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Journal of Clinical Immunology

, Volume 37, Issue 5, pp 397–412 | Cite as

Human IκBα Gain of Function: a Severe and Syndromic Immunodeficiency

  • Bertrand BoissonEmail author
  • Anne Puel
  • Capucine Picard
  • Jean-Laurent Casanova
CME Review

Abstract

Germline heterozygous gain-of-function (GOF) mutations of NFKBIA, encoding IκBα, cause an autosomal dominant (AD) form of anhidrotic ectodermal dysplasia with immunodeficiency (EDA-ID). Fourteen unrelated patients have been reported since the identification of the first case in 2003. All mutations enhanced the inhibitory activity of IκBα, by preventing its phosphorylation on serine 32 or 36 and its subsequent degradation. The mutation certainly or probably occurred de novo in 13 patients, whereas it was inherited from a parent with somatic mosaicism in one patient. Eleven mutations, belonging to two groups, were identified: (i) missense mutations affecting S32, S36, or neighboring residues (8 mutations, 11 patients) and (ii) nonsense mutations upstream from S32 associated with the reinitiation of translation downstream from S36 (3 mutations, 3 patients). Thirteen patients had developmental features of EDA, the severity and nature of which differed between cases. All patient cells tested displayed impaired NF-κB-mediated responses to the stimulation of various surface receptors involved in cell-intrinsic (fibroblasts), innate (monocytes), and adaptive (B and T cells) immunity, including TLRs, IL-1Rs, TNFRs, TCR, and BCR. All patients had profound B-cell deficiency. Specific immunological features, found in some, but not all patients, included a lack of peripheral lymph nodes, lymphocytosis, dysfunctional α/β T cells, and a lack of circulating γ/δ T cells. The patients had various pyogenic, mycobacterial, fungal, and viral severe infections. Patients with a missense mutation tended to display more severe phenotypes, probably due to higher levels of GOF proteins. In the absence of hematopoietic stem cell transplantation (HSCT), this condition cause death before the age of 1 year (one child). Two survivors have been on prophylaxis (at 9 and 22 years). Six children died after HSCT. Five survived, four of whom have been on prophylaxis (3 to 21 years post HSCT), whereas one has been well with no prophylaxis. Heterozygous GOF mutations in IκBα underlie a severe and syndromic immunodeficiency, the interindividual variability of which might partly be ascribed to the dichotomy of missense and nonsense mutations, and the hematopoietic component of which can be rescued by HSCT.

Keywords

NFKBIA gain of function combined immunodeficiency pediatrics hematopoietic stem cell transplantation 

Notes

Acknowledgments

We would first like to thank Dr. Cancrini (P1), Dr. Lankester (P2), Drs. Geha and McDouglas (P3), Drs. Onhishi and Okada (P5), and Drs. Moriya and Morio (P11, P12) for taking the time to answer our questions and sharing information about the reported patients with us. We also thank Dr. Alain Israel for careful review of the manuscript. We thank Stéphanie Boisson-Dupuis, Jacinta Bustamante, Michael Ciancanelli, Emmanuelle Jouanguy, and Shen-Ying Zhang of the Human Genetics of Infectious Diseases Laboratory for helpful discussions. We also thank Maya Chrabieh, Yelena Nemiroskaya, Lahouari Amar, Dominick Papandrea, Mark Woollett, Cécile Patissier, and Céline Desvallees for their assistance. This work was supported by the St. Giles Foundation, the Rockefeller University, INSERM, Paris Descartes University, Howard Hughes Medical Institute, National Institutes of Health (NIH 5P01AI061093), and the French National Research Agency (ANR 14-CE15-0009-01).

Compliance with Ethical Standards

Conflict of Interest

The authors declare that they have no conflict of interest.

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© Springer Science+Business Media New York 2017

Authors and Affiliations

  1. 1.St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller BranchRockefeller UniversityNew YorkUSA
  2. 2.Laboratory of Human Genetics of Infectious Diseases, Necker BranchINSERM UMR1163, Necker Hospital for Sick ChildrenParisFrance
  3. 3.Imagine InstituteParis Descartes UniversityParisFrance
  4. 4.Pediatric Hematology-Immunology and Rheumatology UnitAP-HP, Necker Hospital for Sick ChildrenParisFrance
  5. 5.Study Center for ImmunodeficienciesAP-HP, Necker Hospital for Sick ChildrenParisFrance
  6. 6.Howard Hughes Medical InstituteNew YorkUSA

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