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, 6 Ekrem Unal 5 Mehmet Akif Ozdemir 5 Zineb Jouhadi 7 Khadija Khadir 7 Leila Ben-Khemis 1 Meriem Ben-Ali 1 Imen Ben-Mustapha 1 Lamia Borchani 8 Dietmar Pfeifer 9 Thilo Jakob 9 Monia Khemiri 10 a Charlotta Asplund 11 Manuela O Gustafsson 11 Karin E Lundin 11 Elin Falk-Sörqvist 12 Lotte N Moens 13 Hatice Eke Gungor 14 Karin R Engelhardt 12 Magdalena Dziadzio 12 Hans Stauss 12 Bernhard Fleckenstein 15 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 16 Sellama Nadifi 17 Mats Nilsson 13 Mohamed Bejaoui 18 Alejandro A Schäffer 19 C I Edvard Smith 11 Anne Dell 11 Mohamed-Ridha Barbouche 1 Bodo Grimbacher 2, 12
* Corresponding author
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.
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Submitted on : Thursday, September 4, 2014 - 12:34:33 PM
Last modification on : Thursday, August 8, 2019 - 2:10:40 PM

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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, Elsevier, 2014, 133 (5), pp.1410-9, 1419.e1-13. ⟨10.1016/j.jaci.2014.02.025⟩. ⟨pasteur-01060838⟩

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