediatrics, Division of Pediatric Hematology and Oncology, Faculty of Medicine, Erciyes University, Kayseri, Turkey.
Ekrem
E
Unal
Department of Pediatrics, Division of Pediatric Hematology and Oncology, Faculty of Medicine, Erciyes University, Kayseri, Turkey.
Mehmet Akif
MA
Ozdemir
Department of Pediatric Infectious Diseases, CHU IBN ROCHD, Hassan II University, Casablanca, Morocco.
Zineb
Z
Jouhadi
Department of Pediatric Infectious Diseases, CHU IBN ROCHD, Hassan II University, Casablanca, Morocco.
Khadija
K
Khadir
Laboratory of Immunopathology, Vaccinology and Molecular Genetics, Pasteur Institute of Tunis and University Tunis El Manar, Tunis, Tunisia.
Leila
L
Ben-Khemis
Laboratory of Immunopathology, Vaccinology and Molecular Genetics, Pasteur Institute of Tunis and University Tunis El Manar, Tunis, Tunisia.
Meriem
M
Ben-Ali
Laboratory of Immunopathology, Vaccinology and Molecular Genetics, Pasteur Institute of Tunis and University Tunis El Manar, Tunis, Tunisia.
Imen
I
Ben-Mustapha
Laboratory of Venoms and Therapeutic Molecules, Institut Pasteur de Tunis, Tunis, Tunisia.
Lamia
L
Borchani
Department of Medicine I, Specialties: Hematology, Oncology, and Stem-Cell Transplantation, University Medical Center Freiburg, Freiburg, Germany.
Dietmar
D
Pfeifer
Allergy Research Group, Department of Dermatology, University Medical Center Freiburg, Freiburg, Germany.
Thilo
T
Jakob
Pediatrics Department A, Children's Hospital of Tunis, Tunis, Tunisia.
Monia
M
Khemiri
Clinical Research Center, Department of Laboratory Medicine, Karolinska Institutet, Karolinska University Hospital Huddinge, Huddinge, Sweden.
A Charlotta
AC
Asplund
Clinical Research Center, Department of Laboratory Medicine, Karolinska Institutet, Karolinska University Hospital Huddinge, Huddinge, Sweden.
Manuela O
MO
Gustafsson
Clinical Research Center, Department of Laboratory Medicine, Karolinska Institutet, Karolinska University Hospital Huddinge, Huddinge, Sweden.
Karin E
KE
Lundin
Department of Immunology, Genetics and Pathology, Uppsala University, Rudbeck Laboratory, Uppsala, Sweden.
Elin
E
Falk-Sörqvist
Department of Immunology, Genetics and Pathology, Uppsala University, Rudbeck Laboratory, Uppsala, Sweden.
Lotte N
LN
Moens
Department of Pediatrics, Division of Pediatric Immunology, Faculty of Medicine, Erciyes University, Kayseri, Turkey.
Hatice Eke
HE
Gungor
Royal Free Hospital, Institute of Immunity & Transplantation, University College London, London, United Kingdom.
Karin R
KR
Engelhardt
Royal Free Hospital, Institute of Immunity & Transplantation, University College London, London, United Kingdom.
Magdalena
M
Dziadzio
Royal Free Hospital, Institute of Immunity & Transplantation, University College London, London, United Kingdom.
Hans
H
Stauss
Institute of Virology, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany.
Bernhard
B
Fleckenstein
Center for Chronic Immunodeficiency (CCI), University Medical Center Freiburg, Freiburg, Germany.
Rebecca
R
Meier
Center for Chronic Immunodeficiency (CCI), University Medical Center Freiburg, Freiburg, Germany.
Khairunnadiya
K
Prayitno
Center for Chronic Immunodeficiency (CCI), University Medical Center Freiburg, Freiburg, Germany.
Andrea
A
Maul-Pavicic
Center for Chronic Immunodeficiency (CCI), University Medical Center Freiburg, Freiburg, Germany.
Sandra
S
Schaffer
Center for Chronic Immunodeficiency (CCI), University Medical Center Freiburg, Freiburg, Germany.
Mirzokhid
M
Rakhmanov
Center for Chronic Immunodeficiency (CCI), University Medical Center Freiburg, Freiburg, Germany.
Philipp
P
Henneke
Center for Chronic Immunodeficiency (CCI), University Medical Center Freiburg, Freiburg, Germany.
Helene
H
Kraus
Center for Chronic Immunodeficiency (CCI), University Medical Center Freiburg, Freiburg, Germany.
Hermann
H
Eibel
Division of Immunology, Labor Berlin and Institute of Medical Immunology, Charité, Campus Virchow Klinikum, Berlin, Germany.
Uwe
U
Kölsch
Department of Genetics, Hassan II University, Casablanca, Morocco.
Sellama
S
Nadifi
Department of Immunology, Genetics and Pathology, Uppsala University, Rudbeck Laboratory, Uppsala, Sweden.
Mats
M
Nilsson
Pediatrics Department, Bone Marrow Transplantation Center, Tunis, Tunisia.
Mohamed
M
Bejaoui
National Center for Biotechnology Information, National Institutes of Health, Department of Health and Human Services, Bethesda, Md.
Alejandro A
AA
Schäffer
Clinical Research Center, Department of Laboratory Medicine, Karolinska Institutet, Karolinska University Hospital Huddinge, Huddinge, Sweden.
C I Edvard
CI
Smith
Department of Life Sciences, Imperial College London, London, United Kingdom.
Anne
A
Dell
Laboratory of Immunopathology, Vaccinology and Molecular Genetics, Pasteur Institute of Tunis and University Tunis El Manar, Tunis, Tunisia.
Mohamed-Ridha
MR
Barbouche
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.
Bodo
B
Grimbacher
D000328:Adult; D019943:Amino Acid Substitution; D049109:Cell Proliferation; D002648:Child; D002896:Chromosomes, Human, Pair 6 / Q000235:genetics* / Q000378:metabolism; D005260:Female; D030342:Genetic Diseases, Inborn / Q000201:enzymology / Q000235:genetics* / Q000276:immunology; D008040:Genetic Linkage; D006031:Glycosylation; D006720:Homozygote; D006801:Humans; D007109:Immunity / Q000235:genetics*; D007073:Immunoglobulin E; D007223:Infant; D007589:Job Syndrome / Q000201:enzymology / Q000235:genetics* / Q000276:immunology; D008297:Male; D020125:Mutation, Missense; D010733:Phosphoglucomutase / Q000235:genetics* / Q000276:immunology / Q000378:metabolism; D013601:T-Lymphocytes / Q000201:enzymology / Q000276:immunology; D014416:Tunisia
D007073:Immunoglobulin E; C549916:PGM3 protein, human; D010733:Phosphoglucomutase
Hyper-IgE syndrome; Staphylococcus aureus; dedicator of cytokinesis 8; glycosylation; phosphoglucomutase 3; signal transducer and activator of transcription 3