A Novel X-Linked Disorder of Immune Deficiency and Hypohidrotic Ectodermal Dysplasia Is Allelic to Incontinentia Pigmenti and Due to Mutations in IKK-gamma (NEMO)

Abstract

Hypohidrotic ectodermal dysplasia (HED), a congenital disorder of teeth, hair, and eccrine sweat glands, is usually inherited as an X-linked recessive trait, although rarer autosomal dominant and recessive forms exist. We have studied males from four families with HED and immunodeficiency (HED-ID), in which the disorder segregates as an X-linked recessive trait. Affected males manifest dysgammaglobulinemia and, despite therapy, have significant morbidity and mortality from recurrent infections. Recently, mutations in IKK-gamma (NEMO) have been shown to cause familial incontinentia pigmenti (IP). Unlike HED-ID, IP affects females and, with few exceptions, causes male prenatal lethality. IKK-gamma is required for the activation of the transcription factor known as "nuclear factor kappa B" and plays an important role in T and B cell function. We hypothesize that "milder" mutations at this locus may cause HED-ID. In all four families, sequence analysis reveals exon 10 mutations affecting the carboxy-terminal end of the IKK-gamma protein, a domain believed to connect the IKK signalsome complex to upstream activators. The findings define a new X-linked recessive immunodeficiency syndrome, distinct from other types of HED and immunodeficiency syndromes. The data provide further evidence that the development of ectodermal appendages is mediated through a tumor necrosis factor/tumor necrosis factor receptor-like signaling pathway, with the IKK signalsome complex playing a significant role.

Mutations in the NF-κB signaling pathway: implications for human disease

“…Mutations generating IP (red), EDA-ID) (blue) and immunodeficiencies without EDA (green) (Smahi et al, 2000;Zonana et al, 2000;Aradhya et al, 2001a;Aradhya et al, 2001b;Do¨ffinger et al, 2001;Jain et al, 2001;Fusco et al, 2004;Orange et al, 2004;FilipeSantos et al, 2006;Puel et al, 2006) (Zonana et al, 2000;Do¨ffinger et al, 2001;Jain et al, 2001;Aradhya et al, 2001a In contrast, the association of NEMO mutations with the EDA-ID defect in skin adnexes development is more puzzling. Because morphogenesis of all the affected appendages, such as hair, sweat glands and teeth, is dependent upon a specific interaction between the TNF-like ligand ectodysplasin A and its receptor EDAR (Mikkola and Thesleff, 2003), the analysis of EDA-ID pathology has revealed an unexpected link between ectodysplasin signaling and NF-kB activation, involving NEMO.…”

IKBKG (nuclear factor-κB essential modulator) mutation can be associated with opportunistic infection without impairing Toll-like receptor function

“…1 Complete deficiency of NEMO activity is incompatible with male survival, because at least some NEMO function is required for fetal development. Women who possess 1 completely nonfunctional copy of NEMO have incontinentia pigmenti characterized by dermal scarring and abnormal pigmentation.…”

NF-κB-related genetic diseases

“…Most of them indeed carry mutations in NEMO but instead of leading to large truncations of the NEMO molecule as observed in IP, the mutations are mostly missense mutations or small deletions only affecting the ZF (Table 1). [30][31][32][33][34] Their molecular characterization is likely to provide valuable insights into NEMO function but for only few of them some specific defect has been identified.…”