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A Novel Gain-of-Function IKBA Mutation Underlies Ectodermal Dysplasia with Immunodeficiency and Polyendocrinopathy

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Abstract

Purpose

This study reports the identification of a novel heterozygous IKBA missense mutation (p.M37K) in a boy presenting with ectodermal dysplasia with immunodeficiency (EDA-ID) who had wild type IKBKG gene encoding NEMO. Our aim was to characterize the clinical course of this IκB-α gain-of-function mutant and to investigate if the p.M37K substitution affects NF-κB activation by interfering with IκB-α degradation, thus impairing NF-κB signaling and causing the EDA-ID phenotype.

Methods

NF-κB signaling was evaluated by measuring IκB-α degradation in patient fibroblasts. In addition, transiently transfected HeLa cells expressing either the M37K-mutant IκB-α allele, the previously characterized S36A-mutant IκB-α allele, or wild type IκB-α were evaluated for IκB-α degradation and NF-κB nuclear translocation following stimulation with TNF-α.

Results

Clinical findings revealed a classical ectodermal dysplasia phenotype complicated by recurrent mucocutaneous candidiasis, hypothyroidism, hypopituitarism, and profound combined immunodeficiency with decreased numbers of IL-17 T cells. IκB-α degradation after TNF-α and TLR agonist stimulation was abolished in patient fibroblasts as well as in HeLa cells expressing M37K-IκB-α similar to cells expressing S36A-IκB-α resulting in impaired nuclear translocation of NF-κB and reduced NF-κB dependent luciferase activity compared to cells expressing wild type IκB-α. Patient whole blood cells failed to secrete IL-6 in response to IL-1ß, Pam2CSK4, showed reduced responses to LPS and PMA/Ionomycin, and lacked IL-10 production in response to TNF-α.

Conclusion

The novel heterozygous mutation p.M37K in IκB-α impairs NF-κB activation causing autosomal dominant EDA-ID with an expanded clinical phenotype.

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Abbreviations

AD-EDA-ID:

Autosomal dominant ectodermal dysplasia with immunodeficiency

CMC:

Chronic mucocutaneous candidiasis

EDA-ID:

Ectodermal dysplasia with immunodeficiency

GHRH:

Growth hormone releasing hormone

GVHD:

Graft versus host disease

HSCT:

Hematopoietic stem cell transplantation

IKBA:

NF-κB inhibitor IκB-α

IPEX:

Immunodysregulation, polyendocrinopathy, enteropathy, X-linked

NEMO:

Nuclear Factor κB Essential Modulator

NF-κB:

Nuclear Factor κB

PID:

Primary Immunodeficiency

TLR:

Toll like receptor

Tregs:

T regulatory cells

SCIG:

Subcutaneous immunoglobulin

XL-EDA-ID:

X linked form of ectodermal dysplasia with immunodeficiency

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Acknowledgment

We thank the family for participating. For technical assistance and performing flow cytometry we thank Irmgard Eckerlein, Ottilie Bieberle, and Mayumi Hoffmann. This work was supported by the ESID long-term fellowship 2010 (to LFS), the Jeffrey Modell Foundation (to HDO), DFG RE2799/3-1 and the Fritz-Thyssen research foundation grant (Az. 10.07.1.159) (to EDR).

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Authors and Affiliations

  1. Department of Pediatrics, University of Washington and Seattle Children’s Research Institute, 1900 9th Avenue, Seattle, WA, 98101-1304, USA

    Lena F. Schimke, Stacey Rylaarsdam, Otávio Cabral-Marques, Nicholas Hubbard, Stephanie Anover Sombke, Hans D. Ochs & Troy R. Torgerson

  2. Dr. Von Haunersches Kinderspital, Ludwig Maximilians University, Munich, Germany

    Lena F. Schimke, Nikolaus Rieber, Laura Kallmann, Gundula Notheis, Hans-Peter Schwarz, Birgit Kammer, Bernd H. Belohradsky & Michael H. Albert

  3. Department of Pediatrics I, University of Tübingen, Tübingen, Germany

    Nikolaus Rieber

  4. Department of Immunology, University of Sao Paulo, Sao Paulo, Brazil

    Otávio Cabral-Marques

  5. Human Genetics of Infectious Diseases, INSERM U980, Necker Medical School, Paris, France

    Anne Puel, Capucine Picard & Jean-Laurent Casanova

  6. Paris Descartes University, Paris Sorbonne Cité, France

    Anne Puel, Capucine Picard & Jean-Laurent Casanova

  7. Department of Neuroscience, Karolinska Institutet, Stockholm, Sweden

    Tomas Hökfelt

  8. Children’s Hospital, Fulda, Germany

    Reinald Repp

  9. Study Center of Primary Immunodeficiencies, Assistance Publique Hôpitaux de Paris, Necker Hospital, Paris, France

    Capucine Picard

  10. St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, USA

    Jean-Laurent Casanova

  11. Kinderklinik und Kinderpoliklinik im Dr. von Haunerschen Kinderspital, Ludwig Maximilians Universität, Lindwurmstr. 4, D-80337, München, Germany

    Ellen D. Renner

Authors
  1. Lena F. Schimke
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Corresponding authors

Correspondence to Ellen D. Renner or Troy R. Torgerson.

Additional information

Lena F. Schimke and Nikolaus Rieber contributed equally to this study.

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Schimke, L.F., Rieber, N., Rylaarsdam, S. et al. A Novel Gain-of-Function IKBA Mutation Underlies Ectodermal Dysplasia with Immunodeficiency and Polyendocrinopathy. J Clin Immunol 33, 1088–1099 (2013). https://doi.org/10.1007/s10875-013-9906-1

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