The range of defects associated with nuclear factor kappaB essential modulator.
OBJECTIVE
Impaired ability to signal and activate specific gene transcription through nuclear factor kappaB (NFkappaB) has been directly linked to immunodeficiency. Hypomorphic mutations in the gene encoding NFkappaB essential modulator (NEMO), located on the X chromosome, impair NFkappaB function and lead to ectodermal dysplasia with immunodeficiency (ED-ID) with increased susceptibility to pyogenic bacteria, viruses and nonpathogenic mycobacterial infections. This is due to impaired, but not abolished, response to a variety of stimuli including Toll-like receptor agonists. Alternatively, loss-of-function (amorphic) mutations in the same gene lead to incontinentia pigmenti. The purpose of this review is to explore the range of immunologic defects associated with mutations in NEMO, a key regulatory molecule in the NFkappaB pathway.


RESULTS
In addition to the discovery of X-linked recessive hypomorphic mutations in NEMO as the cause of anhidrotic ED-ID, autosomal-dominant hypermorphic mutations in inhibitor of NFkappaB (IkappaB) alpha have been described recently. In addition, a better understanding of genotype-phenotype correlation in ED-ID patients is evolving.


CONCLUSIONS
ED-ID is a combined, variable but profound immunodeficiency characterized by susceptibility to pyogenic bacteria and mycobacterial infection. Understanding the features of particular NEMO mutations will provide insight into the role of this gene and will help define the crucial role of the function and regulation of NFkappaB in the immune response.
Uzel
Gulbu
G
Laboratory of Clinical Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland 20892-1684, USA. guzel@mail.nih.gov
D000818:Animals; D001424:Bacterial Infections / Q000209:etiology; D004476:Ectodermal Dysplasia / Q000150:complications / Q000235:genetics*; D005260:Female; D006801:Humans; D051550:I-kappa B Kinase / Q000235:genetics*; D020672:I-kappa B Proteins / Q000235:genetics; D007153:Immunologic Deficiency Syndromes / Q000150:complications / Q000235:genetics*; D008297:Male; D009154:Mutation; D009164:Mycobacterium Infections / Q000209:etiology; D016328:NF-kappa B / Q000276:immunology
D020672:I-kappa B Proteins; C491731:IKBKG protein, human; D016328:NF-kappa B; D051550:I-kappa B Kinase