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Journal of Clinical Immunology

, Volume 37, Issue 8, pp 801–810 | Cite as

Functional Evaluation of an IKBKG Variant Suspected to Cause Immunodeficiency Without Ectodermal Dysplasia

  • Glynis Frans
  • Jutte van der Werff Ten Bosch
  • Leen Moens
  • Rik Gijsbers
  • Majid Changi-Ashtiani
  • Hassan Rokni-Zadeh
  • Mohammad Shahrooei
  • Greet Wuyts
  • Isabelle Meyts
  • Xavier BossuytEmail author
Original Article

Abstract

Hypomorphic IKBKG mutations in males are typically associated with anhidrotic ectodermal dysplasia with immunodeficiency (EDA-ID). Some mutations cause immunodeficiency without EDA (NEMO-ID). The immunological profile associated with these NEMO-ID variants is not fully documented. We present a 2-year-old patient with suspected immunodeficiency in which a hemizygous p.Glu57Lys IKBKG variant was identified. At the age of 1 year, he had an episode of otitis media that evolved into a bilateral mastoiditis (Pseudomonas spp). Hypogammaglobulinemia, specific (polysaccharide) antibody deficiency, and low switched memory B cell subsets were noticed. The mother was heterozygous for the variant but had no signs of incontinentia pigmenti. Patient peripheral blood mononuclear cells produced low amounts of IL-6 after stimulation with IL-1β, Pam3CSK4, and FSL-1. In patient fibroblasts, IκB-α was degraded normally upon stimulation with IL-1β or TNF-α. Transduction of wild-type and variant NEMO in NEMO−/− deficient SV40 fibroblasts revealed a slight but significant reduction of IL-6 production upon stimulation with IL-1β and TNF-α. In conclusion, we demonstrated that p.Glu57Lys leads to specific immunological defects in vitro. No other pathogenic PID variants were identified through whole exome sequencing. As rare polymorphisms have been described in IKBKG and polygenic inheritance remains an option in the presented case, this study emphasizes the need for thorough functional and genetic evaluation when encountering and interpreting suspected disease-causing NEMO-ID variants.

Keywords

Immunodeficiency NF-κB essential modulator NEMO toll-like receptors NF-κB pathway 

Notes

Acknowledgments

We thank Jean-Laurent Casanova for providing NEMO-deficient SV40 transformed fibroblasts. We are indebted to the patient and his parents.

Authorship Contributions

GF drafted the manuscript and conducted experiments. JVDWTB characterized the immune deficiency and coordinates the clinical care of the patient. LM, RG, and GW conducted experiments. HRZ, MC-A, and MS performed whole exome sequencing and bioinformatics analysis. XB supervised the routine laboratory immunology work up and TLR testing. IM and XB designed the study and finalized the manuscript. Each author has critically revised the final version of the manuscript and has read and approved the final manuscript.

Funding Information

This work was supported by a GOA grant from the Research Council of the KU Leuven, Belgium. IM is supported by a KOF mandate of the KU Leuven, Belgium.

Compliance with Ethical Standards

Conflicts of Interest

The authors declare that they have no conflict of interest.

Ethical Approval

The study was performed in accordance with the 1964 Helsinki declaration and its later amendments. Informed consent was obtained for genetic analysis and report of the case. The study was approved by the Ethics Committee of UZ Leuven.

Supplementary material

10875_2017_448_MOESM1_ESM.docx (21 kb)
ESM 1 (DOCX 20 kb)

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Copyright information

© Springer Science+Business Media, LLC 2017

Authors and Affiliations

  • Glynis Frans
    • 1
  • Jutte van der Werff Ten Bosch
    • 2
  • Leen Moens
    • 1
  • Rik Gijsbers
    • 3
    • 4
  • Majid Changi-Ashtiani
    • 5
  • Hassan Rokni-Zadeh
    • 6
  • Mohammad Shahrooei
    • 7
    • 8
  • Greet Wuyts
    • 1
  • Isabelle Meyts
    • 9
    • 10
  • Xavier Bossuyt
    • 1
    • 11
    Email author
  1. 1.Department of Microbiology and Immunology, Experimental Laboratory ImmunologyKU LeuvenLeuvenBelgium
  2. 2.Department of Pediatric Hematology, Oncology and ImmunologyUniversity Hospital BrusselsBrusselsBelgium
  3. 3.Leuven Viral Vector CoreKU LeuvenLeuvenBelgium
  4. 4.Department of Pharmaceutical and Pharmacological Sciences, Laboratory for Viral Vector Technology & Gene TherapyKU LeuvenLeuvenBelgium
  5. 5.School of MathematicsInstitute for Research in Fundamental Sciences (IPM)TehranIran
  6. 6.Department of Medical Biotechnology and NanotechnologyZanjan University of Medical SciencesZanjanIran
  7. 7.Department of Microbiology and Immunology, Laboratory of Clinical Bacteriology and MycologyKU LeuvenLeuvenBelgium
  8. 8.Specialized Immunology Laboratory of Dr. ShahrooeiAhvazIran
  9. 9.Department of PediatricsUniversity Hospitals LeuvenLeuvenBelgium
  10. 10.Department of Microbiology and Immunology, Childhood ImmunologyKU LeuvenLeuvenBelgium
  11. 11.Department of Laboratory MedicineUniversity Hospitals LeuvenLeuvenBelgium

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