EDA-ID and IP, Two Faces of the Same Coin: How the SameIKBKG/NEMOMutation Affecting the NF-κB Pathway Can Cause Immunodeficiency and/or Inflammation

Abstract

Anhidrotic Ectodermal Dysplasia with ImmunoDeficiency (EDA-ID, OMIM 300291) and Incontinentia Pigmenti (IP, OMIM 308300) are two rare diseases, caused by mutations of the IKBKG/NEMO gene. The protein NEMO/IKKγ is essential for the NF-κB activation pathway, involved in a variety of physiological and cellular processes, such as immunity, inflammation, cell proliferation, and survival. A wide spectrum of IKBKG/NEMO mutations have been identified so far, and, on the basis of their effect on NF-κB activation, they are considered hypomorphic or amorphic (loss of function) mutations. IKBKG/NEMO hypomorphic mutations, reducing but not abolishing NF-κB activation, have been identified in EDA-ID and IP patients. Instead, the amorphic mutations, abolishing NF-κB activation by complete IKBKG/NEMO gene silencing, cause only IP. Here, we present an overview of IKBKG/NEMO mutations in EDA-ID and IP patients and describe similarities and differences between the clinical/immunophenotypic and genetic aspects, highlighting any T and B lymphocyte defect, and paying particular attention to the cellular and molecular defects that underlie the pathogenesis of both diseases.

Simulation of the dynamics of primary immunodeficiencies in CD4+ T-cells

“…Some PIDs have been linked to both IKKB and NEMO [74–77]. A complete loss of function homozygous truncating variant, a duplicating variant, and a nonsynonymous nucleotide substitution on the gene that codes for IKKB have been reported to cause the disease [77–79].…”

“…IKBKB loss of function variants abrogates signaling and response via the NF-κB pathway in these patients [24]. Genetic studies have revealed several PID cases linked to IKBKG , the gene that codes for NEMO [74, 75, 80–82]. The disease results from amino acid substitution and exon skipping variations.…”

Integrity of IKK/NF‐κB Shields Thymic Stroma That Suppresses Susceptibility to Autoimmunity, Fungal Infection, and Carcinogenesis

“…The enforced interaction among inflammation, damaged epithelial cells, and fungi in the epithelial tissues may promote GI tumorigenesis in CMC patients. [96][97][98][99][100][101][102][103][104] Embyonic lethality LOF CHUK, severe encasement malformation [50] CHUK deletions and somatic [79,80] suggesting that type I IFN-mediated pathways regulate mTEC development. Stat1 À/À mice are sensitive to infection by microbial pathogens and viruses.…”

“…[57,[95][96][97] Individuals with two or more ectodermal structural abnormalities -such as in the hair, teeth, nails, sweat glands, salivary glands, cranial-facial structure, digits, and other parts of the body -can be diagnosed as having this disease. The signs and symptoms of ectodermal dysplasia are evident soon after birth.…”

“…These mutations include X420W, R175P, L227P, A288G, D311N, C417F, and C417R, which result in truncated NEMO proteins and repress NF-kB activation. [58,97] Immune cells express reduced IFNγ, IL-1β, IL-18, and TNFα in response to treatment with LPS, accounting for severe infectious diseases. These mutations do not affect IKKα and IKKβ levels.…”