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Hypomorphic homozyg...
Hypomorphic homozygous mutations in phosphoglucomutase 3 (PGM3) impair immunity and increase serum IgE levels
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Sassi, Atfa (author)
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Lazaroski, Sandra (author)
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Wu, Gang (author)
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show more...
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Haslam, Stuart M. (author)
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Fliegauf, Manfred (author)
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Mellouli, Fethi (author)
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Patiroglu, Turkan (author)
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Unal, Ekrem (author)
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Ozdemir, Mehmet Akif (author)
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Jouhadi, Zineb (author)
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- Khadir, Khadija (author)
- Karolinska Institutet
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Ben-Khemis, Leila (author)
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Ben-Ali, Meriem (author)
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Ben-Mustapha, Imen (author)
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Borchani, Lamia H. (author)
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Pfeifer, Dietmar (author)
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Jakob, Thilo (author)
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Khemiri, Monia (author)
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Asplund, A. Charlotta (author)
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- Gustafsson, Manuela O. (author)
- Karolinska Institutet
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Lundin, Karin E. (author)
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- Falk-Sörqvist, Elin (author)
- Uppsala universitet,Molekylära verktyg
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- Moens, Lotte N. (author)
- Uppsala universitet,Molekylära verktyg
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Gungor, Hatice Eke (author)
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Engelhardt, Karin R. (author)
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Dziadzio, Magdalena (author)
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Stauss, Hans (author)
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Fleckenstein, Bernhard (author)
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Meier, Rebecca (author)
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Prayitno, Khairunnadiya (author)
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Maul-Pavicic, Andrea (author)
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Schaffer, Sandra (author)
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Rakhmanov, Mirzokhid (author)
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Henneke, Philipp (author)
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Kraus, Helene (author)
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Eibel, Hermann (author)
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Koelsch, Uwe (author)
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Nadifi, Sellama (author)
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- Nilsson, Mats (author)
- Uppsala universitet,Molekylära verktyg
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Bejaoui, Mohamed (author)
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Schaeffer, Alejandro A. (author)
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- Smith, C. I. Edvard (author)
- Karolinska Institutet
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Dell, Anne (author)
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Barbouche, Mohamed-Ridha (author)
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Grimbacher, Bodo (author)
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(creator_code:org_t)
- Elsevier BV, 2014
- 2014
- English.
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In: Journal of Allergy and Clinical Immunology. - : Elsevier BV. - 0091-6749 .- 1097-6825. ; 133:5, s. 1410-U681
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https://europepmc.or...
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https://urn.kb.se/re...
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https://doi.org/10.1...
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Abstract
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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.
Subject headings
- MEDICIN OCH HÄLSOVETENSKAP -- Medicinska och farmaceutiska grundvetenskaper -- Immunologi inom det medicinska området (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Basic Medicine -- Immunology in the medical area (hsv//eng)
Keyword
- Hyper-IgE syndrome
- glycosylation
- Staphylococcus aureus
- signal transducer and activator of transcription 3
- dedicator of cytokinesis 8
- phosphoglucomutase 3
Publication and Content Type
- ref (subject category)
- art (subject category)
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- By the author/editor
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Sassi, Atfa
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Lazaroski, Sandr ...
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Wu, Gang
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Haslam, Stuart M ...
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Fliegauf, Manfre ...
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Mellouli, Fethi
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show more...
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Patiroglu, Turka ...
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Unal, Ekrem
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Ozdemir, Mehmet ...
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Jouhadi, Zineb
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Khadir, Khadija
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Ben-Khemis, Leil ...
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Ben-Ali, Meriem
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Ben-Mustapha, Im ...
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Borchani, Lamia ...
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Pfeifer, Dietmar
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Jakob, Thilo
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Khemiri, Monia
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Asplund, A. Char ...
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Gustafsson, Manu ...
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Lundin, Karin E.
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Falk-Sörqvist, E ...
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Moens, Lotte N.
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Gungor, Hatice E ...
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Engelhardt, Kari ...
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Dziadzio, Magdal ...
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Stauss, Hans
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Fleckenstein, Be ...
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Meier, Rebecca
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Prayitno, Khairu ...
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Maul-Pavicic, An ...
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Schaffer, Sandra
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Rakhmanov, Mirzo ...
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Henneke, Philipp
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Kraus, Helene
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Eibel, Hermann
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Koelsch, Uwe
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Nadifi, Sellama
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Nilsson, Mats
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Bejaoui, Mohamed
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Schaeffer, Aleja ...
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Smith, C. I. Edv ...
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Dell, Anne
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Barbouche, Moham ...
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Grimbacher, Bodo
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show less...
- About the subject
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- MEDICAL AND HEALTH SCIENCES
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MEDICAL AND HEAL ...
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and Basic Medicine
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and Immunology in th ...
- Articles in the publication
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Journal of Aller ...
- By the university
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Uppsala University
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Karolinska Institutet