Human nuclear factor kappa B essential modulator mutation can result in immunodeficiency without ectodermal dysplasia.
BACKGROUND
Many receptors rely on the appropriate activation of nuclear factor (NF) kappa B to induce cellular function. This process depends critically on the phosphorylation of the inhibitor of NF-kappa B (I kappa B) by the I kappa B kinase. This targets I kappa B for ubiquitination and degradation, allowing NF-kappa B to translocate to the nucleus, where it can direct transcription. Hypomorphic human mutations affecting one I kappa B kinase component, the NF-kappa B essential modulator (NEMO), result in impaired signaling from receptors required for ectodermal development and immune function. Male subjects with these mutant NEMO molecules have an X-linked syndrome known as ectodermal dysplasia with immunodeficiency, which is characterized by severe infections, with herpesviruses, bacteria, and mycobacterial susceptibility.


OBJECTIVE
We sought to genetically and biochemically characterize a patient with a mutant NEMO molecule without ectodermal abnormalities.


METHODS
We evaluated NEMO in a patient who had immunodeficiency and atypical mycobacterial infection but normal ectoderm.


RESULTS
We identified a novel NEMO mutant causing immunodeficiency without ectodermal dysplasia. The mutation, which altered the exon 9 splice site, was present in cells of ectodermal and hematopoetic origin and resulted in a heterogeneous mixture of mutant and wild-type cDNA species. Immunologic function was variably impaired, with reduced CD40-induced B-cell proliferation, partially reduced NF-kappa B p65 nuclear translocation, and variable Toll-like receptor-induced TNF production. This variability might be explained by an inconsistent ratio of mutant to wild-type NEMO. The lack of any ectodermal phenotype, however, suggested a separation in the hematopoetic and ectodermal function of NEMO that leads to NF-kappa B activation.


CONCLUSIONS
Mutation of the gene encoding NEMO can result in immunodeficiency without ectodermal dysplasia.
Orange
Jordan S
JS
Division of Immunology, Children's Hospital of Philadelphia, Pa., USA.
Levy
Ofer
O
Brodeur
Scott R
SR
Krzewski
Konrad
K
Roy
Rene M
RM
Niemela
Julie E
JE
Fleisher
Thomas A
TA
Bonilla
Francisco A
FA
Geha
Raif S
RS
D000293:Adolescent; D002352:Carrier Proteins; D004476:Ectodermal Dysplasia / Q000235:genetics / Q000276:immunology*; D040181:Genetic Diseases, X-Linked / Q000235:genetics / Q000276:immunology; D006801:Humans; D051550:I-kappa B Kinase; D007113:Immunity, Innate; D007153:Immunologic Deficiency Syndromes / Q000235:genetics* / Q000276:immunology; D008297:Male; D009154:Mutation; D011506:Proteins / Q000235:genetics* / Q000378:metabolism
D002352:Carrier Proteins; C491731:IKBKG protein, human; D011506:Proteins; D051550:I-kappa B Kinase