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

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• 作者：Atfa Sassi ; PhD^a ; ^&lowast ; ; Sandra Lazaroski ; PhD^b ; ^&lowast ; ; Gang Wu ; MSc^c ; ^&lowast ; ; Stuart M. Haslam ; PhD^c ; Manfred Fliegauf ; PhD^b ; Fethi Mellouli ; MD^d ; Turkan Patiroglu ; MD^e ; ^f ; Ekrem Unal ; MD^e ; Mehmet Akif Ozdemir ; MD^e ; Zineb Jouhadi ; MD^g ; Khadija Khadir ; MD^g ; Leila Ben-Khemis ; MSc^a ; Meriem Ben-Ali ; PhD^a ; Imen Ben-Mustapha ; MD^a ; Lamia Borchani ; PhD^h ; Dietmar Pfeifer ; PhDⁱ ; Thilo Jakob ; MD^j ; Monia Khemiri ; MD^k ; A. Charlotta Asplund ; BSc^l ; Manuela O. Gustafsson ; MSc^l ; Karin E. Lundin ; PhD^l ; Elin Falk-Sö ; rqvist ; MSc^m ; Lotte N. Moens ; PhD^m ; Hatice Eke Gungor ; MD^f ; Karin R. Engelhardt ; PhDⁿ ; Magdalena Dziadzio ; MD ; PhDⁿ ; Hans Stauss ; MD ; PhDⁿ ; Bernhard Fleckenstein ; MD^o ; Rebecca Meier ; BSc^b ; Khairunnadiya Prayitno ; MSc^b ; Andrea Maul-Pavicic ; PhD^b ; Sandra Schaffer^b ; Mirzokhid Rakhmanov ; PhD^b ; Philipp Henneke ; MD^b ; Helene Kraus ; MSc^b ; Hermann Eibel ; PhD^b ; Uwe Kö ; lsch ; MD^p ; Sellama Nadifi ; PhD^q ; Mats Nilsson ; PhD^m ; Mohamed Bejaoui ; MD^d ; Alejandro A. Schä ; ffer ; PhD^r ; ^&lowast ; ; C.I. Edvard Smith ; MD ; PhD^l ; ^&lowast ; ; Anne Dell ; PhD^c ; ^&lowast ; ; Mohamed-Ridha Barbouche ; MD ; PhD^a ; ^&lowast ; ; Bodo Grimbacher ; MD^b ; ⁿ ; ^&lowast ; ; ^{bodo.grimbacher@uniklinik-freiburg.de" class="auth_mail}
• 关键词：Hyper-IgE syndrome ; glycosylation ; Staphylococcus aureus ; signal transducer and activator of transcription 3 ; dedicator of cytokinesis 8 ; phosphoglucomutase 3
• 刊名：Journal of Allergy and Clinical Immunology
• 出版年：May 2014
• 年：2014
• 卷：133
• 期：5
• 页码：1410-1419.e13
• 全文大小：4111 K

文摘

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.