Mechanisms of genotype-phenotype correlation in autosomal dominant anhidrotic ectodermal dysplasia with immune deficiency

J Allergy Clin Immunol. 2018 Mar;141(3):1060-1073.e3. doi: 10.1016/j.jaci.2017.05.030. Epub 2017 Jun 17.


Background: Autosomal dominant anhidrotic ectodermal dysplasia with immune deficiency (AD EDA-ID) is caused by heterozygous point mutations at or close to serine 32 and serine 36 or N-terminal truncations in IκBα that impair its phosphorylation and degradation and thus activation of the canonical nuclear factor κ light chain enhancer of activated B cells (NF-κB) pathway. The outcome of hematopoietic stem cell transplantation is poor in patients with AD EDA-ID despite achievement of chimerism. Mice heterozygous for the serine 32I mutation in IκBα have impaired noncanonical NF-κB activity and defective lymphorganogenesis.

Objective: We sought to establish genotype-phenotype correlation in patients with AD EDA-ID.

Methods: A disease severity scoring system was devised. Stability of IκBα mutants was examined in transfected cells. Immunologic, biochemical, and gene expression analyses were performed to evaluate canonical and noncanonical NF-κB signaling in skin-derived fibroblasts.

Results: Disease severity was greater in patients with IκBα point mutations than in those with truncation mutations. IκBα point mutants were expressed at significantly higher levels in transfectants compared with truncation mutants. Canonical NF-κB-dependent IL-6 secretion and upregulation of the NF-κB subunit 2/p100 and RELB proto-oncogene, NF-κB subunit (RelB) components of the noncanonical NF-κB pathway were diminished significantly more in patients with point mutations compared with those with truncations. Noncanonical NF-κB-driven generation of the transcriptionally active p100 cleavage product p52 and upregulation of CCL20, intercellular adhesion molecule 1 (ICAM1), and vascular cell adhesion molecule 1 (VCAM1), which are important for lymphorganogenesis, were diminished significantly more in LPS plus α-lymphotoxin β receptor-stimulated fibroblasts from patients with point mutations compared with those with truncations.

Conclusions: IκBα point mutants accumulate at higher levels compared with truncation mutants and are associated with more severe disease and greater impairment of canonical and noncanonical NF-κB activity in patients with AD EDA-ID.

Keywords: Ectodermal dysplasia with immune deficiency; NF-κB inhibitor α; canonical nuclear factor κB pathway; hematopoietic stem cell transplantation; lymphorganogenesis; noncanonical nuclear factor κB pathway.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Carrier Proteins / genetics
  • Carrier Proteins / immunology
  • Chemokine CCL20 / genetics
  • Chemokine CCL20 / immunology
  • Ectodermal Dysplasia / genetics*
  • Ectodermal Dysplasia / immunology*
  • Ectodermal Dysplasia / pathology
  • Genetic Diseases, X-Linked / genetics*
  • Genetic Diseases, X-Linked / immunology*
  • Genetic Diseases, X-Linked / pathology
  • Genotype*
  • HEK293 Cells
  • Humans
  • Immunologic Deficiency Syndromes / genetics*
  • Immunologic Deficiency Syndromes / immunology*
  • Immunologic Deficiency Syndromes / pathology
  • Intercellular Adhesion Molecule-1 / genetics
  • Intercellular Adhesion Molecule-1 / immunology
  • Interleukin-6 / genetics
  • Interleukin-6 / immunology
  • NF-KappaB Inhibitor alpha / genetics
  • NF-KappaB Inhibitor alpha / immunology
  • NF-kappa B p52 Subunit / genetics
  • NF-kappa B p52 Subunit / immunology
  • Point Mutation
  • Primary Immunodeficiency Diseases
  • Proto-Oncogene Mas
  • Signal Transduction* / genetics
  • Signal Transduction* / immunology


  • 11-cis-retinal-binding protein
  • CCL20 protein, human
  • Carrier Proteins
  • Chemokine CCL20
  • ICAM1 protein, human
  • IL6 protein, human
  • Interleukin-6
  • MAS1 protein, human
  • NF-kappa B p52 Subunit
  • NFKBIA protein, human
  • Proto-Oncogene Mas
  • Intercellular Adhesion Molecule-1
  • NF-KappaB Inhibitor alpha

Supplementary concepts

  • Ectodermal dysplasia, hypohidrotic, with immune deficiency