Journal of Clinical Immunology

, Volume 33, Issue 6, pp 1088–1099

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

Authors

  • Lena F. Schimke
    • Department of PediatricsUniversity of Washington and Seattle Children’s Research Institute
    • Dr. Von Haunersches KinderspitalLudwig Maximilians University
  • Nikolaus Rieber
    • Dr. Von Haunersches KinderspitalLudwig Maximilians University
    • Department of Pediatrics IUniversity of Tübingen
  • Stacey Rylaarsdam
    • Department of PediatricsUniversity of Washington and Seattle Children’s Research Institute
  • Otávio Cabral-Marques
    • Department of PediatricsUniversity of Washington and Seattle Children’s Research Institute
    • Department of ImmunologyUniversity of Sao Paulo
  • Nicholas Hubbard
    • Department of PediatricsUniversity of Washington and Seattle Children’s Research Institute
  • Anne Puel
    • Human Genetics of Infectious DiseasesINSERM U980, Necker Medical School
    • Paris Descartes University
  • Laura Kallmann
    • Dr. Von Haunersches KinderspitalLudwig Maximilians University
  • Stephanie Anover Sombke
    • Department of PediatricsUniversity of Washington and Seattle Children’s Research Institute
  • Gundula Notheis
    • Dr. Von Haunersches KinderspitalLudwig Maximilians University
  • Hans-Peter Schwarz
    • Dr. Von Haunersches KinderspitalLudwig Maximilians University
  • Birgit Kammer
    • Dr. Von Haunersches KinderspitalLudwig Maximilians University
  • Tomas Hökfelt
    • Department of NeuroscienceKarolinska Institutet
  • Reinald Repp
    • Children’s Hospital
  • Capucine Picard
    • Human Genetics of Infectious DiseasesINSERM U980, Necker Medical School
    • Paris Descartes University
    • Study Center of Primary ImmunodeficienciesAssistance Publique Hôpitaux de Paris, Necker Hospital
  • Jean-Laurent Casanova
    • Human Genetics of Infectious DiseasesINSERM U980, Necker Medical School
    • Paris Descartes University
    • St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller BranchThe Rockefeller University
  • Bernd H. Belohradsky
    • Dr. Von Haunersches KinderspitalLudwig Maximilians University
  • Michael H. Albert
    • Dr. Von Haunersches KinderspitalLudwig Maximilians University
  • Hans D. Ochs
    • Department of PediatricsUniversity of Washington and Seattle Children’s Research Institute
    • Kinderklinik und Kinderpoliklinik im Dr. von Haunerschen KinderspitalLudwig Maximilians Universität
    • Department of PediatricsUniversity of Washington and Seattle Children’s Research Institute
Original Research

DOI: 10.1007/s10875-013-9906-1

Cite this article as:
Schimke, L.F., Rieber, N., Rylaarsdam, S. et al. J Clin Immunol (2013) 33: 1088. doi:10.1007/s10875-013-9906-1

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.

Keywords

Ectodermal dysplasia with immunodeficiencyIKBANF-κB signalingpolyendocrinopathy

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

Supplementary material

10875_2013_9906_MOESM1_ESM.docx (141 kb)
ESM 1(DOCX 141 kb)

Copyright information

© Springer Science+Business Media New York 2013