IKBKG – Ectodermal Dysplasia with Immunodeficiency

NEMO, encoded by IKBKG, is the regulatory subunit of the IκB kinase complex required for canonical NF-κB activation. Hypomorphic and loss-of-function variants in IKBKG underlie X-linked anhidrotic ectodermal dysplasia with immunodeficiency (EDA-ID), manifesting as combined immunodeficiency with ectodermal defects.

Genetic evidence includes at least 72 unrelated male probands with pathogenic IKBKG variants (PMID:18851874). A systematic review identified 564 individuals with IKBKG mutations, of whom 15.8% presented with EDA-ID, confirming consistent X-linked segregation and high genetic penetrance (PMID:40612668).

The variant spectrum comprises nonsense, missense, frameshift, splice-site, and indel mutations clustering in the coiled-coil and zinc-finger domains. A recurrent hypomorphic allele, c.916G>A (p.Asp306Asn), impairs NEMO ubiquitylation upon CD40 stimulation and segregates in multiple affected kindreds (PMID:26117626).

Functional assays demonstrate that hypomorphic and null IKBKG alleles reduce IκBα phosphorylation and degradation, impair NF-κB nuclear translocation, and compromise CD40- and LPS-induced signaling in patient cells. Reconstitution in NEMO-deficient lines confirms diminished IKK activation and defective NF-κB–dependent cytokine production (PMID:12045264; PMID:16379012).

Clinically, affected males exhibit ectodermal dysplasia features (hypohidrosis, dental anomalies [HP:0000968]) and immunodeficiency with recurrent bacterial and mycobacterial infections (bronchiectasis, osteomyelitis [HP:0002721]). Female carriers may manifest skewed X-inactivation phenotypes but typically present with incontinentia pigmenti.

Overall, the IKBKG–EDA-ID association is definitive: multiple unrelated cases, X-linked recessive segregation, and concordant functional studies firmly establish causality. Inclusion of IKBKG in diagnostic immunodeficiency and ectodermal dysplasia panels is essential. Key Take-home: Pathogenic IKBKG variants cause X-linked EDA-ID via impaired NF-κB signaling, guiding molecular diagnosis and management.

References

• The Journal of clinical investigation • 2002 • Deficient natural killer cell cytotoxicity in patients with IKK-gamma/NEMO mutations. PMID:12045264
• The Journal of allergy and clinical immunology • 2008 • Hypomorphic nuclear factor-kappaB essential modulator mutation database and reconstitution system identifies phenotypic and immunologic diversity. PMID:18851874
• The Journal of biological chemistry • 2006 • A point mutation in NEMO associated with anhidrotic ectodermal dysplasia with immunodeficiency pathology results in destabilization of the oligomer and reduces lipopolysaccharide- and tumor necrosis factor-mediated NF-kappa B activation. PMID:16379012
• Genes & diseases • 2025 • Clinical relevance of loss-of-function mutations of NEMO/IKBKG. PMID:40612668
• Clinical immunology (Orlando, Fla.) • 2015 • Novel hypomorphic mutation in IKBKG impairs NEMO-ubiquitylation causing ectodermal dysplasia, immunodeficiency, incontinentia pigmenti, and immune thrombocytopenic purpura. PMID:26117626

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