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

  • Lena F. Schimke
  • Nikolaus Rieber
  • Stacey Rylaarsdam
  • Otávio Cabral-Marques
  • Nicholas Hubbard
  • Anne Puel
  • Laura Kallmann
  • Stephanie Anover Sombke
  • Gundula Notheis
  • Hans-Peter Schwarz
  • Birgit Kammer
  • Tomas Hökfelt
  • Reinald Repp
  • Capucine Picard
  • Jean-Laurent Casanova
  • Bernd H. Belohradsky
  • Michael H. Albert
  • Hans D. Ochs
  • Ellen D. Renner
  • Troy R. Torgerson
Original Research



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.


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.


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.


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


Ectodermal dysplasia with immunodeficiency IKBA NF-κB signaling polyendocrinopathy 



Autosomal dominant ectodermal dysplasia with immunodeficiency


Chronic mucocutaneous candidiasis


Ectodermal dysplasia with immunodeficiency


Growth hormone releasing hormone


Graft versus host disease


Hematopoietic stem cell transplantation


NF-κB inhibitor IκB-α


Immunodysregulation, polyendocrinopathy, enteropathy, X-linked


Nuclear Factor κB Essential Modulator


Nuclear Factor κB


Primary Immunodeficiency


Toll like receptor


T regulatory cells


Subcutaneous immunoglobulin


X linked form of ectodermal dysplasia with immunodeficiency

Supplementary material

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


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Copyright information

© Springer Science+Business Media New York 2013

Authors and Affiliations

  • Lena F. Schimke
    • 1
    • 2
  • Nikolaus Rieber
    • 2
    • 3
  • Stacey Rylaarsdam
    • 1
  • Otávio Cabral-Marques
    • 1
    • 4
  • Nicholas Hubbard
    • 1
  • Anne Puel
    • 5
    • 6
  • Laura Kallmann
    • 2
  • Stephanie Anover Sombke
    • 1
  • Gundula Notheis
    • 2
  • Hans-Peter Schwarz
    • 2
  • Birgit Kammer
    • 2
  • Tomas Hökfelt
    • 7
  • Reinald Repp
    • 8
  • Capucine Picard
    • 5
    • 6
    • 9
  • Jean-Laurent Casanova
    • 5
    • 6
    • 10
  • Bernd H. Belohradsky
    • 2
  • Michael H. Albert
    • 2
  • Hans D. Ochs
    • 1
  • Ellen D. Renner
    • 11
  • Troy R. Torgerson
    • 1
  1. 1.Department of PediatricsUniversity of Washington and Seattle Children’s Research InstituteSeattleUSA
  2. 2.Dr. Von Haunersches KinderspitalLudwig Maximilians UniversityMunichGermany
  3. 3.Department of Pediatrics IUniversity of TübingenTübingenGermany
  4. 4.Department of ImmunologyUniversity of Sao PauloSao PauloBrazil
  5. 5.Human Genetics of Infectious DiseasesINSERM U980, Necker Medical SchoolParisFrance
  6. 6.Paris Descartes UniversityParis Sorbonne CitéFrance
  7. 7.Department of NeuroscienceKarolinska InstitutetStockholmSweden
  8. 8.Children’s HospitalFuldaGermany
  9. 9.Study Center of Primary ImmunodeficienciesAssistance Publique Hôpitaux de Paris, Necker HospitalParisFrance
  10. 10.St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller BranchThe Rockefeller UniversityNew YorkUSA
  11. 11.Kinderklinik und Kinderpoliklinik im Dr. von Haunerschen KinderspitalLudwig Maximilians UniversitätMünchenGermany

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