Hypomorphic homozygous mutations in phosphoglucomutase 3 (PGM3) impair immunity and increase serum IgE levels.
Sassi, Atfa PhD; Lazaroski, Sandra PhD; Wu, Gang MSc; Haslam, Stuart M. PhD; Fliegauf, Manfred PhD; Mellouli, Fethi MD; Patiroglu, Turkan MD; Unal, Ekrem MD; Ozdemir, Mehmet Akif MD; Jouhadi, Zineb MD; Khadir, Khadija MD; Ben-Khemis, Leila MSc; Ben-Ali, Meriem PhD; Ben-Mustapha, Imen MD; Borchani, Lamia PhD; Pfeifer, Dietmar PhD; Jakob, Thilo MD; Khemiri, Monia MD; Asplund, Charlotta A. BSc; Gustafsson, Manuela O. MSc; Lundin, Karin E. PhD; Falk-Sorqvist, Elin MSc; Moens, Lotte N. PhD; Gungor, Hatice Eke MD; Engelhardt, Karin R. PhD; Dziadzio, Magdalena MD, PhD; Stauss, Hans MD, PhD; Fleckenstein, Bernhard MD; Meier, Rebecca BSc; Prayitno, Khairunnadiya MSc; Maul-Pavicic, Andrea PhD; Schaffer, Sandra; Rakhmanov, Mirzokhid PhD; Henneke, Philipp MD; Kraus, Helene MSc; Eibel, Hermann PhD; Kolsch, Uwe MD; Nadifi, Sellama PhD; Nilsson, Mats PhD; Bejaoui, Mohamed MD; Schaffer, Alejandro A. PhD; Smith, Edvard C.I. MD, PhD; Dell, Anne PhD; Barbouche, Mohamed-Ridha MD, PhD; Grimbacher, Bodo MD
[Miscellaneous Article]
Journal of Allergy & Clinical Immunology.
133(5):1410-1419e13, May 2014.
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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.
(C) 2014Elsevier, Inc.
