1. Hypomorphic homozygous mutations in phosphoglucomutase 3 (PGM3) impair immunity and increase serum IgE levels
- Author
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Sassi, Atfa, Lazaroski, Sandra, Wu, Gang, Haslam, Stuart M, Fliegauf, Manfred, Mellouli, Fethi, Patiroglu, Turkan, Unal, Ekrem, Ozdemir, Mehmet Akif, Jouhadi, Zineb, Khadir, Khadija, Ben-Khemis, Leila, Ben-Ali, Meriem, Ben-Mustapha, Imen, Borchani, Lamia, Pfeifer, Dietmar, Jakob, Thilo, Khemiri, Monia, Asplund, A Charlotta, Gustafsson, Manuela O, Lundin, Karin E, Falk-Sörqvist, Elin, Moens, Lotte N, Gungor, Hatice Eke, Engelhardt, Karin R, Dziadzio, Magdalena, Stauss, Hans, Fleckenstein, Bernhard, Meier, Rebecca, Prayitno, Khairunnadiya, Maul-Pavicic, Andrea, Schaffer, Sandra, Rakhmanov, Mirzokhid, Henneke, Philipp, Kraus, Helene, Eibel, Hermann, Kölsch, Uwe, Nadifi, Sellama, Nilsson, Mats, Bejaoui, Mohamed, Schäffer, Alejandro A, Smith, CI Edvard, Dell, Anne, Barbouche, Mohamed-Ridha, and Grimbacher, Bodo
- Subjects
Biomedical and Clinical Sciences ,Immunology ,Clinical Research ,Genetics ,Rare Diseases ,Emerging Infectious Diseases ,Aetiology ,2.1 Biological and endogenous factors ,Adult ,Amino Acid Substitution ,Cell Proliferation ,Child ,Chromosomes ,Human ,Pair 6 ,Female ,Genetic Diseases ,Inborn ,Genetic Linkage ,Glycosylation ,Homozygote ,Humans ,Immunity ,Immunoglobulin E ,Infant ,Job Syndrome ,Male ,Mutation ,Missense ,Phosphoglucomutase ,T-Lymphocytes ,Tunisia ,Hyper-IgE syndrome ,glycosylation ,Staphylococcus aureus ,signal transducer and activator of transcription 3 ,dedicator of cytokinesis 8 ,phosphoglucomutase 3 ,Allergy - Abstract
BackgroundRecurrent 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.ObjectiveWe sought to elucidate the genetic cause in patients with HIES who do not carry mutations in STAT3 or DOCK8.MethodsAfter 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.ResultsMutational 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.ConclusionImpairment 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