A Novel Gain-of-Function IKBA Mutation Underlies Ectodermal Dysplasia with Immunodeficiency and Polyendocrinopathy
- First Online:
- 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
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.
KeywordsEctodermal dysplasia with immunodeficiencyIKBANF-κB signalingpolyendocrinopathy
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
Toll like receptor
T regulatory cells
X linked form of ectodermal dysplasia with immunodeficiency