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

JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY

卷:133

Article

Sassi, Atfa^1,2  Lazaroski, Sandra³  Wu, Gang⁶  Haslam, Stuart M.⁶  Fliegauf, Manfred³  Mellouli, Fethi⁷  Patiroglu, Turkan^8,9  Unal, Ekrem⁸  Ozdemir, Mehmet Akif⁸  Jouhadi, Zineb¹⁰  Khadir, Khadija¹⁰  Ben-Khemis, Leila^1,2  Ben-Ali, Meriem^1,2  Ben-Mustapha, Imen^1,2  Borchani, Lamia H.¹²  Pfeifer, Dietmar⁴  Jakob, Thilo⁵  Khemiri, Monia¹³  Asplund, A. Charlotta¹⁴  Gustafsson, Manuela O.¹⁴  Lundin, Karin E.¹⁴  Falk-Soerqvist, Elin¹⁵  Moens, Lotte N.¹⁵  Gungor, Hatice Eke⁹  Engelhardt, Karin R.¹⁶  Dziadzio, Magdalena¹⁶  Stauss, Hans¹⁶  Fleckenstein, Bernhard¹⁷  Meier, Rebecca³  Prayitno, Khairunnadiya³  Maul-Pavicic, Andrea³  Schaffer, Sandra³  Rakhmanov, Mirzokhid³  Henneke, Philipp³  Kraus, Helene³  Eibel, Hermann³  Koelsch, Uwe^18,19  Nadifi, Sellama¹¹  Nilsson, Mats¹⁵  Bejaoui, Mohamed⁷  Schaeffer, Alejandro A.²⁰  Smith, C. I. Edvard⁴  Dell, Anne⁶  Barbouche, Mohamed-Ridha^1,2  Grimbacher, Bodo^3,16 

[1] Pasteur Inst Tunis, Lab Immunopathol Vaccinol & Mol Genet, Tunis, Tunisia

[2] Univ Tunis El Manar, Tunis, Tunisia

[3] Univ Med Ctr Freiburg, Ctr Chron Immunodeficiency, D-79108 Freiburg, Germany

[4] Univ Med Ctr Freiburg, Dept Med Specialt Hematol Oncol & Stem Cell Trans, D-79108 Freiburg, Germany

[5] Univ Med Ctr Freiburg, Dept Dermatol, Allergy Res Grp, D-79108 Freiburg, Germany

[6] Univ London Imperial Coll Sci Technol & Med, Dept Life Sci, London SW7 2AZ, England

[7] Bone Marrow Transplantat Ctr, Dept Pediat, Tunis, Tunisia

[8] Erciyes Univ, Fac Med, Dept Pediat, Div Pediat Hematol & Oncol, Kayseri, Turkey

[9] Erciyes Univ, Fac Med, Dept Pediat, Div Pediat Immunol, Kayseri, Turkey

[10] Hassan II Univ, CHU IBN ROCHD, Dept Pediat Infect Dis, Casablanca, Morocco

[11] Hassan II Univ, Dept Genet, Casablanca, Morocco

[12] Inst Pasteur Tunis, Lab Venoms & Therapeut Mol, Tunis, Tunisia

[13] Childrens Hosp Tunis, Pediat Dept A, Tunis, Tunisia

[14] Karolinska Univ Hosp Huddinge, Karolinska Inst, Clin Res Ctr, Dept Lab Med, Huddinge, Sweden

[15] Uppsala Univ, Rudbeck Lab, Dept Immunol Genet & Pathol, Uppsala, Sweden

[16] UCL, Royal Free Hosp, Inst Immun & Transplantat, London WC1E 6BT, England

[17] Univ Erlangen Nurnberg, Inst Virol, D-91054 Erlangen, Germany

[18] Campus Virchow Klinikum, Div Immunol, Lab Berlin, Berlin, Germany

[19] Campus Virchow Klinikum, Charite, Inst Med Immunol, Berlin, Germany

[20] NIH, Natl Ctr Biotechnol Informat, US Dept HHS, Bethesda, MD 20892 USA

关键词: Hyper-IgE syndrome;    glycosylation;    Staphylococcus aureus;    signal transducer and activator of transcription 3;    dedicator of cytokinesis 8;    phosphoglucomutase 3;   

DOI  :  10.1016/j.jaci.2014.02.025

来源: Elsevier

【 摘 要 】

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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